On May 19, 2021 Sanofi reported that Phase 1 data from the AMEERA-1 study evaluating amcenestrant, an investigational oral selective estrogen receptor degrader (SERD), will be presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Sanofi, MAY 19, 2021, View Source [SID1234580270]). In a pooled analysis, amcenestrant in combination with palbociclib showed encouraging antitumor activity in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC).

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"These early clinical data show that the combination of amcenestrant with palbociclib achieved encouraging antitumor activity," said Sarat Chandarlapaty, M.D., Ph.D., Medical Oncologist, Memorial Sloan Kettering Cancer Center. "The analysis also demonstrated no clinically significant cardiac or ocular findings and an overall safety profile in line with what we saw in the monotherapy setting. It’s notable to see this kind of activity in patients with ER+ metastatic breast cancer, where there is a clear need for new therapeutic options."

In this preliminary analysis from the open-label AMEERA-1 study, amcenestrant was evaluated in dose escalation cohorts (Part C) at 200mg (n=9) and 400mg (n=6) daily and in a dose expansion cohort (Part D; n=30) at 200mg daily, all in combination with a standard dose of palbociclib. Eligible patients included post-menopausal women with ER+/HER2- MBC who were pre-treated with endocrine therapy in the advanced setting for at least six months or had resistance to adjuvant endocrine therapy.

In the pooled population exposed with amcenestrant at 200mg daily evaluable for response (n=35), the objective response rate (ORR) was 34% (90% CI: 21.1-49.6), with confirmed partial responses (PR) in 12/35 patients, and the clinical benefit rate (CBR) was 74% (90% CI: 59.4-85.9), with clinical benefit in 26/35 patients at 24 weeks. Amcenestrant 200mg daily in combination with palbociclib demonstrated a favorable overall safety profile (n=39), with treatment related adverse events (TRAEs) attributable to amcenestrant similar to those observed with monotherapy. For all grade events, amcenestrant TRAEs occurred in 72% and to palbociclib in 90% of patients, and for grade ≥3 in 15% and 46% of patients, respectively. The most frequent non-hematological amcenestrant TRAEs included fatigue (18%) and nausea (18%), all grade ≤2. No clinically significant cardiac or ocular safety findings occurred.

"The Phase 3 AMEERA-5 study was built upon promising preclinical and clinical data, including the data presented here at ASCO (Free ASCO Whitepaper), and expands our knowledge of amcenestrant as a potential best-in-class oral endocrine backbone therapy for ER+/HER2- breast cancer," said John Reed, M.D., Ph.D., Global Head of Research and Development at Sanofi. "A significant need exists for more treatment options for ER+ breast cancer, the most common type of breast cancer, accounting for approximately 75% of all breast cancers diagnosed today."

Amcenestrant is an oral SERD that antagonizes and degrades the estrogen receptor (ER) resulting in inhibition of the ER signaling pathway. Amcenestrant is currently under clinical investigation and its safety and efficacy have not been evaluated by any regulatory authority.

Amcenestrant clinical development program

The comprehensive development program for amcenestrant has been designed to evaluate its role: (1) as a single agent in second-line or later lines of treatment of ER+/HER2- MBC, (2) in combination with palbociclib in the first-line treatment of ER+/HER2- MBC, and (3) to explore its potential in early-stage breast cancer patients in the adjuvant setting. Late last year, the Phase 3 AMEERA-5 clinical trial investigating amcenestrant in combination with palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, as a first-line therapy for patients with ER+ MBC, was initiated.

A pivotal study (AMEERA-3) of amcenestrant versus physician’s choice in locally advanced or metastatic ER+ breast cancer is fully recruited. The pivotal readout is now expected in H2 2021. Of note, the trial recently passed a Data Safety Monitoring Committee (DSMC) futility analysis.

About ER+ metastatic breast cancer

MBC is breast cancer that has spread outside the mammary gland to another part of the body, such as the liver, brain, bones or lungs. It is also known as Stage IV and is the most advanced stage of breast cancer.1 About two of every three cases of breast cancer are HR+, meaning the cancer is fueled by the hormones estrogen or progesterone.2 HR+ breast cancers can be classified as ER+ and/or progesterone receptor-positive (PR+).2 ER+ breast cancer accounts for approximately 75% of all breast cancers3 and is the most common type of breast cancer diagnosed today.4 The five-year relative survival for distant (cancer that has metastasized) female breast cancer is 28.1%.5 Endocrine therapies were among the first treatments to be administered for HR+ MBC and are considered standard of care in the first-line setting. However, new options are needed as resistance often emerges, limiting the effectiveness of these treatments for patients with metastatic disease over time.6

About the AMEERA-1 clinical trial

AMEERA-1 is an open-label, Phase 1/2, first-in-human study designed to evaluate amcenestrant as a monotherapy and in combination with targeted therapies in postmenopausal women with ER+/HER2- MBC. Parts A (dose escalation) and B (dose expansion) were designed to determine the maximum tolerated dose of amcenestrant administered as monotherapy, while Parts C and D are evaluating dose escalation and expansion for amcenestrant in combination with palbociclib to determine the recommended Phase 2 dose for the combination and to characterize its safety profile. Primary efficacy objectives include antitumor activity by ORR and CBR per RECIST v1.1 criteria, as well as characterizing the overall safety profile of amcenestrant as a monotherapy and in combination with palbociclib. Eligible patients included women with histological diagnosis of breast adenocarcinoma with locally advanced or metastatic ER+/HER2- disease and at least six months of prior exposure to endocrine therapy, including patients with early relapse while on adjuvant endocrine therapy that was initiated more than 24 months ago, or who relapsed less than 12 months after completion of adjuvant endocrine therapy.7

Dr. Chandarlapaty has provided consulting services to Sanofi.

On May 19, 2021 MEI Pharma, Inc. (NASDAQ: MEIP), a late-stage pharmaceutical company focused on advancing new therapies for cancer, and Kyowa Kirin Co., Ltd. (Kyowa Kirin, TSE: 4151), a global specialty pharmaceutical company that utilizes the latest biotechnology to discover and deliver novel medicines, reported new data for zandelisib, an investigational phosphatidylinositol 3-kinase delta ("PI3Kδ") inhibitor in clinical development for the treatment of B-cell malignancies (Press release, MEI Pharma, MAY 19, 2021, View Source [SID1234580269]). The research and the design of a Phase 3 study will be presented in three posters at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2021 being held virtually June 4-8, 2021.

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"We are encouraged by the zandelisib data being shared at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting, specifically the data that showed zandelisib activity across differing patient groups, including POD24 – a group that typically has a poor prognosis and would generally be expected to meet the inclusion criteria of our Phase 3 COASTAL study. Additionally, the data reporting on the combination of zandelisib and zanubrutinib, demonstrated the potential to induce robust and durable responses against various B-cell malignancies with a combination that is generally well-tolerated," said Richard Ghalie, M.D., chief medical officer at MEI Pharma. "With topline data from the Phase 2 TIDAL study on track to be reported by the end of this year, we remain committed, in collaboration with our global partner Kyowa Kirin, to the zandelisib development program and its potential to deliver a best-in-class treatment option to patients with B-cell malignancies as a monotherapy or in combination with other therapies."

The presentations will present updated data from a Phase 1b study of zandelisib + – rituximab that show the compound continues to be generally well tolerated with an 82% overall response rate in patients with relapsed or refractory (r/r) follicular lymphoma (FL) who had progression of disease within 24 months of first line chemoimmunotherapy (POD24). An overall response rate of 93% was observed in patients with r/r FL and were non-POD24. POD24 status is a robust predictor of reduced overall survival in FL patients. The response rate in all 37 r/r FL patients was 87%.

Additionally, the presentations will include new data from the Phase 1b trial exploring zandelisib in combination with zanubrutinib (marketed as BRUKINSA), an inhibitor of Bruton’s tyrosine kinase ("BTK") developed by BeiGene, Ltd. ("BeiGene"), in patients with (r r) B-cell malignancies. In this study, the combination of zandelisib and zanubrutinib was generally well tolerated in the 20 patients enrolled in the safety evaluation cohort. The combination administered on an optimized dosing regimen did not result in additive toxicity to each agent alone. Further, 100% of patients (n=16) with r/r indolent B-cell malignancies and chronic lymphocytic leukemia (CLL) achieved an objective response.

The trial design for the Phase 3 COASTAL study evaluating zandelisib in combination with rituximab in patients with r r indolent non-Hodgkin’s lymphoma (iNHL), will also be highlighted in a poster presentation. The COASTAL study is intended to act as the required confirmatory study for the potential U.S. accelerated approval of zandelisib in patients with r/r FL or marginal zone lymphoma (MZL) who have received one or more prior lines of treatment and is also intended to support FDA approval for additional indications and regulatory marketing applications globally.

"Data from the early Phase 1 trials indicate that zandelisib displays high selectivity for the phosphatidylinositol 3-kinase delta (PI3K) isoform as well as durability, with PI3K playing a key role in the proliferation and survival of hematologic cancers," said Yoshifumi Torii, Ph.D., Executive Officer, Vice President, Head of R&D Division of Kyowa Kirin. "Zandelisib has distinct pharmaceutical properties and we look forward to continuing the development of the compound, in partnership with MEI Pharma, with the hope that more data will add to the understanding of zandelisib and potentially yield another option for patients with B-cell malignancies."

Details on the three posters are included below.

Updated Clinical Data from the Phase 1b Study Evaluating Zandelisib in Patients with Relapsed or Refractory Follicular Lymphoma

Poster title: Efficacy and Safety of the PI3Kδ Inhibitor Zandelisib (ME-401) on an Intermittent Schedule (IS) in Patients with Relapsed Refractory Follicular Lymphoma (FL) with Progression of Disease within 24 Months of First-Line Chemoimmunotherapy (POD24)
Available for on-demand viewing online: Beginning on June 4, 2021 at 6:00 a.m. PT here
Poster will also be available for download via the MEI Pharma website
John Pagel, M.D., Ph.D., lead author on the poster, study investigator, and Chief of Hematologic Malignancies, Swedish Cancer Center, commented: "The group of relapsed or refractory follicular lymphoma patients that experience progression of disease within 24 months of first line chemoimmunotherapy have a poorer long-term prognosis compared to the patients with follicular lymphoma who relapse later than 24 months and represent an area of high need for new treatment options. The positive results reported today indicate the potential for zandelisib to provide a new treatment option for high-risk patients with relapsed or refractory follicular lymphoma."

Study Details:
The ongoing Phase 1b clinical study is a multi-arm, open-label, dose optimization trial evaluating zandelisib as a monotherapy and in combination with other therapies in patients with r r B-cell malignancies. The data reported today is for patients receiving zandelisib administered on the intermittent schedule: once daily at 60 mg for two 28-day cycles and then on an intermittent schedule of once daily dosing for the first 7 days of each subsequent 28-day cycle (i.e. the intermittent schedule or IS). A total of 37 r/r FL patients have been treated with zandelisib on the intermittent schedule, as a monotherapy or in combination with rituximab. Of the 37 r/r FL patients, 22 were POD24. POD24 is a robust predictor in FL of reduced overall survival.

The overall response rate in 37 patients with r r FL was 87% with 27% achieving a complete response. The overall response rate in POD24 patients was 82% and 93% in non-POD24 patients. The complete response rate in POD24 patients was 18% and 40% in non-POD24 patients.

Overall Response Rate

All

(N = 37)

POD24

(n = 22)

Non-POD24

(n = 15)

ORR, n (%)*

32 (87)

18 (82)

14 (93)

Monotherapy, n N (%)

Combination with rituximab, n N (%)

14 18 (78)

18 19 (95)

8 11 (73)

10 11 (91)

6 7 (86)

8 8 (100)

Prior lines of therapy, n N (%)

1 line of prior therapy

≥ 2 lines of prior therapy

14 16 (88)

18 21 (86)

5 7 (71)

13 15 (87)

9 9 (100)

5 6 (83)

CR rate, n (%)

10 (27)

4 (18)

6 (40)

* Imaging scans were obtained after 2 and 6 cycles, and then every 6 cycles. Response was reported based on Lugano criteria.

Duration of Response
Median duration of response in POD24 and non-POD24 patients has not yet been reached. Median duration follow-up is 15.8 months (range: 5.6-33.1) in POD24 patients and 17 months (range: 1.2-28.6) in non-POD24.

Follow-up = Time from first response to treatment discontinuation date or data cutoff of 10DEC2020 for ongoing patients

Follow-up = Time from first response to treatment discontinuation date or data cutoff of 10DEC2020 for ongoing patients

Progression Free Survival
Progression free survival in POD24 patients is 12.5 months and in the non-POD24 group the median is not yet reached. Median follow-up time in the POD24 and non-POD24 groups is 19.4 (range 1.8-36.5) and 18.2 (range: 3.0-30.4) months, respectively.

Follow-up = Time from first day on study to treatment discontinuation or data cutoff of 10DEC2020

Follow-up = Time from first day on study to treatment discontinuation or data cutoff of 10DEC2020

Adverse Events
Zandelisib was generally well-tolerated. No difference in adverse events was observed between POD24 and non-POD24 groups. The discontinuation rate due to any treatment emergent adverse event was 8% (n=3), and the incidence of Grade ≥ 3 TEAE was as follows:

Grade ≥3 Adverse Events in ≥2 Patients

N = 37

N (%)

Neutropenia

6 (16)

ALT AST increased

3 (8)

Rash

3 (8)

Diarrhea

2 (5)

Colitis

2 (5)

Hypokalemia

2 (5)

Hyponatremia

2 (5)

Coronavirus infection

2 (5)

Phase 1b Study Evaluating Zandelisib in Combination with Zanubrutinib in Patients with B-cell Malignancies

Poster title: Initial Results of the Combination of PI3Kδ Inhibitor Zandelisib (ME-401) and the BTK Inhibitor Zanubrutinib in Patients (pts) with r r B-cell Malignancies
Available for on-demand viewing online: Beginning on June 4, 2021 at 6:00 a.m. PT here.
Poster will also be available for download via the MEI Pharma website
Jacob Soumerai, M.D., lead author on the poster, study investigator and Assistant Professor at Harvard Medical School and Massachusetts General Hospital Cancer Center, commented: "The data reported today for zandelisib in combination with zanubrutinib are encouraging, both in terms of preliminary safety and efficacy, and support the expansion of the evaluation of this orally administered combination in various B-cell malignancies."

Study Details
The ongoing Phase 1b clinical study is a multi-arm, open-label, dose optimization trial evaluating zandelisib as a monotherapy and in combination with other therapies in patients with r r B-cell malignancies. The data reported today is for 20 patients receiving zandelisib in combination with zanubrutinib. Two treatment dosing regimens were explored: Group A received zandelisib 60 mg, oral, daily continuously for 8 weeks followed by days 1-7 of each subsequent 28-day cycle, and zanubrutinib (marketed as BRUKINSA by BeiGene, Ltd.), 160 mg oral, twice daily; Group B received zandelisib 60 mg, oral, daily on days 1-7 of each 28-day cycle starting Cycle 1 and zanubrutinib 80 mg, oral, twice daily. Group A enrolled a total of 7 patients: 1 FL, 3 CLL, 1 MZL, 1 mantle cell lymphoma (MCL), and 1 diffuse large B-cell lymphoma/high grade B-cell lymphoma (DLBCL/HGBCL). Group B enrolled a total of 13 patients: 7 FL, 2 CLL, 1 MZL, and 3 DLBCL HGBCL. Treatment was continued until disease progression, intolerance or withdrawal of consent.

Overall Response Rates
The overall response rate in all evaluable patients with r r indolent B-cell malignancies and CLL was 100%. No response was noted in the 2 patients with DLBCL/HGBCL. Responses were durable with median follow up of 6.6 months (0.6-21.3) with the majority of responders still on treatment.

Evaluable

n = 18

FL
(n = 8)

CLL SLL
(n = 5)

MZL
(n = 2)

MCL
(n = 1)

DLBCL HGBCL
(n = 2)

ORR*, n (%)

8 (100)

5 (100)

2 (100)

1 (100)

0

Group A

1 (100)

3 (100)

1 (100)

1 (100)

0

Group B

7 (100)

2 (100)

1 (100)

0

0

*CR CRi in 2/8 FL (25%) and 2/5 CLL (40%). Imaging scans at month 3, 7, 13, and then every 6 months until progression. Response reported based on Lugano criteria and iwCLL. 2/20 patients (1 DLBCL, 1 HGBCL) did not have on-therapy scans: 1 had clinical PD and 1 had AE due to prior therapy and discontinued early. Median follow-up time was 6.6 months for all patients (range 0.6-21.3), 3.6 months for Group A (range 0.6-21.3), and 6.6 months for Group B (range 1.9-14.1).

Treatment Emergent Adverse Events
The combination of zandelisib 60 mg oral, daily on days 1-7 of each 28-day cycle starting Cycle 1 and zanubrutinib 80 mg, oral, twice daily was well tolerated across the various B-cell malignancies in the completed part of the study. The combination administered on the optimized, Group B, dosing regimen did not result in additive toxicity to each agent alone. One of the two patients with Grade 3 AST ALT increases in Group B was successfully retreated and continued therapy.

Group A

(n = 7)

Group B

(n = 13)

Adverse Event, n (%)

All Grades

Grade ≥ 3

All Grades

Grade ≥ 3

Neutropenia

4 (57)

*3 (43)

6 (46)

3 (23)

ALT increased

2 (29)

2 (29)

2 (15)

**2 (15)

AST increased

2 (29)

2 (29)

3 (23)

**2 (15)

Anemia

1 (14)

*1 (14)

2 (15)

1 (8)

Hyperkalemia

2 (29)

0

2 (15)

1 (8)

Thrombocytopenia

4 (57)

*2 (29)

3 (23)

1 (8)

Pleural Effusion

2 (29)

*1 (14)

0

0

Rash

1 (14)

1 (14)

2 (15)

0

Appendicitis

0

0

1 (8)

1 (8)

Ascites

1 (14)

*1 (14)

0

0

CMV colitis

1 (14)

1 (14)

0

0

Fatigue

4 (57)

1 (14)

2 (15)

0

Pneumonia

2 (29)

*1 (14)

0

0

Tumor lysis syndrome

0

0

1 (8)

1 (8)

Diarrhea

3 (43)

0

3 (23)

0

Atrial fibrillation

1 (14)

0

0

0

* Group A: 1 DLBCL patient experienced Grade 3 AE on Day 0 attributed to prior therapy and discontinued treatment on Day 17, then progressed on Day 23 and died with Grade 4 thrombocytopenia and pleural effusion, Grade 3 pneumonia, anemia, and ascites. ** Group B: DLT.

This Phase 1b study is continuing to enroll expansion cohorts in r r FL and MCL to further evaluate the combination of zandelisib 60 mg administered on days 1-7 starting Cycle 1 and zanubrutinib administered at 80 mg bid.

COASTAL Phase 3 Study Design

Poster title: Coastal: A phase 3 study of the PI3Kδ inhibitor zandelisib with rituximab (R) versus immunochemotherapy in patients with relapsed indolent non-Hodgkin’s lymphoma (iNHL)
Available for on-demand viewing online: Beginning on June 4, 2021 at 6:00 a.m. PT here.
Poster will also be available for download via the MEI Pharma website
The global, randomized, two-arm Phase 3 study will compare zandelisib plus rituximab to standard of care chemotherapy plus rituximab, is expected to enroll 534 patients, and the primary efficacy endpoint is progression-free survival. Zandelisib will be administered once daily for two 28-day cycles followed by an intermittent schedule of once daily dosing for one week of each subsequent 28-day cycle.

"As a potent, highly selective inhibitor of the PI3Kδ isoform, zandelisib has a differentiated therapeutic profile that makes it an ideal candidate to evaluate in different B-cell malignancies, both as a monotherapy and combined with other agents" said Professor Wojciech Jurczak, M.D., Ph.D., COASTAL principal investigator, Department of Clinical Oncology, Maria Sklodowska-Curie National Research Institute of Oncology in Kraków, Poland. "The initiation of the COASTAL study will be an important milestone as we evaluate zandelisib’s potential as a best-in-class PI3Kδ therapy, optimized by a unique dosing schedule."

Clinical study of zandelisib as a monotherapy or in combination with other agents support its clinical development for B-cell malignancies. In clinical studies, zandelisib administered as a 2-month induction followed by intermittent schedule maintenance dosing achieved an 83-89% response rate, with median duration of response not reached in r r follicular and marginal zone lymphomas when given as a monotherapy or in combination with rituximab. Durable responses have been reached in patients treated with zandelisib as either a monotherapy or in combination, regardless of prior therapies or tumor bulk. Utilizing an optimized dosing schedule of zandelisib, there has been less than 10% of Grade 3 or higher immune-mediated adverse events of special interest associated with PI3Kδ inhibitors in patients with B-cell malignancies. Zandelisib is currently in the Phase 2 TIDAL study as a monotherapy for patients with r/r follicular or marginal zone lymphoma. The COASTAL study enrollment is expected to be initiated around mid-2021.

About Zandelisib
Zandelisib (formerly called ME-401), a selective PI3Kδ inhibitor, is an investigational cancer treatment being developed as an oral, once-daily, treatment for patients with B-cell malignancies. In March 2020 the U.S. FDA granted zandelisib Fast Track designation for treatment of adult patients with relapsed or refractory follicular lymphoma who have received at least 2 prior systemic therapies.

In April 2020, MEI and Kyowa Kirin Co., Ltd. (Kyowa Kirin) entered a global license, development, and commercialization agreement to further develop and commercialize zandelisib. MEI and Kyowa Kirin are co-developing and co-promoting zandelisib in the U.S., with MEI booking all revenue from the U.S. sales. Kyowa Kirin has exclusive commercialization rights outside of the U.S.

Ongoing clinical studies of zandelisib include TIDAL (Trials of PI3K DeltA in Non-Hodgkin’s Lymphoma), a global Phase 2 study evaluating zandelisib as a monotherapy across two study arms: the first study arm for the treatment of adults with relapsed and refractory follicular lymphoma and the second study arm for marginal zone lymphomas, in both cases after failure of at least two prior systemic therapies including chemotherapy and an anti-CD20 antibody. The primary endpoint of the study is the objective response rate. Subject to the results and discussions with FDA, data from each study arm are intended to be submitted to FDA to support separate accelerated approval marketing applications under 21 CFR Part 314.500, Subpart H.

Also ongoing is a Phase 2 pivotal study in Japan in patients with indolent B-cell non-Hodgkin’s lymphoma (iNHL) without small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), and Waldenström’s macroglobulinemia (WM) conducted by Kyowa Kirin.

About PI3K Delta
Phosphatidylinositol 3-kinase delta ("PI3Kδ") is often overexpressed in cancer cells and plays a key role in the proliferation and survival of hematologic cancers. Zandelisib displays high selectivity for the PI3K delta isoform and has distinct pharmaceutical properties from other PI3K delta inhibitors.

About Follicular Lymphoma
Follicular lymphoma (FL) is the most common indolent lymphoma, comprising about 20-30% of all non-Hodgkin lymphomas (NHL). The disease also forms on B cells, is chronic in most cases and tends to progress slowly. Most people diagnosed with FL are over 65 years of age. Sometimes follicular lymphomas can change into diffuse large B-cell lymphoma, a fast-growing (aggressive) type of NHL.

On May 19, 2021 Sierra Oncology, Inc. (SRRA), a late-stage biopharmaceutical company on a quest to deliver targeted therapies that treat rare forms of cancer, reported three abstracts have been accepted into the program for the 2021 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) being held virtually from June 4-8, 2021 (Press release, Sierra Oncology, MAY 19, 2021, View Source [SID1234580268]).

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Association of Transfusion Independence with Improved Overall Survival in Myelofibrosis Patients Receiving Momelotinib

Dr. Ruben Mesa, MD, Director of the Mays Cancer Center, UT Health San Antonio, MD Anderson Cancer Center, will present a poster examining the association between transfusion independence and overall survival for momelotinib patients from SIMPLIFY-1 (JAKi-naïve) and SIMPLIFY-2 (JAKi-exposed).

Previously published data from both SIMPLIFY studies demonstrate robust overall survival for momelotinib-treated patients compared to survival in patients randomized to ruxolitinib (SIMPLIFY-1) or best available therapy (SIMPLIFY-2), followed by momelotinib after week 24 in each (median not yet reached in SIMPLIFY-1 and 34.3 months in SIMPLIFY-2). Additionally, previously reported week 24 transfusion independence rates were higher in the momelotinib arms of SIMPLIFY-1 (67% vs. 49%) and SIMPLIFY-2 (43% vs. 21%). The new analyses suggest JAKi-naïve patients receiving momelotinib who maintain or achieve transfusion independence at week 24 have favorable overall survival compared to non-responders, with a similar trend observed in SIMPLIFY-2.

The full abstract is now available on the ASCO (Free ASCO Whitepaper) website. Data from this analysis will also be included in an oral presentation at the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Meeting being held virtually June 9-17, 2021.

Presentation Details

Abstract: 7046
Title: Association of transfusion independence with improved overall survival in myelofibrosis patients receiving momelotinib
Presenter: Ruben Mesa, MD
Poster Session Name: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes and Allotransplant
Virtual Presentation Available: Friday, June 4, 2021 beginning at 8:00 am CDT

Two additional momelotinib abstracts were accepted for online publication at ASCO (Free ASCO Whitepaper). The first highlights the improved transfusion independence of momelotinib irrespective of baseline degree of anemia, platelet count or transfusion status. The second examines the improvement in longitudinal and individual symptoms for myelofibrosis patients treated with momelotinib in the SIMPLIFY-1 study.

Improved Transfusion Independence Rates for Momelotinib vs. Ruxolitinib in Anemic JAKi Naïve Myelofibrosis Patients Independent of Baseline Platelet or Transfusion Status

Progressive anemia is a common occurrence in myelofibrosis, with nearly all patients requiring transfusions as their disease advances. As described above, the analyses in Abstract 7046 show that JAKi-naïve patients receiving momelotinib who maintain or achieve transfusion independence at week 24 have favorable overall survival compared to non-responders, with a similar trend observed in SIMPLIFY-2. Therefore, it is important to understand which patients are most likely to achieve transfusion independence at week 24.

Abstract e19039 will highlight new analyses from SIMPLIFY-1 to demonstrate that the prognostically important week 24 transfusion independence rates in JAK inhibitor-naïve myelofibrosis patients were consistently higher in anemic patients receiving momelotinib compared to ruxolitinib, regardless of the platelet count, transfusion status or degree of anemia at baseline. Data to be featured further support the potential benefits of inhibiting ACVR1 / ALK2 in addition to JAK1 and JAK2 in myelofibrosis patients, as published by Jean-Jacques Kiladjian, MD, PhD, Professor of Clinical Pharmacology, Paris Diderot University; Consultant Hematologist, Head, Clinical Investigation Center, Saint Louis Hospital, Paris, France.

The full abstract is now available on the ASCO (Free ASCO Whitepaper) website. Data from this analysis will also be included in a poster presentation at the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Meeting being held virtually June 9-17, 2021.

Presentation Details

Abstract: e19039
Title: Improved Transfusion Independence Rates for Momelotinib vs. Ruxolitinib in Anemic JAKi Naïve Myelofibrosis Patients Independent of Baseline Platelet or Transfusion Status
Presenter: Jean-Jacques Kiladjian, MD, PhD

Longitudinal and Individual Symptom Analyses of Momelotinib and Ruxolitinib Treated Myelofibrosis Patients from SIMPLIFY-1

Previously reported results from the SIMPLIFY-1 study examining momelotinib vs. ruxolitinib in JAKi-naïve myelofibrosis patients did not meet the secondary endpoint of non-inferiority of >50% total symptom score (TSS) reduction at week 24 (momelotinib 28% vs ruxolitinib 42%). Abstract e19040 seeks to better understand the impact of momelotinib relative to ruxolitinib on 7 individual symptom items and the total symptom score (TSS).

Baseline scores across the 7 individual items included in the TSS were heterogenous in both the momelotinib and ruxolitinib groups. Scores for 6 of the 7 items were more severe or very severe (scores 7-10) in the momelotinib arm, relative to ruxolitinib, at baseline. Despite the imbalance in baseline score, item-level health state shifts showed similar improvement for momelotinib and ruxolitinib. Mean TSS improvements were also similar for momelotinib and ruxolitinib. Mean TSS change at week 24 was 6.35 for momelotinib vs. 7.87 for ruxolitinib in the ITT and was 8.80 for momelotinib vs. 10.46 for ruxolitinib in the symptomatic subset. The between-group difference was 1.52 (95% CI: (0.196, 2.847)) in the ITT and 1.67 (95% CI: -0.134, 3.468) in the symptomatic subset.

The comparable item health state shifts at week 24 and similar improvements in mean TSS, with a minimal between-group difference of 1.52 on the 70-point scale, suggest momelotinib provides clinically relevant and comparable symptom improvements to ruxolitinib. The full abstract is now available on the ASCO (Free ASCO Whitepaper) website.

Presentation Details

Abstract: e19040
Title: Longitudinal and Individual Symptom Analyses of Momelotinib and Ruxolitinib Treated Myelofibrosis Patients from SIMPLIFY-1
Presenter: Ruben Mesa, MD, PhD

On May 19, 2021 Seagen Inc.(Nasdaq:SGEN) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") reported updated results from two clinical trials examining PADCEV (enfortumab vedotin-ejfv) alone (EV-201 Cohort 2) and PADCEV in combination with Merck’s (known as MSD outside the United States and Canada) KEYTRUDA (pembrolizumab) (EV-103 Cohort A) in patients with locally advanced or metastatic urothelial cancer who are not able to receive cisplatin chemotherapy (Press release, Seagen, MAY 19, 2021, View Source [SID1234580267]).

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"EV-201 Cohort 2 is the first study to report objective responses in patients with advanced urothelial cancer that progressed following immunotherapy and who have medical conditions that prevent them from receiving cisplatin chemotherapy," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head, Astellas. "The analysis that will be presented at ASCO (Free ASCO Whitepaper) showed that after a median follow-up of 16 months, many patients continued to benefit from PADCEV – an important finding for these patients, who have very limited treatment options."

"EV-103 is the first clinical trial to combine the antibody-drug conjugate PADCEV with Merck’s anti-PD-1 therapy KEYTRUDA in patients newly diagnosed with locally advanced or metastatic urothelial cancer," said Roger Dansey, M.D., Chief Medical Officer, Seagen. "The updated data from EV-103 Cohort A, with two years of follow-up, build upon findings from the initial analysis, showing continued durability for this platinum-free combination."

Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors: An updated analysis of EV-201 Cohort 2(Abstract 4524)

Patients in Cohort 2 of EV-201 received prior treatment with an immunotherapy but had not received a platinum-containing chemotherapy in the locally advanced or metastatic setting and were ineligible for cisplatin chemotherapy.

With a median follow-up of 16 months, 51 percent of patients who received PADCEV had a confirmed objective response [95% Confidence Interval (CI): 39.8, 61.3] per blinded independent central review (the primary endpoint), with 22 percent of patients experiencing a complete response (CR). Median duration of response (DOR) was 13.8 months [95% CI: 6.4, not reached]. Patients lived a median of 6.7 months without cancer progression [progression-free survival (PFS) (95% CI: 5.0-8.3)] and had a median overall survival (OS) of 16.1 months (95% CI: 11.3, 24.1).

The most common all-grade treatment-related adverse events (TRAEs) were alopecia (51%), peripheral sensory neuropathy (49%) and fatigue (34%), and the most common Grade 3 or greater TRAEs were neutropenia (9%), maculopapular rash (8%) and fatigue (7%). Grade 3 or greater TRAEs of special interest included skin reactions (17%), peripheral neuropathy (8%) and hyperglycemia (6%). Four deaths were previously reported as treatment-related by investigators in patients age 75 years and older with multiple comorbidities.

The U.S. Food and Drug Administration (FDA) recently granted Priority Review to a supplemental application for PADCEV based on the primary analysis from EV-201 Cohort 2, which was published this month inThe Lancet Oncology.

Study EV-103: Update on durability results and long-term outcome of enfortumab vedotin + pembrolizumab in first-line locally advanced or metastatic urothelial carcinoma (la/mUC)(Abstract 4528)

In the dose-escalation cohort and expansion Cohort A in EV-103, patients were treated with a combination of PADCEV and the anti-PD-1 therapy KEYTRUDA as a first-line treatment for locally advanced or metastatic disease. Participants were ineligible for cisplatin-based chemotherapy, had no prior systemic treatment for locally advanced or metastatic disease, and did not receive adjuvant/neoadjuvant platinum-based therapy within 12 months prior to enrollment.

The primary outcome measure in this analysis was safety. With a median follow-up of 24.9 months, the longer-term analysis demonstrated a safety profile generally consistent with previous findings with no new safety signals observed. The most common TRAEs were peripheral sensory neuropathy (55.6%), fatigue (51.1%) and alopecia (48.9%), and the most common Grade 3 or greater TRAEs were increased lipase (17.8%), maculopapular rash (11.1%) and fatigue (11.1%). Grade 3 or greater TRAEs of interest included skin reactions (20%), hyperglycemia (8.9%) and peripheral neuropathy (4.4%). There was one death previously reported as possibly related to study treatment (multiple organ dysfunction syndrome).

As previously reported, results demonstrated an objective response rate of 73.3 percent (95% CI: 58.1, 85.4) per investigator assessment, with 15.6 percent of patients experiencing a CR. The median PFS was 12.3 months (95% CI: 8.0, not reached). With longer-term follow-up, the study showed a median DOR of 25.6 months (95% CI: 8.3, not reached) and median OS of 26.1 months (95% CI: 15.7, not reached).

The FDA granted Breakthrough Therapy designation last year for the PADCEV and KEYTRUDA combination for patients with unresectable locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy in the first-line setting.

About Urothelial Cancer

Urothelial cancer is the most common type of bladder cancer (90 percent of cases) and can also be found in the renal pelvis (where urine collects inside the kidney), ureter (tube that connects the kidneys to the bladder) and urethra.1 Globally, approximately 573,000 new cases of bladder cancer and more than 212,000 deaths are reported annually.2

About the EV-201 Trial

The EV-201 trial (NCT03219333) is a single-arm, dual-cohort, pivotal phase 2 clinical trial of enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1 or PD-L1 inhibitor, including those who have also been treated with a platinum-containing chemotherapy (Cohort 1) and those who have not received a platinum-containing chemotherapy in this setting and who are ineligible for cisplatin (Cohort 2). The trial enrolled 128 patients in Cohort 1 and 91 patients in Cohort 2 at multiple centers internationally.1 The primary endpoint is confirmed objective response rate per blinded independent central review. Secondary endpoints include assessments of duration of response, disease control rate, progression-free survival, overall survival, safety and tolerability.

About the EV-103 Trial

EV-103 (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter phase 1b/2 trial of PADCEV alone or in combination, evaluating safety, tolerability and efficacy in muscle invasive urothelial cancer, and in locally advanced or metastatic urothelial cancer in first- or second-line settings.

The dose-escalation cohort and expansion Cohort A include locally advanced or metastatic urothelial cancer patients who are ineligible for cisplatin-based chemotherapy. Patients were dosed in a 21-day cycle, receiving an intravenous (IV) infusion of enfortumab vedotin on Days 1 and 8 and pembrolizumab on Day 1. At the time of the initial analysis, 45 patients (5 from the dose-escalation cohort and 40 from the dose-expansion Cohort A) with locally advanced and/or metastatic urothelial cancer had been treated with enfortumab vedotin (1.25 mg/kg) plus pembrolizumab in the first-line setting.

The primary outcome measure of the cohorts included in this analysis is safety. Key secondary objectives related to efficacy include objective response rate, disease control rate, duration of response, progression-free survival and overall survival.

Additional enrolling cohorts in the EV-103 study include:

PADCEV as monotherapy or in combination with pembrolizumab in a first-line setting for locally advanced or metastatic disease, in patients ineligible for cisplatin-based chemotherapy (Cohort K)
PADCEV as a monotherapy in muscle-invasive disease (Cohort L)
About PADCEV (enfortumab vedotin-ejfv)

PADCEV was approved by the U.S. Food and Drug Administration (FDA) in December 2019 and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting. PADCEV was approved under the FDA’s Accelerated Approval Program based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.3

PADCEV is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.3,4 Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).4 PADCEV is co-developed by Astellas and Seagen.

PADCEV (enfortumab vedotin-ejfv) U.S. Important Safety Information

Warnings and Precautions

Skin reactions: Severe cutaneous adverse reactions, including fatal cases of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later.

Skin reactions occurred in 54% of the 310 patients treated with PADCEV in clinical trials. Twenty-six percent (26%) of patients had maculopapular rash and 30% had pruritus. Grade 3-4 skin reactions occurred in 10% of patients and included symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), dermatitis bullous, dermatitis exfoliative, and palmar-plantar erythrodysesthesia. In one clinical trial, the median time to onset of severe skin reactions was 0.8 months (range: 0.2 to 5.3). Of the patients who experienced rash, 65% had complete resolution and 22% had partial improvement. Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines as clinically indicated. Withhold PADCEV and consider referral for specialized care for severe (Grade 3) skin reactions, suspected SJS, or TEN. Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.

Hyperglycemia occurred in patients treated with PADCEV, including death and diabetic ketoacidosis, in those with and without pre-existing diabetes mellitus. The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. In one clinical trial, 8% of patients developed Grade 3-4 hyperglycemia. Patients with baseline hemoglobin A1C ≥8% were excluded. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV.

Peripheral neuropathy (PN), predominantly sensory, occurred in 49% of the 310 patients treated with PADCEV in clinical trials; 2% experienced Grade 3 reactions. In one clinical trial, peripheral neuropathy occurred in patients treated with PADCEV with or without preexisting peripheral neuropathy. The median time to onset of Grade ≥2 was 3.8 months (range: 0.6 to 9.2). Neuropathy led to treatment discontinuation in 6% of patients. At the time of their last evaluation, 19% had complete resolution, and 26% had partial improvement. Monitor patients for symptoms of new or worsening peripheral neuropathy and consider dose interruption or dose reduction of PADCEV when peripheral neuropathy occurs. Permanently discontinue PADCEV in patients that develop Grade ≥3 peripheral neuropathy.

Ocular disorders occurred in 46% of the 310 patients treated with PADCEV. The majority of these events involved the cornea and included keratitis, blurred vision, limbal stem cell deficiency and other events associated with dry eyes. Dry eye symptoms occurred in 36% of patients, and blurred vision occurred in 14% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.9 months (range: 0.3 to 6.2). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.

Infusion site extravasation: Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 310 patients, 1.3% of patients experienced skin and soft tissue reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. One percent (1%) of patients developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.

Embryo-fetal toxicity: PADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.

Adverse Reactions

Serious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (≥3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).

Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).

The most common adverse reactions (≥20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade ≥3 adverse reactions (≥5%) were rash (13%), diarrhea (6%) and fatigue (6%).

Lab Abnormalities

In one clinical trial, Grade 3-4 laboratory abnormalities reported in ≥5% were: lymphocytes decreased (10%), hemoglobin decreased (10%), phosphate decreased (10%), lipase increased (9%), sodium decreased (8%), glucose increased (8%), urate increased (7%), neutrophils decreased (5%).

Drug Interactions

Effects of other drugs on PADCEV Concomitant use with a strong CYP3A4 inhibitor may increase free MMAE exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with strong CYP3A4 inhibitors.

Specific Populations

Lactation Advise lactating women not to breastfeed during treatment with PADCEV and for at least 3 weeks after the last dose.

Hepatic impairment Avoid the use of PADCEV in patients with moderate or severe hepatic impairment.

On May 19, 2021 Eli Lilly and Company’s (NYSE: LLY) oncology portfolio reported that it will be presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, held June 4-8, 2021 (Press release, Eli Lilly, MAY 19, 2021, View Source [SID1234580266]). The data include new analyses of Verzenio (abemaciclib) from the Phase 3 monarchE trial in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early breast cancer (EBC) with a high risk of recurrence who received neoadjuvant chemotherapy. In addition, the first clinical data from the Phase 1 study of Lilly’s oral selective estrogen receptor degrader (SERD) will be presented at the meeting.

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Breast Cancer Highlights
Verzenio (abemaciclib)
Lilly will present a subgroup analysis from the positive Phase 3 monarchE trial in high-risk early breast cancer detailing the invasive disease-free survival, distant relapse-free survival, and safety outcomes in patients who received neoadjuvant chemotherapy, as well as an analysis of a subgroup of patients from China. In addition, Lilly is publishing new pre-clinical data which examine unique attributes of Verzenio among CDK4 & 6 inhibitors. Lilly will also present an analysis of real world evidence on the risk of recurrence in early breast cancer.

Oral SERD
Loxo Oncology at Lilly will present an analysis of interim clinical data from the ongoing, first-in-human, Phase 1a trial of LY3484356 in patients with estrogen receptor positive advanced breast cancer and endometrial endometrioid cancer. The submitted abstract utilized a November 2020 data cut-off date, and the poster presentation will utilize an April 2021 data cut-off date.

Lung and Thyroid Cancer Highlights
Retevmo (selpercatinib)
Lilly will present new data on Retevmo, including preliminary results from the Phase 1/2 LIBRETTO-121 trial in pediatric patients with advanced RET-altered solid tumors, as well as further efficacy and safety updates from the Phase 1/2 LIBRETTO-001 study of Retevmo in patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) and advanced or metastatic RET-altered thyroid cancer.

In addition, analyses of racial disparities in biomarker testing – including next-generation sequencing – and clinical trial enrollment among patients with NSCLC will be presented at the meeting.

Gastrointestinal Cancer Highlights
CYRAMZA (ramucirumab) and ERBITUX (cetuximab)
Lilly will present data on prognostic and predictive factors in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein treated with CYRAMZA, along with real world evidence on ERBITUX in patients with metastatic colorectal cancer.

A list of the oral and poster presentations, along with their viewing details, as well as published abstracts are shared below.

Breast Cancer

Medicine

Abstract Title and Lead Author

Presentation Details

Verzenio
(abemaciclib)

Abemaciclib combined with adjuvant
endocrine therapy in patients with
high risk early breast cancer who
received neoadjuvant chemotherapy;
Miguel Martin

Abstract 517

Session: Breast Cancer—
Local/Regional/Adjuvant

Poster Discussion

Friday, June 4, at 9:00-10:00 a.m.
EDT

Verzenio
(abemaciclib)

Efficacy and safety analysis of
Chinese patients in monarchE:
abemaciclib combined with adjuvant
endocrine therapy for high risk HR+,
HER2- early breast cancer; Shao Zhimin

Abstract 522

Session: Breast Cancer—
Local/Regional/Adjuvant

Poster

Available on demand starting
Friday, June 4 at 9:00 a.m. EDT

Verzenio
(abemaciclib)

Characterizing demographics, clinical,
and genomic characteristics for US
patients with HR+, HER2- metastatic
breast cancer following progression
on a CDK4 and 6 inhibitor; Fabrice Andre

Abstract 1015

Session: Breast Cancer—
Metastatic

Poster Discussion

Friday, June 4, at 9:00-10:00 a.m. EDT

Verzenio
(abemaciclib)

eMonarcHER: A phase 3 study of
abemaciclib plus standard adjuvant
endocrine therapy in patients with
HR+, HER2+, node-positive, high
risk early breast cancer; Sara M.
Tolaney

Abstract TPS596

Session: Breast Cancer—
Local/Regional/Adjuvant

Poster

Available on demand starting
Friday, June 4 at 9:00 a.m. EDT

Verzenio
(abemaciclib)

A phase Ib study of xentuzumab
plus abemaciclib and fulvestrant
in patients (pts) with advanced
hormone receptor-positive (HR+),
HER2-negative breast cancer (BC)
with visceral or non-visceral disease;
Douglas Yee

Abstract 1057

Session: Breast Cancer—
Metastatic

Poster

Available on demand starting
Friday, June 4 at 9:00 a.m. EDT

Verzenio
(abemaciclib)

Recurrence risk in early breast
cancer as defined by clinicopathologic
features; Kristin M. Sheffield

Abstract e18581

Publication only: Health
Services Research and
Quality Improvement

Verzenio
(abemaciclib)

Abemaciclib, a CDK4 & 6 inhibitor
with unique pharmacological
properties for breast cancer
therapy; Torres Raquel

Abstract e12506

Publication only: Breast
Cancer—Local/Regional/Adjuvant

LY3484356
(oral SERD)

A first-in-human phase 1a/b trial
of LY3484356, an oral selective
estrogen receptor (ER) degrader
(SERD) in ER+ advanced breast
cancer (aBC) and endometrial
endometrioid cancer (EEC):
Results from the EMBER study;
Komal Jhaveri

Abstract 1050

Session: Breast Cancer—
Metastatic

Poster

Available on demand starting
Friday, June 4 at 9:00 a.m. EDT

Lung and Thyroid Cancers

Medicine

Abstract Title and Lead Author

Presentation Details

Retevmo
(selpercatinib)

Oral Selpercatinib in Pediatric
Patients (pts) with Advanced
RET-Altered Solid or Primary
CNS Tumors: Preliminary Results
from the Phase 1/2 LIBRETTO-121
Trial; Daniel Morgenstern

Abstract 10009

Session: Pediatric Oncology II

Oral presentation

Friday, June 4, at 9:00 a.m. EDT

Retevmo
(selpercatinib)

Updated Overall Efficacy and
Safety of Selpercatinib in Patients
(pts) with RET Fusion+ Non-Small-
Cell Lung Cancer (NSCLC); Benjamin
Besse

Abstract 9065

Session: Lung Cancer—Non-
Small Cell Metastatic

Poster

Available on demand starting
Friday, June 4 at 9:00 a.m. EDT

Retevmo
(selpercatinib)

Selpercatinib efficacy and safety
in patients with RET-altered thyroid
cancer: a clinical trial update; Eric
Sherman

Abstract 6073

Session: Head and Neck Cancer

Poster

Available on demand starting
Friday, June 4 at 9:00 a.m. EDT

Retevmo
(selpercatinib)

Efficacy of Selpercatinib After Prior
Systemic Therapy in Patients with
RET Mutant Medullary Thyroid
Cancer; Lori J. Wirth

Abstract 6074

Session: Head and Neck Cancer

Poster

Available on demand starting
Friday, June 4 at 9:00 a.m. EDT

Retevmo
(selpercatinib)

Response to Selpercatinib Versus
Prior Systemic Therapy in Patients
(Pts) with RET Fusion+ Non-Small-
Cell Lung Cancer (NSCLC); Alexander
E. Drillon

Abstract 9032

Session: Lung Cancer—Non-
Small Cell Metastatic

Available on demand starting
Friday, June 4 at 9:00 a.m. EDT

N/A

Racial Disparities in Biomarker Testing
and Clinical Trial Enrollment in Non-
Small Cell Lung Cancer (NSCLC);
Debora S. Bruno

Abstract 9005

Session: Lung Cancer—Non-
Small Cell Metastatic

Oral presentation

Friday, June 4, at 1:00 p.m. EDT

N/A

Challenges in Lung Cancer
Multidisciplinary Collaboration
Experienced by Specialists in Four
Countries; Monaliben Patel MD

Abstract e23002

Publication only: Professional
Development and Education Advances

Gastrointestinal Cancers

Medicine

Abstract Title and Lead Author

Presentation Details

CYRAMZA

(ramucirumab)

Prognostic and predictive factors in
patients treated with ramucirumab
(RAM) with advanced hepatocellular
carcinoma (aHCC) and elevated alpha-
fetoprotein (AFP): results from two
Phase III trials; Joseph M. Llovet

Abstract 4146

Session: Gastrointestinal Cancer—
Gastroesophageal, Pancreatic,
and Hepatobiliary

Poster

Available on demand starting
Friday, June 4 at 9:00 a.m. EDT

ERBITUX
(cetuximab)

Real-World Time on Treatment and
Overall Survival in Patients with
Metastatic Colorectal cancer receiving
Cetuximab in Second Line after failing
Irinotecan or Oxaliplatin-based Regimens;
Wambul Gathirua-Mwangi

Abstract e15568

Publication only: Gastrointestinal
Cancer – Colorectal and Anal

ERBITUX
(cetuximab)

A Retrospective Analysis of Real-World
Time on Treatment and Overall Survival
in Patients with Metastatic Colorectal
Cancer receiving Cetuximab in Third Line;
Wambui Gathirua-Mwangi

Abstract e15575

Publication only:

Gastrointestinal Cancer –
Colorectal and Anal

Prostate Cancer

Medicine

Abstract Title and Lead Author

Presentation Details

Verzenio
(abemaciclib)

CYCLONE 1: A Phase 2 study of
abemaciclib in patients with metastatic
castration-resistant prostate cancer
(mCRPC) previously treated with a
novel hormonal agent and taxane-based
chemotherapy; Neeraj Agarwal

Abstract TPS5086

Session: Genitourinary Cancer—
Prostate, Testicular, and Penile

Poster

Available on demand starting
Friday, June 4 at 9:00 a.m. EDT

Other

Medicine

Abstract Title and Lead Author

Presentation Details

olaratumab

Phase (Ph) 1b/2 evaluation of
olaratumab in combination with
gemcitabine and docetaxel in
advanced soft tissue sarcoma (STS);
Steven Attia

Abstract 11517

Session: Sarcoma

Poster Discussion

Friday, June 4, at 9:00 a.m. –
11:00 a.m. EDT

N/A

Racial distribution of clinical trial
participants in the United States;
Monaliben Patel

Abstract e18516

Publication only: Health Services
Research and Quality Improvement

Notes to Editors

About Verzenio (abemaciclib)
Verzenio (abemaciclib) is an inhibitor of cyclin-dependent kinases (CDK)4 & 6, which are activated by binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4 & 6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation.

In vitro, continuous exposure to Verzenio inhibited Rb phosphorylation and blocked progression from G1 to S phase of the cell cycle, resulting in senescence and apoptosis (cell death). Preclinically, Verzenio dosed daily without interruption resulted in reduction of tumor size. Inhibiting CDK4 & 6 in healthy cells can result in side effects, some of which may be serious. Clinical evidence also suggests that Verzenio crosses the blood-brain barrier. In patients with advanced cancer, including breast cancer, concentrations of Verzenio and its active metabolites (M2 and M20) in cerebrospinal fluid are comparable to unbound plasma concentrations.

Verzenio is Lilly’s first solid oral dosage form to be made using a faster, more efficient process known as continuous manufacturing. Continuous manufacturing is a new and advanced type of manufacturing within the pharmaceutical industry, and Lilly is one of the first companies to use this technology.

INDICATION FOR VERZENIO
Verzenio is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer:

in combination with an aromatase inhibitor for postmenopausal women as initial endocrine-based therapy
in combination with fulvestrant for women with disease progression following endocrine therapy
as a single agent for adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting
About LY3484356
LY3484356 is an investigational, oral selective estrogen receptor degrader (SERD) with pure antagonistic properties. The estrogen receptor (ER) is the key therapeutic target for patients with ER+/HER2- breast cancer. Novel degraders of ER may overcome endocrine therapy resistance while providing consistent oral pharmacology and convenience of administration. LY3484356 was specifically designed to deliver continuous estrogen receptor target inhibition throughout the dosing period and regardless of ESR1 mutational status.

LY3484356 is currently being studied in the first-in-human, multi-center Phase 1a/1b EMBER trial in patients with estrogen receptor positive locally advanced or metastatic breast cancer and other select non-breast cancers and in the Phase 1 EMBER-2 trial in preoperative, postmenopausal women with stage I-III, ER+/HER2- breast cancer. For additional information about LY3484356 clinical trials, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology at Lilly clinical trial team by e-mailing [email protected].

About Retevmo (selpercatinib)
Retevmo (selpercatinib, capsules 40mg, 80mg; formerly known as LOXO-292) (pronounced reh-TEHV-moh) is a selective and potent RET kinase inhibitor. Retevmo may affect both tumor cells and healthy cells, which can result in side effects. RET-driver alterations are predominantly mutually exclusive from other oncogenic drivers. Retevmo is an U.S. FDA-approved oral prescription medicine, 120 mg or 160 mg dependent on weight (<50 kg or ≥50 kg, respectively), taken twice daily until disease progression or unacceptable toxicity.1 Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

INDICATIONS FOR RETEVMO
Retevmo is indicated for the treatment of adult patients with metastatic rearranged during transfection fusion-positive non-small cell lung cancer (NSCLC), and the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy, or advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). Retevmo was approved under the FDA’s Accelerated Approval regulations based on the LIBRETTO-001 Phase 1/2 trial’s endpoints of objective response rate (ORR) and duration of response (DoR).

About CYRAMZA (ramucirumab)
In the U.S., CYRAMZA (ramucirumab) has six FDA approvals to treat four different types of cancers. CYRAMZA is being investigated in a broad global development program that has enrolled more than 15,000 patients across more than 100 trials worldwide. These include several studies investigating CYRAMZA in combination with other anti-cancer therapies for the treatment of multiple tumor types. To date, more than 150,000 patients have been treated with CYRAMZA.

CYRAMZA is an antiangiogenic therapy. It is a vascular endothelial growth factor (VEGF) Receptor 2 antagonist that binds specifically to VEGFR-2, thereby blocking the binding of the receptor ligands (VEGF-A, VEGF-C, and VEGF-D) – which may slow tumor growth. CYRAMZA inhibited angiogenesis in an in vivo animal model.

U.S. INDICATIONS FOR CYRAMZA
Gastric Cancer
CYRAMZA, as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

Non-Small Cell Lung Cancer
CYRAMZA, in combination with erlotinib, for first-line treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations.

CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

Colorectal Cancer
CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

Hepatocellular Carcinoma
CYRAMZA, as a single agent, is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have an alpha-fetoprotein (AFP) of ≥400 ng/mL and have been treated with sorafenib.

About ERBITUX (cetuximab)
Indications and Usage for ERBITUX (cetuximab) injection
Head and Neck Cancer
ERBITUX (cetuximab) is approved:

ERBITUX, in combination with radiation therapy (RT), is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN)
ERBITUX is indicated in combination with platinum-based therapy and fluorouracil (CT) for the first-line treatment of patients with recurrent locoregional disease or metastatic SCCHN
ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed
Metastatic Colorectal Cancer
ERBITUX is indicated for the treatment of KRAS wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:

In combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) for first-line treatment
In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy
As a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan
Limitations of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown

IMPORTANT SAFETY INFORMATION FOR VERZENIO (abemaciclib)

Diarrhea occurred in 81% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 90% of patients receiving Verzenio alone in MONARCH 1. Grade 3 diarrhea occurred in 9% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 13% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 20% of patients receiving Verzenio alone in MONARCH 1. Episodes of diarrhea have been associated with dehydration and infection.

Diarrhea incidence was greatest during the first month of Verzenio dosing. In MONARCH 3, the median time to onset of the first diarrhea event was 8 days, and the median duration of diarrhea for Grades 2 and 3 were 11 and 8 days, respectively. In MONARCH 2, the median time to onset of the first diarrhea event was 6 days, and the median duration of diarrhea for Grades 2 and 3 were 9 days and 6 days, respectively. In MONARCH 3, 19% of patients with diarrhea required a dose omission and 13% required a dose reduction. In MONARCH 2, 22% of patients with diarrhea required a dose omission and 22% required a dose reduction. The time to onset and resolution for diarrhea were similar across MONARCH 3, MONARCH 2, and MONARCH 1.

Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy such as loperamide, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow-up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue Verzenio until toxicity resolves to ≤Grade 1, and then resume Verzenio at the next lower dose.

Neutropenia occurred in 41% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 46% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 37% of patients receiving Verzenio alone in MONARCH 1. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 22% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 32% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 27% of patients receiving Verzenio alone in MONARCH 1. In MONARCH 3, the median time to first episode of Grade ≥3 neutropenia was 33 days, and in MONARCH 2 and MONARCH 1, was 29 days. In MONARCH 3, median duration of Grade ≥3 neutropenia was 11 days, and for MONARCH 2 and MONARCH 1 was 15 days.

Monitor complete blood counts prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Febrile neutropenia has been reported in <1% of patients exposed to Verzenio in the MONARCH studies. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider.

Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with Verzenio and other CDK4/6 inhibitors. Across clinical trials (MONARCH 1, MONARCH 2, MONARCH 3), 3.3% of Verzenio-treated patients had ILD/pneumonitis of any grade, 0.6% had Grade 3 or 4, and 0.4% had fatal outcomes. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations.

Dose interruption or dose reduction is recommended in patients who develop persistent or recurrent Grade 2 ILD/pneumonitis. Permanently discontinue Verzenio in all patients with grade 3 or 4 ILD/pneumonitis.

Grade ≥3 increases in alanine aminotransferase (ALT) (6% versus 2%) and aspartate aminotransferase (AST) (3% versus 1%) were reported in the Verzenio and placebo arms, respectively, in MONARCH 3. Grade ≥3 increases in ALT (4% versus 2%) and AST (2% versus 3%) were reported in the Verzenio and placebo arms respectively, in MONARCH 2.

In MONARCH 3, for patients receiving Verzenio plus an aromatase inhibitor with Grade ≥3 increases in ALT or AST, median time to onset was 61 and 71 days, respectively, and median time to resolution to Grade <3 was 14 and 15 days, respectively. In MONARCH 2, for patients receiving Verzenio plus fulvestrant with Grade ≥3 increases in ALT or AST, median time to onset was 57 and 185 days, respectively, and median time to resolution to Grade <3 was 14 and 13 days, respectively.

For assessment of potential hepatotoxicity, monitor liver function tests (LFTs) prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or Grade 3 or 4, hepatic transaminase elevation.

Venous thromboembolic events were reported in 5% of patients treated with Verzenio plus an aromatase inhibitor as compared to 0.6% of patients treated with an aromatase inhibitor plus placebo in MONARCH 3. Venous thromboembolic events were reported in 5% of patients treated with Verzenio plus fulvestrant in MONARCH 2 as compared to 0.9% of patients treated with fulvestrant plus placebo. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. Across the clinical development program, deaths due to venous thromboembolism have been reported. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.

Verzenio can cause fetal harm when administered to a pregnant woman based on findings from animal studies and the mechanism of action. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Verzenio and for at least 3 weeks after the last dose. There are no data on the presence of Verzenio in human milk or its effects on the breastfed child or on milk production. Advise lactating women not to breastfeed during Verzenio treatment and for at least 3 weeks after the last dose because of the potential for serious adverse reactions in breastfed infants. Based on findings in animals, Verzenio may impair fertility in males of reproductive potential.

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 3 for Verzenio plus anastrozole or letrozole and ≥2% higher than placebo plus anastrozole or letrozole vs placebo plus anastrozole or letrozole were diarrhea (81% vs 30%), neutropenia (41% vs 2%), fatigue (40% vs 32%), infections (39% vs 29%), nausea (39% vs 20%), abdominal pain (29% vs 12%), vomiting (28% vs 12%), anemia (28% vs 5%), alopecia (27% vs 11%), decreased appetite (24% vs 9%), leukopenia (21% vs 2%), creatinine increased (19% vs 4%), constipation (16% vs 12%), ALT increased (16% vs 7%), AST increased (15% vs 7%), rash (14% vs 5%), pruritus (13% vs 9%), cough (13% vs 9%), dyspnea (12% vs 6%), dizziness (11% vs 9%), weight decreased (10% vs 3%), influenza-like illness (10% vs 8%), and thrombocytopenia (10% vs 2%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 2 for Verzenio plus fulvestrant and ≥2% higher than placebo plus fulvestrant vs placebo plus fulvestrant were diarrhea (86% vs 25%), neutropenia (46% vs 4%), fatigue (46% vs 32%), nausea (45% vs 23%), infections (43% vs 25%), abdominal pain (35% vs 16%), anemia (29% vs 4%), leukopenia (28% vs 2%), decreased appetite (27% vs 12%), vomiting (26% vs 10%), headache (20% vs 15%), dysgeusia (18% vs 3%), thrombocytopenia (16% vs 3%), alopecia (16% vs 2%), stomatitis (15% vs 10%), ALT increased (13% vs 5%), pruritus (13% vs 6%), cough (13% vs 11%), dizziness (12% vs 6%), AST increased (12% vs 7%), peripheral edema (12% vs 7%), creatinine increased (12% vs <1%), rash (11% vs 4%), pyrexia (11% vs 6%), and weight decreased (10% vs 2%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 1 with Verzenio were diarrhea (90%), fatigue (65%), nausea (64%), decreased appetite (45%), abdominal pain (39%), neutropenia (37%), vomiting (35%), infections (31%), anemia (25%), thrombocytopenia (20%), headache (20%), cough (19%), leukopenia (17%), constipation (17%), arthralgia (15%), dry mouth (14%), weight decreased (14%), stomatitis (14%), creatinine increased (13%), alopecia (12%), dysgeusia (12%), pyrexia (11%), dizziness (11%), and dehydration (10%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 3 were neutropenia (22% vs 2%), diarrhea (9% vs 1%), leukopenia (8% vs <1%), ALT increased (7% vs 2%), and anemia (6% vs 1%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 2 were neutropenia (27% vs 2%), diarrhea (13% vs <1%), leukopenia (9% vs 0%), anemia (7% vs 1%), and infections (6% vs 3%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions from MONARCH 1 with Verzenio were neutropenia (24%), diarrhea (20%), fatigue (13%), infections (7%), leukopenia (6%), anemia (5%), and nausea (5%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 3 in ≥10% for Verzenio plus anastrozole or letrozole and ≥2% higher than placebo plus anastrozole or letrozole vs placebo plus anastrozole or letrozole were increased serum creatinine (98% vs 84%; 2% vs 0%), decreased white blood cells (82% vs 27%; 13% vs <1%), anemia (82% vs 28%; 2% vs 0%), decreased neutrophil count (80% vs 21%; 22% vs 3%), decreased lymphocyte count (53% vs 26%; 8% vs 2%), decreased platelet count (36% vs 12%; 2% vs <1%), increased ALT (48% vs 25%; 7% vs 2%), and increased AST (37% vs 23%; 4% vs <1%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 2 in ≥10% for Verzenio plus fulvestrant and ≥2% higher than placebo plus fulvestrant vs placebo plus fulvestrant were increased serum creatinine (98% vs 74%; 1% vs 0%), decreased white blood cells (90% vs 33%; 23% vs 1%), decreased neutrophil count (87% vs 30%; 33% vs 4%), anemia (84% vs 33%; 3% vs <1%), decreased lymphocyte count (63% vs 32%; 12% vs 2%), decreased platelet count (53% vs 15%; 2% vs 0%), increased ALT (41% vs 32%; 5% vs 1%), and increased AST (37% vs 25%; 4% vs 4%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 1 were increased serum creatinine (98%; <1%), decreased white blood cells (91%; 28%), decreased neutrophil count (88%; 27%), anemia (68%; 0%), decreased lymphocyte count (42%; 14%), decreased platelet count (41%; 2%), increased ALT (31%; 3%), and increased AST (30%; 4%).

Strong and moderate CYP3A inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity. Avoid concomitant use of the strong CYP3A inhibitor ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold. In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the Verzenio dose to 100 mg twice daily with concomitant use of strong CYP3A inhibitors other than ketoconazole. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the Verzenio dose to 50 mg twice daily with concomitant use of strong CYP3A inhibitors. If a patient taking Verzenio discontinues a strong CYP3A inhibitor, increase the Verzenio dose (after 3 to 5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor. With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the Verzenio dose in 50 mg decrements. Patients should avoid grapefruit products.

Avoid concomitant use of strong or moderate CYP3A inducers and consider alternative agents. Coadministration of strong or moderate CYP3A inducers decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity.

With severe hepatic impairment (Child-Pugh Class C), reduce the Verzenio dosing frequency to once daily. The pharmacokinetics of Verzenio in patients with severe renal impairment (CLcr <30 mL/min), end stage renal disease, or in patients on dialysis is unknown. No dosage adjustments are necessary in patients with mild or moderate hepatic (Child-Pugh A or B) and/or renal impairment (CLcr ≥30-89 mL/min).

AL HCP ISI 17SEP2019

Please see full Prescribing Information for Verzenio.

IMPORTANT SAFETY INFORMATION FOR RETEVMO (selpercatinib)

Hepatotoxicity: Serious hepatic adverse reactions occurred in 2.6% of patients treated with Retevmo. Increased aspartate aminotransferase (AST) occurred in 51% of patients, including Grade 3 or 4 events in 8% and increased alanine aminotransferase (ALT) occurred in 45% of patients, including Grade 3 or 4 events in 9%. The median time to first onset for increased AST was 4.1 weeks (range: 5 days to 2 years) and increased ALT was 4.1 weeks (range: 6 days to 1.5 years). Monitor ALT and AST prior to initiating Retevmo, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue Retevmo based on the severity.

Hypertension occurred in 35% of patients, including Grade 3 hypertension in 17% and Grade 4 in one (0.1%) patient. Overall, 4.6% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate Retevmo in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating Retevmo. Monitor blood pressure after 1 week, at least monthly thereafter, and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue Retevmo based on the severity.

Retevmo can cause concentration-dependent QT interval prolongation. An increase in QTcF interval to >500 ms was measured in 6% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 15% of patients. Retevmo has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction. Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia and hypocalcemia prior to initiating Retevmo and during treatment. Monitor the QT interval more frequently when Retevmo is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and dose reduce or permanently discontinue Retevmo based on the severity.

Serious, including fatal, hemorrhagic events can occur with Retevmo. Grade ≥3 hemorrhagic events occurred in 2.3% of patients treated with Retevmo including 3 (0.4%) patients with fatal hemorrhagic events, including one case each of cerebral hemorrhage, tracheostomy site hemorrhage, and hemoptysis. Permanently discontinue Retevmo in patients with severe or life-threatening hemorrhage.

Hypersensitivity occurred in 4.3% of patients receiving Retevmo, including Grade 3 hypersensitivity in 1.6%. The median time to onset was 1.7 weeks (range 6 days to 1.5 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis. If hypersensitivity occurs, withhold Retevmo and begin corticosteroids at a dose of 1 mg/kg prednisone (or equivalent). Upon resolution of the event, resume Retevmo at a reduced dose and increase the dose of Retevmo by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity. Continue steroids until patient reaches target dose and then taper. Permanently discontinue Retevmo for recurrent hypersensitivity.

Tumor lysis syndrome (TLS) occurred in 1% of patients with medullary thyroid carcinoma receiving Retevmo. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, Retevmo has the potential to adversely affect wound healing. Withhold Retevmo for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Retevmo after resolution of wound healing complications has not been established.

Based on data from animal reproduction studies and its mechanism of action, Retevmo can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Retevmo and for at least 1 week after the final dose. There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Retevmo and for 1 week after the final dose.

Severe adverse reactions (Grade 3-4) occurring in ≥15% of patients who received Retevmo in LIBRETTO-001, were hypertension (18%), prolonged QT interval (4%), diarrhea (3.4%), dyspnea (2.3%), fatigue (2%), abdominal pain (1.9%), hemorrhage (1.9%), headache (1.4%), rash (0.7%), constipation (0.6%), nausea (0.6%), vomiting (0.3%), and edema (0.3%).

Serious adverse reactions occurred in 33% of patients who received Retevmo. The most frequently reported serious adverse reaction (in ≥ 2% of patients) was pneumonia.

Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions which occurred in >1 patient included sepsis (n=3), cardiac arrest (n=3) and respiratory failure (n=3).

Common adverse reactions (all grades) occurring in ≥15% of patients who received Retevmo in LIBRETTO-001, were dry mouth (39%), diarrhea (37%), hypertension (35%), fatigue (35%), edema (35%), rash (27%), constipation (25%), nausea (23%), abdominal pain (23%), headache (23%), cough (18%), prolonged QT interval (17%), dyspnea (16%), vomiting (15%), and hemorrhage (15%).

Laboratory abnormalities (all grades; Grade 3-4) ≥20% worsening from baseline in patients who received Retevmo in LIBRETTO-001, were AST increased (51%; 8%), ALT increased (45%; 9%), increased glucose (44%; 2.2%), decreased leukocytes (43%; 1.6%), decreased albumin (42%; 0.7%), decreased calcium (41%; 3.8%), increased creatinine (37%; 1.0%), increased alkaline phosphatase (36%; 2.3%), decreased platelets (33%; 2.7%), increased total cholesterol (31%; 0.1%), decreased sodium (27%; 7%), decreased magnesium (24%; 0.6%), increased potassium (24%; 1.2%), increased bilirubin (23%; 2.0%), and decreased glucose (22%; 0.7%).

Concomitant use of acid-reducing agents decreases selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity. Avoid concomitant use of proton-pump inhibitors (PPIs), histamine-2 (H2) receptor antagonists, and locally-acting antacids with Retevmo. If coadministration cannot be avoided, take Retevmo with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid).

Concomitant use of strong and moderate CYP3A inhibitors increases selpercatinib plasma concentrations which may increase the risk of Retevmo adverse reactions including QTc interval prolongation. Avoid concomitant use of strong and moderate CYP3A inhibitors with Retevmo. If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the Retevmo dosage as recommended and monitor the QT interval with ECGs more frequently.

Concomitant use of strong and moderate CYP3A inducers decreases selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity. Avoid coadministration of Retevmo with strong and moderate CYP3A inducers.

Concomitant use of Retevmo with CYP2C8 and CYP3A substrates increases their plasma concentrations which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of Retevmo with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling.

The safety and effectiveness of Retevmo have not been established in pediatric patients less than 12 years of age. The safety and effectiveness of Retevmo have been established in pediatric patients aged 12 years and older for medullary thyroid cancer (MTC) who require systemic therapy and for advanced RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). Use of Retevmo for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older. Monitor open growth plates in adolescent patients. Consider interrupting or discontinuing Retevmo if abnormalities occur.

No dosage modification is recommended for patients with mild to severe renal impairment (estimated Glomerular Filtration Rate [eGFR] ≥15 to 89 mL/min, estimated by Modification of Diet in Renal Disease [MDRD] equation). A recommended dosage has not been established for patients with end-stage renal disease.

Reduce the dose when administering Retevmo to patients with severe hepatic impairment (total bilirubin greater than 3 to 10 times upper limit of normal [ULN] and any AST). No dosage modification is recommended for patients with mild or moderate hepatic impairment. Monitor for Retevmo-related adverse reactions in patients with hepatic impairment.

SE HCP ISI All_25MAR2021

Please see full U.S. Prescribing Information for Retevmo.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA (ramucirumab)
Warnings and Precautions

Hemorrhage

CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Grade ≥3 hemorrhagic events. In 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade hemorrhage ranged from 13-55%. Grade 3-5 hemorrhage incidence ranged from 2-5%.
Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in REGARD and RAINBOW; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown.
Patients with NSCLC receiving therapeutic anticoagulation or with evidence of major airway invasion by cancer were excluded from REVEL. In addition, patients with NSCLC with a recent history of gross hemoptysis, those receiving chronic therapy with NSAIDs or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major blood vessel invasion or intratumor cavitation were excluded from REVEL and RELAY; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown.
Permanently discontinue CYRAMZA in patients who experience severe (Grade 3 or 4) bleeding.
Gastrointestinal Perforations

CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. In 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade and Grade 3-5 gastrointestinal perforations ranged from <1-2%.
Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.
Impaired Wound Healing

CYRAMZA has the potential to adversely affect wound healing. CYRAMZA has not been studied in patients with serious or non-healing wounds.
Withhold CYRAMZA for 28 days prior to elective surgery. Do not administer CYRAMZA for at least 2 weeks following a major surgical procedure and until adequate wound healing. The safety of resumption of CYRAMZA after resolution of wound healing complications has not been established.
Arterial Thromboembolic Events (ATEs)

Serious, sometimes fatal, ATEs, including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, occurred across clinical trials. In 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade ATE was 1-3%. Grade 3-5 ATE incidence was <1-2%.
Permanently discontinue CYRAMZA in patients who experience an ATE.
Hypertension

An increased incidence of severe hypertension occurred in patients receiving CYRAMZA. Across five clinical studies, excluding RELAY, in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade hypertension ranged from 11-26%. Grade 3-5 hypertension incidence ranged from 6-15%. In 221 patients with NSCLC receiving CYRAMZA in combination with erlotinib in the RELAY study, the incidence of new or worsening hypertension was higher (45%), as was the incidence of Grade 3-5 hypertension (24%). Of the patients experiencing new or worsening hypertension in RELAY (N=100 CYRAMZA and erlotinib; N=27 placebo and erlotinib), 13% of those treated with CYRAMZA and erlotinib required initiation of 3 or more antihypertensive medications compared to 4% of patients treated with placebo and erlotinib.
Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Withhold CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA for medically significant hypertension that cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.
Infusion-Related Reactions (IRR)

IRR, including severe and life-threatening IRR, occurred in CYRAMZA clinical trials. Symptoms of IRR included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. In 2137 patients with various cancers treated with CYRAMZA in which premedication was recommended or required, the incidence of all Grade IRR ranged from <1- 9%. Grade 3-5 IRR incidence was <1%.
Premedicate prior to each CYRAMZA infusion. Monitor patients during the infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Reduce the infusion rate by 50% for Grade 1-2 IRR. Permanently discontinue CYRAMZA for Grade 3- 4 IRR.
Worsening of Pre-existing Hepatic Impairment

Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.
Based on safety data from REACH-2, in patients with Child-Pugh A liver cirrhosis, the pooled incidence of hepatic encephalopathy and hepatorenal syndrome was higher for patients who received CYRAMZA (6%) compared to patients who received placebo (0%).
Posterior Reversible Encephalopathy Syndrome (PRES)

PRES (also known as Reversible Posterior Leukoencephalopathy Syndrome [RPLS]) has been reported in <0.1% of 2137 patients with various cancers treated with CYRAMZA. Symptoms of PRES include seizure, headache, nausea/vomiting, blindness, or altered consciousness, with or without associated hypertension.
Permanently discontinue CYRAMZA in patients who develop PRES. Symptoms may resolve or improve within days, although some patients with PRES can experience ongoing neurologic sequelae or death.
Proteinuria Including Nephrotic Syndrome

In 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade proteinuria ranged from 3-34%. Grade ≥3 proteinuria (including 4 patients with nephrotic syndrome) incidence ranged from <1-3%.
Monitor for proteinuria. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.
Thyroid Dysfunction

In 2137 patients with various cancers treated with CYRAMZA, the incidence of Grade 1-2 hypothyroidism ranged from <1-3%; there were no reports of Grade 3-5 hypothyroidism. Monitor thyroid function during treatment with CYRAMZA.
Embryo-Fetal Toxicity

CYRAMZA can cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for 3 months after the last dose.
Lactation

Because of the potential risk for serious adverse reactions in breastfed children from ramucirumab, advise women not to breastfeed during treatment with CYRAMZA and for 2 months after the last dose.
Adverse Reactions
REGARD:

The most common adverse reactions (all Grades) observed in single agent CYRAMZA-treated gastric cancer patients at a rate of ≥5% and ≥2% higher than placebo were hypertension (16% vs 8%), diarrhea (14% vs 9%), headache (9% vs 3%), and hyponatremia (6% vs 2%).
The most common serious adverse reactions with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.
Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in REGARD were neutropenia (4.7%), epistaxis (4.7%), rash (4.2%), intestinal obstruction (2.1%), and arterial thromboembolic events (1.7%).
Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and IRR. In REGARD, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in REGARD was 0.8% and the rate of IRR was 0.4%.
RAINBOW:

The most common adverse reactions (all Grades) observed in patients treated with CYRAMZA with paclitaxel at a rate of ≥5% and ≥2% higher than placebo with paclitaxel were fatigue/asthenia (57% vs 44%), neutropenia (54% vs 31%), diarrhea (32% vs 23%), epistaxis (31% vs 7%), hypertension (25% vs 6%), peripheral edema (25% vs 14%), stomatitis (20% vs 7%), proteinuria (17% vs 6%), thrombocytopenia (13% vs 6%), hypoalbuminemia (11% vs 5%), and gastrointestinal hemorrhage events (10% vs 6%).
The most common serious adverse reactions with CYRAMZA with paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients who received CYRAMZA with paclitaxel received granulocyte colony-stimulating factors.
Adverse reactions resulting in discontinuation of any component of the CYRAMZA with paclitaxel combination in ≥2% of patients in RAINBOW were neutropenia (4%) and thrombocytopenia (3%).
Clinically relevant adverse reactions reported in ≥1% and <5% of patients receiving CYRAMZA with paclitaxel were sepsis (3.1%), including 5 fatal events, and gastrointestinal perforations (1.2%), including 1 fatal event.
REVEL:

The most common adverse reactions (all Grades) observed in patients treated with CYRAMZA with docetaxel at a rate of ≥5% and ≥2% higher than placebo with docetaxel were neutropenia (55% vs 46%), fatigue/asthenia (55% vs 50%), stomatitis/mucosal inflammation (37% vs 19%), epistaxis (19% vs 7%), febrile neutropenia (16% vs 10%), peripheral edema (16% vs 9%), thrombocytopenia (13% vs 5%), lacrimation increased (13% vs 5%), and hypertension (11% vs 5%).
The most common serious adverse reactions with CYRAMZA with docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA with docetaxel- treated patients versus 37% in patients who received placebo with docetaxel.
Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA with docetaxel-treated patients (9%) than in placebo with docetaxel-treated patients (5%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were IRR (0.5%) and epistaxis (0.3%).
For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of Grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA with docetaxel compared to 6% overall incidence and 1% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of Grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA with docetaxel compared to 12% overall incidence and 2% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel.
Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA with docetaxel-treated patients in REVEL were hyponatremia (4.8%) and proteinuria (3.3%).
RELAY:

The most common adverse reactions (all Grades) observed in patients treated with CYRAMZA with erlotinib at a rate of ≥ 5% and ≥2% higher than placebo with erlotinib were infections (81% vs 76%), diarrhea (70% vs 71%), hypertension (45% vs 12%), stomatitis (42% vs 36%), alopecia (34% vs 20%), epistaxis (34% vs 12%), proteinuria (34% vs 8%), peripheral edema (23% vs 4%), headache (15% vs 7%), gastrointestinal hemorrhage (10% vs 3%), gingival bleeding (9% vs 1%), and pulmonary hemorrhage (7% vs 2%).
The most common serious adverse reactions with CYRAMZA with erlotinib were pneumonia (3.2%), cellulitis (1.8%), and pneumothorax (1.8%). Red blood cell transfusions were given to 3.2% of CYRAMZA-treated patients versus 0 patients who received placebo.
Treatment discontinuation of all study drugs due to adverse reactions occurred in 13% of CYRAMZA with erlotinib-treated patients, with increased alanine aminotransferase (1.4%) and paronychia (1.4%) being the most common. The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (8.6%) and hyperbilirubinemia (6%).
Of the 221 patients who received CYRAMZA with erlotinib, 119 (54%) were 65 and over, while 29 (13%) were 75 and over. Adverse reactions occurring at a 10% or higher incidence in patients receiving CYRAMZA with erlotinib and with a 10% or greater difference between patients aged 65 or older compared to patients aged less than 65 years were: diarrhea (75% versus 65%), hypertension (50% versus 40%), increased ALT (49% versus 35%), increased AST (49% versus 33%), stomatitis (46% versus 36%), decreased appetite (32% versus 19%), dysgeusia (23% versus 12%), and weight loss (19% versus 6%).
RAISE:

The most common adverse reactions (all Grades) observed in patients treated with CYRAMZA with FOLFIRI at a rate of ≥5% and ≥2% higher than placebo with FOLFIRI were diarrhea (60% vs 51%), neutropenia (59% vs 46%), decreased appetite (37% vs 27%), epistaxis (33% vs 15%), stomatitis (31% vs 21%), thrombocytopenia (28% vs 14%), hypertension (26% vs 9%), peripheral edema (20% vs 9%), proteinuria (17% vs 5%), palmar-plantar erythrodysesthesia syndrome (13% vs 5%), gastrointestinal hemorrhage events (12% vs 7%), and hypoalbuminemia (6% vs 2%). Twenty percent of patients treated with CYRAMZA with FOLFIRI received granulocyte colony- stimulating factors.
The most common serious adverse reactions with CYRAMZA with FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%).
Treatment discontinuation of any study drug due to adverse reactions occurred more frequently in CYRAMZA with FOLFIRI-treated patients (29%) than in placebo with FOLFIRI-treated patients (13%). The most common adverse reactions leading to discontinuation of any component of CYRAMZA with FOLFIRI as compared to placebo with FOLFIRI were neutropenia (12.5% vs 5.3%) and thrombocytopenia (4.2% vs 0.8%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (1.5%), and gastrointestinal perforation (1.7%).
Clinically relevant adverse reaction reported in ≥1% and <5% of patients receiving CYRAMZA with FOLFIRI was gastrointestinal perforation (1.7%), including 4 fatal events.
Thyroid-stimulating hormone (TSH) levels were evaluated in 224 patients (115 CYRAMZA with FOLFIRI-treated patients and 109 placebo with FOLFIRI-treated patients) with normal baseline TSH levels. Increased TSH levels were observed in 53 (46%) patients treated with CYRAMZA with FOLFIRI compared with 4 (4%) patients treated with placebo with FOLFIRI.
REACH-2:

The most common adverse reactions (all Grades) observed in single agent CYRAMZA-treated HCC patients at a rate of ≥10% and ≥2% higher than placebo were fatigue (36% vs 20%), peripheral edema (25% vs 14%), hypertension (25% vs 13%), abdominal pain (25% vs 16%), decreased appetite (23% vs 20%), proteinuria (20% vs 4%), nausea (19% vs 12%), ascites (18% vs 7%), headache (14% vs 5%), epistaxis (14% vs 3%), insomnia (11% vs 6%), pyrexia (10% vs 3%), vomiting (10% vs 7%), and back pain (10% vs 7%).
The most common serious adverse reactions with CYRAMZA were ascites (3%) and pneumonia (3%).
Treatment discontinuations due to adverse reactions occurred in 18% of CYRAMZA-treated patients, with proteinuria being the most frequent (2%).
Clinically relevant adverse reactions reported in ≥1% and <10% of CYRAMZA-treated patients in REACH-2 were IRR (9%), hepatic encephalopathy (5%) including 1 fatal event, and hepatorenal syndrome (2%) including 1 fatal event.
RB-P HCP ISI 29MAY2020

Please see full U.S. Prescribing Information for CYRAMZA.

IMPORTANT SAFETY INFORMATION FOR ERBITUX (cetuximab)

WARNING: INFUSION REACTIONS AND CARDIOPULMONARY ARREST

Infusion Reactions

ERBITUX can cause serious and fatal infusion reactions. Severe (Grades 3 and 4) infusion reactions occurred in 2.2% of patients receiving ERBITUX in clinical trials.
The risk of anaphylactic reactions may be increased in patients with a history of tick bites, red meat allergy, or in the presence of IgE antibodies directed against galactose-α-1,3-galactose (alpha-gal). Consider testing patients for alpha-gal IgE antibodies using FDA-cleared methods prior to initiating ERBITUX. Negative results for alpha-gal antibodies do not rule out the risk of severe infusion reactions.
Approximately 90% of the severe infusion reactions occurred with the first infusion of ERBITUX despite premedication with antihistamines.
Serious infusion reactions, requiring immediate medical intervention, included symptoms of rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions.
Caution must be exercised with every ERBITUX infusion as infusion reactions may occur during or several hours following completion of the infusion.
Premedicate with a histamine-1 (H1) receptor antagonist as recommended.
Monitor patients for at least 1 hour following each ERBITUX infusion in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. In patients requiring treatment for infusion reactions, monitor for more than 1 hour to confirm resolution of the reaction. Interrupt the infusion and upon recovery, resume the infusion at a slower rate or permanently discontinue ERBITUX based on severity.
Cardiopulmonary Arrest

ERBITUX can cause cardiopulmonary arrest. Cardiopulmonary arrest or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck receiving radiation therapy and ERBITUX in BONNER. In 3 patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days respectively after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. In EXTREME, fatal cardiac disorders and/or sudden death occurred in 3% of the 219 patients with squamous cell carcinoma of the head and neck treated with a cetuximab product in combination with platinum-based therapy and fluorouracil.
Carefully consider the use of ERBITUX with radiation therapy, or with platinum-based therapy with fluorouracil, in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias.
Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX therapy.
Pulmonary Toxicity

ERBITUX can cause interstitial lung disease (ILD). ILD, which was fatal in one case, occurred in <0.5% of 1570 patients receiving ERBITUX in clinical trials. Monitor patients for signs and symptoms of pulmonary toxicity. Interrupt or permanently discontinue ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD.
Dermatologic Toxicities

ERBITUX can cause dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (e.g., S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis
Acneiform rash occurred in 82% of the 1373 patients who received ERBITUX across clinical trials. Severe (Grades 3 or 4) acneiform rash occurred in 9.7% of patients. Acneiform rash usually developed within the first 2 weeks of therapy; the rash lasted more than 28 days after stopping ERBITUX in most patients.
Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has been observed in patients who received ERBITUX. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis).
Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae.
Sun exposure may exacerbate these effects. Instruct patients to limit sun exposure during ERBITUX therapy.
Withhold, reduce dose or permanently discontinue ERBITUX based on severity of acneiform rash or mucocutaneous disease.
Risks Associated with Use in Combination with Radiation and Cisplatin

ERBITUX is not indicated for the treatment of SCCHN in combination with radiation and cisplatin.
In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either ERBITUX in combination with radiation therapy and cisplatin, or radiation therapy and cisplatin alone. The addition of ERBITUX resulted in an increase in the incidence of Grade 3 and 4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone.
Adverse reactions with fatal outcome were reported in 4% of patients in the ERBITUX combination arm and 3% in the control arm.
In the ERBITUX arm, 2% experienced myocardial ischemia compared to 0.9% in the control arm.
The addition of ERBITUX to radiation and cisplatin did not improve progression-free survival (the primary endpoint).
Hypomagnesemia and Accompanying Electrolyte Abnormalities

ERBITUX can cause hypomagnesemia. Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in study CA225-025 and two other clinical trials in patients with colorectal cancer (CRC) or head and neck cancer, including Grades 3 and 4 in 6% to 17%. In EXTREME, where a cetuximab product was administered in combination with platinum-based therapy, the addition cetuximab to cisplatin and fluorouracil resulted in an increased incidence of hypomagnesemia of any grade (14%) and of Grade 3 or 4 hypomagnesemia (7%). Hypomagnesemia of any grade occurred in 4% of patients who received cetuximab, carboplatin, and fluorouracil. No patient experienced grade 3 or 4 hypomagnesemia. The onset of hypomagnesemia and accompanying electrolyte abnormalities can occur days to months after initiating ERBITUX.
Monitor patients weekly during treatment for hypomagnesemia, hypocalcemia, and hypokalemia, and for at least 8 weeks following the completion of ERBITUX.
Replete electrolytes as necessary.
Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with Ras–Mutant mCRC

ERBITUX is not indicated for the treatment of patients with CRC that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either K-Ras or N-Ras and hereafter referred to as "Ras" or when the Ras status is unknown.
Retrospective subset analyses of Ras-mutant and wild-type populations across several randomized clinical trials, including CRYSTAL, were conducted to investigate the role of Ras mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies. Use of cetuximab in patients with Ras mutations resulted in no clinical benefit with treatment related toxicity. Confirm Ras mutation status in tumor specimens prior to initiating ERBITUX.
Embryo-Fetal Toxicity

Based on animal data and its mechanism of action, ERBITUX can cause fetal harm when administered to a pregnant woman. There are no available data for ERBITUX exposure in pregnant women. In an animal reproduction study, intravenous administration of cetuximab once weekly to pregnant cynomolgus monkeys during the period of organogenesis resulted in an increased incidence of embryolethality and abortion. Disruption or depletion of EGFR in animal models results in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ERBITUX and for 2 months after the last dose of ERBITUX. Verify pregnancy status in females of reproductive potential prior to initiating ERBITUX.
Adverse Reactions

The most common adverse reactions in ERBITUX clinical trials (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.
The most common adverse reactions (all grades; incidence ≥25%) seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (BONNER) were acneiform rash (87% vs 10%), radiation dermatitis (86% vs 90%), weight loss (84% vs 72%), asthenia (56% vs 49%), nausea (49% vs 37%), increased alanine transaminase (43% vs 21%), increased aspartate transaminase (38% vs 24%), increased alkaline phosphatase (33% vs 24%), fever (29% vs 13%), emesis (29% vs 23%), pharyngitis (26% vs 19%) and dehydration (25% vs 19%). The most common grade 3 and 4 adverse reactions for ERBITUX in combination with radiation therapy (≥10%) versus radiation alone included: radiation dermatitis (23% vs 18%), acneiform rash (17% vs 1%), and weight loss (11% vs 7%). The overall incidence of late radiation toxicities (any grade) was higher for patients receiving ERBITUX in combination with radiation therapy, versus radiation therapy alone. The following sites were affected: salivary glands (65% vs 56%), larynx (52% vs 36%), subcutaneous tissue (49% vs 45%), mucous membrane (48% vs 39%), esophagus (44% vs 35%), skin (42% vs 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between radiation therapy alone and the ERBITUX with radiation treatment groups.
The most common adverse reactions (all grades; incidence ≥25%) seen in patients with carcinomas of the head and neck receiving a cetuximab product in combination with platinum-based therapy and fluorouracil (CT) (n=219) versus CT alone (n=215) (EXTREME) were acneiform rash (70% vs 2%), nausea (54% vs 47%), infection (44% vs 27%), rash (28% vs 2%), diarrhea (26% vs 16%) and anorexia (25% vs 14%). The most common grade 3 and 4 adverse reactions for a cetuximab product in combination with CT (≥10%) versus CT alone was infection (11% vs 8%). Because ERBITUX provides approximately 22% higher exposure relative to the cetuximab product used in EXTREME, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX.
The most common adverse reactions (all grades; incidence ≥25%) seen in patients with K-Ras wild-type, EGFR-expressing mCRC treated with a cetuximab product in combination with FOLFIRI (n=317) versus FOLFIRI alone (n=350) (CRYSTAL) were acne-like rash (86% vs 13%), diarrhea (66% vs 60%), neutropenia (49% vs 42%), rash (44% vs 4%), stomatitis (31% vs 19%), anorexia (30% vs 23%), dermatitis acneiform (26% vs <1%) and pyrexia (26% vs 14%). The most common grade 3 and 4 adverse reactions (≥10%) included: neutropenia (31% vs 24%), acne-like rash (18% vs <1%), and diarrhea (16% vs 10%). ERBITUX provides approximately 22% higher exposure compared to the cetuximab product used in CRYSTAL; however, the safety data from CRYSTAL is consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication.
The most common adverse reactions (all grades; incidence ≥25%) seen in patients with K-Ras wild-type, EGFR-expressing mCRC treated with ERBITUX + best supportive care (BSC) (n=118) versus BSC alone (n=124) (CA225-025) were rash/desquamation (95% vs 21%), fatigue (91% vs 79%), nausea (64% vs 50%), pain-other (59% vs 37%), dry skin (57% vs 15%), constipation (53% vs 38%), dyspnea (49% vs 44%), pruritis (47% vs 11%), neuropathy-sensory (45% vs 38%), diarrhea (42% vs 23%), vomiting (40% vs 26%), headache (38% vs 11%), infection without neutropenia (38% vs 19%), other-dermatology (35% vs 7%), stomatitis (32% vs 10%), nail changes (31% vs 4%), cough (30% vs 19%), insomnia (27% vs 13%) and fever (25% vs 16%). The most common grade 3 and 4 adverse reactions (≥10%) included: fatigue (31% vs 29%), pain-other (18% vs 10%), rash/desquamation (16% vs 1%), dyspnea (16% vs 13%), other-gastrointestinal (12% vs 5%), and infection without neutropenia (11% vs 5%).
The most common adverse reactions (all grades) seen in patients with EGFR-expressing recurrent mCRC (n=354) treated with ERBITUX plus irinotecan in clinical trials (CP02-9923 and BOND) were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3-4 adverse reactions included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%)
Use in Specific Populations

Lactation: There is no information regarding the presence of ERBITUX in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG antibodies can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, advise women not to breastfeed during treatment with ERBITUX and for at least 2 months after the last dose of ERBITUX.
Pediatric Use: The safety and effectiveness of ERBITUX in pediatric patients have not been established. No new safety signals were identified in pediatric patients when ERBITUX in combination with irinotecan was administered in an open-label, single-arm dose-finding study in 27 patients with refractory solid tumors aged 1 to 12 years old and in 19 patients aged 13 to 18 years old.
Geriatric Use: In mCRC clinical studies, no overall differences in safety or efficacy of ERBITUX were observed between patients >65 years of age and younger patients. In SCCHN clinical studies of ERBITUX there were insufficient number of patients >65 years of age to determine whether they respond differently from younger patients.
CE HCP ISI_ALL 17NOV2020

Please see full U.S. Prescribing Information for ERBITUX, including Boxed Warnings regarding infusion reactions and cardiopulmonary arrest.

About Lilly Oncology
For more than 50 years, Lilly has been dedicated to delivering life-changing medicines and support to people living with cancer and those who care for them. Lilly is determined to build on this heritage and continue making life better for all those affected by cancer around the world. To learn more about Lilly’s commitment to people with cancer, please visit www.LillyOncology.com.

About Loxo Oncology at Lilly
Loxo Oncology at Lilly was created in December 2019, combining the Lilly Research Laboratories oncology organization and Loxo Oncology, which was acquired by Lilly in early 2019. Loxo Oncology at Lilly brings together the focus and spirit of a biotech with the scale and resources of large pharma, with the goal of rapidly delivering impactful new medicines for people with cancer. Our approach centers on creating new oncology medicines that unequivocally work early in clinical development and will matter to patients.