On September 11, 2022 Eisai (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") and Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside of the United States and Canada) reported the first presentation of results from the final analysis of the Phase 3 LEAP-002 trial investigating LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, plus KEYTRUDA, the anti-PD-1 therapy from Merck & Co., Inc., Rahway, NJ, USA versus LENVIMA monotherapy, as a first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC) (Press release, Eisai, SEP 11, 2022, View Source [SID1234619389]). Results are being presented during a proffered paper session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022, being held in Paris, France and virtually from Sept. 9-13 (abstract #LBA34).

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In the final analysis of the trial, there was a trend toward improvement for one of the study’s dual primary endpoints, overall survival (OS), for patients treated with LENVIMA plus KEYTRUDA versus LENVIMA monotherapy; however, the results did not meet statistical significance per the pre-specified statistical plan (HR=0.84 [95% CI: 0.71-1.00]; p=0.0227). The median OS was 21.2 months (95% CI: 19.0-23.6) for LENVIMA plus KEYTRUDA and 19.0 months (95% CI: 17.2-21.7) for LENVIMA monotherapy. Additionally, treatment with LENVIMA plus KEYTRUDA resulted in a trend toward improvement in the trial’s other dual primary endpoint of progression-free survival (PFS) versus LENVIMA monotherapy; however, the results did not meet the pre-specified threshold at the first interim analysis for statistical significance (HR=0.87 [95% CI: 0.73-1.02]; p=0.0466).

"The LEAP-002 trial reflects our research strategy to build on evolving standards of care to further improve outcomes for more people with unresectable hepatocellular carcinoma," said Dr. Gregory Lubiniecki, Vice President, Global Clinical Development, Merck & Co., Inc., Rahway, NJ, USA Research Laboratories. "The median overall survival of 21.2 months seen with KEYTRUDA plus LENVIMA provides critical insights for further research into the potential role of this combination."

"While the outcome is not what we had hoped, it is important for us to see that patients in the trial treated with LENVIMA monotherapy had a median overall survival of 19.0 months," said Corina Dutcus, M.D., Senior Vice President, Clinical Research, Oncology at Eisai Inc. "Findings from the LEAP-002 trial will not only help advance our understanding and application of LENVIMA plus KEYTRUDA across our clinical development program but will also provide physicians with additional information on LENVIMA monotherapy’s use in unresectable hepatocellular carcinoma, where it is currently approved as a treatment option in multiple regions around the world, including the U.S., the European Union (EU), Japan and China."

LENVIMA monotherapy is approved for the first-line treatment of patients with uHCC in the U.S., the EU and China and for patients with uHCC in Japan. The approval of LENVIMA was based on results of the Phase 3 REFLECT trial, which evaluated the efficacy and safety of LENVIMA versus sorafenib for the first-line treatment of patients with uHCC.

LENVIMA (marketed as KISPLYX for renal cell carcinoma [RCC] in the EU) plus KEYTRUDA is approved in the U.S., the EU and Japan for the treatment of certain types of advanced endometrial carcinoma and advanced RCC. Eisai and Merck & Co., Inc., Rahway, NJ, USA are studying the LENVIMA plus KEYTRUDA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in multiple tumor types, including but not limited to endometrial carcinoma, HCC, melanoma, non-small cell lung cancer, RCC, head and neck cancer, colorectal cancer, gastric cancer and esophageal cancer, across more than 15 clinical trials.

LEAP-002 study design and final analysis results (abstract #LBA34)

LEAP-002 is a multicenter, randomized, double-blinded, active-controlled Phase 3 trial (ClinicalTrials.gov, NCT03713593(New Window)) evaluating LENVIMA plus KEYTRUDA versus LENVIMA monotherapy for the first-line treatment of adult patients with uHCC. Patients were randomized 1:1 to receive LENVIMA (12 mg orally once daily [for patients with screening body weight of at least 60 kg] or 8 mg orally once daily [for patients with screening body weight less than 60 kg]) plus KEYTRUDA (200 mg intravenously [IV] on Day 1 of each three-week cycle); or LENVIMA (12 mg orally once daily [for patients with screening body weight of at least 60 kg] or 8 mg orally once daily [for patients with screening body weight less than 60 kg]) plus saline placebo (IV administered on Day 1 of each three-week cycle). LENVIMA was administered until progressive disease or unacceptable toxicity. KEYTRUDA/placebo was administered for up to 35 cycles (approximately two years).

The dual primary endpoints were PFS, as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1; RECIST v1.1 has been modified for this study to follow a maximum of 10 target lesions in total and a maximum of five target lesions per organ), and OS. Objective response rate (ORR), as assessed by BICR per RECIST v1.1, was a key secondary endpoint. The trial was designed with two interim analyses and a final analysis for OS. Pre-specified efficacy boundaries were one-sided p=0.002 for PFS at interim analysis 1 and p=0.0185 for OS at the final analysis.

As of the data cut-off for the final analysis (June 21, 2022), a total of 794 patients were enrolled and treated, with a median follow-up of 32.1 months (range, 25.8-41.1). A total of 534 OS events had occurred, with 36 patients (9.1%) in the combination arm and 24 patients (6.1%) in the LENVIMA monotherapy arm remaining on study treatment.

The median OS was 21.2 months (95% CI: 19.0-23.6) for LENVIMA plus KEYTRUDA versus 19.0 months (95% CI: 17.2-21.7) for LENVIMA monotherapy at the final analysis. The median PFS was 8.2 months (95% CI, 6.4-8.4) for LENVIMA plus KEYTRUDA versus 8.0 months (95% CI: 6.3-8.2) for LENVIMA monotherapy at the first interim analysis and 8.2 months (95% CI: 6.3-8.3) versus 8.1 months (95% CI: 6.3-8.3), respectively, at the final analysis. The ORR was 26.1% (95% CI: 21.8-30.7) for LENVIMA plus KEYTRUDA versus 17.5% (95% CI: 13.9-21.6) for LENVIMA monotherapy at the final analysis. Median duration of response was 16.6 months (range, 2.0+ to 33.6+) in the KEYTRUDA plus LENVIMA arm versus 10.4 months (range, 1.9 to 35.1+) in the LENVIMA monotherapy arm at the final analysis.

The safety profile of LENVIMA plus KEYTRUDA was consistent with previously reported data on the combination. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 61.5% of patients treated with LENVIMA plus KEYTRUDA versus 56.7% of patients treated with LENVIMA monotherapy. Grade 5 TRAEs occurred in 1.0% of patients treated with LENVIMA plus KEYTRUDA versus 0.8% of patients treated with LENVIMA monotherapy. In patients treated with LENVIMA plus KEYTRUDA, the five most common TRAEs of any grade were hypertension (43.3%), diarrhea (40.3%), hypothyroidism (40.0%), palmar-plantar erythrodysesthesia (PPE) syndrome (33.2%) and proteinuria (30.6%). In patients treated with LENVIMA monotherapy, the five most common TRAEs of any grade were hypertension (46.8%), hypothyroidism (35.7%), proteinuria (34.9%), diarrhea (33.9%) and PPE syndrome (30.6%). Post-study systematic anti-cancer treatments were given for 44.1% of patients receiving LENVIMA plus KEYTRUDA versus 52.1% of those receiving LENVIMA monotherapy.

About hepatocellular carcinoma (HCC)

Hepatocellular carcinoma is the most common type of primary liver cancer1 and the most rapidly increasing cause of cancer deaths in the United States.2 Hepatocellular carcinoma accounts for approximately 90% of primary liver cancers.3 It is estimated there were more than 905,000 new cases of liver cancer and more than 830,000 deaths from the disease globally in 2020,4 making it the sixth most frequently diagnosed cancer worldwide5 and one of the leading causes of cancer deaths around the world. In Japan, it is estimated there were more than 45,000 new cases of liver cancer diagnosed and more than 28,000 deaths from this disease in 2020.6 In the United States, it is estimated there will be over 41,000 new cases of liver cancer and over 30,000 deaths from this disease in 2022.5 Risk factors for liver cancer include gender, ethnicity, chronic viral hepatitis (Hep-B or Hep-C) infection, cirrhosis, alcohol use and metabolic syndrome.7 Hepatocellular carcinoma, which is often diagnosed at an advanced stage,8 has a five-year survival rate of approximately 20% in the United States.9

About LENVIMA (lenvatinib) Capsules

LENVIMA, discovered and developed by Eisai, is an orally available multiple receptor tyrosine　kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. In syngeneic mouse tumor models, LENVIMA decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone. LENVIMA has been approved for the indications below.

Thyroid cancer

・Indication as monotherapy

(Approved in over 80 countries including Japan, the United States, China, and countries in Europe and Asia)

Japan: Radically unresectable thyroid cancer

The United States: The treatment of patients with locally recurrent or metastatic, progressive, radioiodine-refractory differentiated thyroid cancer (DTC)

Europe: The treatment of adult patients with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine (RAI)

Hepatocellular carcinoma

・Indication as monotherapy

(Approved in over 80 countries including Japan, the United States, China, and countries in Europe and Asia)

Japan: Unresectable hepatocellular carcinoma

The United States: The first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)

Europe: The treatment of adult patients with advanced or unresectable hepatocellular carcinoma (HCC) who have received no prior systemic therapy

Thymic carcinoma

・Indication as monotherapy (Approved in Japan)

Japan: Unresectable thymic carcinoma

Renal cell carcinoma (In Europe, the agent was launched under the brand name Kisplyx)

・Indication in combination with everolimus

(Approved in over 65 countries including the United States, and countries in Europe and Asia)

The United States: The treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy

Europe: The treatment of adult patients with advanced renal cell carcinoma following one prior vascular endothelial growth factor (VEGF) targeted therapy

・Indication in combination with KEYTRUDA (generic name: pembrolizumab)

(Approved in over 40 countries including Japan, the United States, and countries in Europe and Asia)

Japan: Radically unresectable or metastatic renal cell carcinoma

The United States: The first-line treatment of adult patients with advanced renal cell carcinoma

Europe: The first-line treatment of adult patients with advanced renal cell carcinoma

Endometrial carcinoma

・Indication in combination with KEYTRUDA

(Approved [including conditional approval] in over 45 countries including Japan, the United States, and countries in Europe and Asia)

Japan: Unresectable, advanced or recurrent endometrial carcinoma that progressed after cancer chemotherapy

The United States: The treatment of patients with advanced endometrial carcinoma (EC) that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Europe: The treatment of adult patients with advanced or recurrent endometrial carcinoma (EC) who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and are not candidates for curative surgery

About KEYTRUDA (pembrolizumab) Injection, 100mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck & Co., Inc., Rahway, NJ, USA has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

About Eisai and the Merck & Co., Inc., Rahway, NJ, USA Collaboration

In March 2018, Eisai and Merck & Co., Inc., Rahway, NJ, USA, known as MSD outside the United States and Canada, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies will jointly develop, manufacture and commercialize LENVIMA, both as monotherapy and in combination with KEYTRUDA, the anti-PD-1 therapy from Merck & Co., Inc., Rahway, NJ, USA.

In addition to ongoing clinical studies evaluating the LENVIMA plus KEYTRUDA combination across several different tumor types, the companies have jointly initiated new clinical studies through the LEAP (LEnvatinib And Pembrolizumab) clinical program and are evaluating the combination in multiple tumor types across more than 15 clinical trials.

Eisai’s Focus on Cancer

Eisai focuses on the development of anticancer drugs, targeting the tumor microenvironment (with experience and knowledge from existing in-house discovered compounds) and the driver gene mutation and aberrant splicing (leveraging RNA Splicing Platform) as areas (Ricchi) where real patient needs are still unmet, and where Eisai can aim to become a frontrunner in oncology. Eisai aspires to discover innovative new drugs with new targets and mechanisms of action from these Ricchi, with the aim of contributing to the cure of cancers.

On September 11, 2022 I-Mab (the "Company") ( Nasdaq: IMAB), a clinical-stage biopharmaceutical company committed to the discovery, development, and commercialization of novel biologics, reported encouraging data from its Phase 2 clinical trial (NCT04202003) of lemzoparlimab (also known as TJC4) in combination with azacitidine (AZA) in patients with newly diagnosed higher risk myelodysplastic syndrome (HR-MDS), presented in an oral presentation on September 10 at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 (Press release, I-Mab Biopharma, SEP 11, 2022, View Source [SID1234619384]).

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The open-labeled Phase 2 clinical trial is designed to investigate the efficacy and safety of lemzoparlimab in combination with AZA in patients with newly diagnosed HR-MDS. A total of 53 patients were enrolled as of March 31, 2022, receiving lemzoparlimab at a weekly dose of 30 mg/kg intravenously (IV) and AZA at 75 mg/m2 subcutaneously (SC) on Days 1–7 in a 28-day cycle.

Top-line data showed that for patients who began treatments 6 months or longer prior to the analysis (n=15), the overall response rate (ORR) and complete response rate (CRR) was 86.7% and 40% respectively. For patients who began treatment 4 months or longer prior to the analysis (n=29), the ORR and CRR was 86.2% and 31% respectively. While the study enrolled more patients with worse baseline conditions due to underlying disease (74% of patients had grade ≥3 anemia and 51% of patients had grade ≥3 thrombocytopenia), the results showed that lemzoparlimab combined with AZA was well-tolerated and the safety profile was consistent with AZA monotherapy.

Decreased red blood cells, measured as hemoglobin, and decreased platelets are major causes of morbidity for patients with HR-MDS and the median hemoglobin and platelet levels for patients on study increased in response to treatment. Of the 29 patients who were dependent upon blood transfusions at baseline, 9 patients (31%) became transfusion independent at the time of analysis. Furthermore, the majority of CR patients showed reduction in variant allele frequency (VAF) of MDS-related gene mutation including TP53, TET2 and RUNX1, with 56% achieving minimal residual disease negativity (≤10-4) by flow cytometry. These data are consistent with the anti-leukemic activities and expected drug safety of lemzoparlimab.

"Without the need of priming dose, the latest Phase 2 data show clinically meaningful efficacy of lemzoparlimab treatment in combination with AZA among patients with newly diagnosed HR-MDS," said Prof. Zhijian Xiao, Professor at Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences, and leading principal investigator of the study. "The results are encouraging and provide further clinical validation to the promise of lemzoparlimab as a potential best-in-class CD47 antibody, especially for patients with HR-MDS or who are unfit for intensive therapy."

"The clinical activity seen with lemzoparlimab in combination with AZA thus far, in addition to the favorable safety profile, continues to show promise in this difficult-to-treat patient population," said Prof. Chunkang Chang, Director of Hematology Department of Shanghai Sixth People’s Hospital, and leading principal investigator of the study. "Lemzoparlimab represents a potentially important novel treatment option for patients with HR-MDS as well as many other hematological malignancies. We’re very enthusiastic about the results to date and look forward to advancing the trial and broadening its application into other malignancies."

"We are excited about the topline data of lemzoparlimab in HR-MDS selected for proffered oral presentation at ESMO (Free ESMO Whitepaper) Congress 2022," said Dr. Andrew Zhu, President of I-Mab. "The Phase 2 clinical data demonstrated a good safety profile, along with promising efficacy, and underscored I-Mab’s commitment to bring transformational therapies to patients in need. These results warrant our focused efforts to advance lemzoparlimab towards initiation of a Phase 3 registrational trial."

The Company is on track to initiate a Phase 3 clinical trial in patients with MDS in China.

About CD47 and Lemzoparlimab

CD47 is a cell surface protein over-expressed in a wide variety of cancers and can act to protect tumors by delivering a "don’t eat me" signal to otherwise tumor-engulfing macrophages. CD47 antibody blocks this signal and enables macrophages to attack tumor cells. However, development of CD47 antibody as a cancer therapy has been hampered by its hematologic side effects, such as severe anemia, caused by natural binding of CD47 antibody to red blood cells. Scientists at I-Mab discovered a novel CD47 antibody, lemzoparlimab, that is designed to target tumor cells while exerting a minimal untoward effect on red blood cells.

Multiple clinical studies of lemzoparlimab are ongoing to explore indications in treating patients with myelodysplastic syndrome (MDS), acute myelocytic leukemia (AML), non-Hodgkin’s lymphoma (NHL), and advanced solid tumors in combination with chemotherapy and immune checkpoint inhibitors.

On September 11, 2022 IDEAYA Biosciences, Inc. ( Nasdaq:IDYA), a synthetic lethality focused precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported that interim results from its Phase 2 clinical trial evaluating darovasertib and crizotinib synthetic lethal combination in metastatic uveal melanoma (MUM) patients (ClinicalTrials.gov Identifier: NCT03947385) (Press release, Ideaya Biosciences, SEP 11, 2022, View Source [SID1234619383]).

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"The confirmed partial responses and high percentage of patients with tumor shrinkage shown in these interim Phase 2 data are extremely encouraging for patients with metastatic uveal melanoma. The 50% overall response rate and greater than 5 months median progression free survival observed in first-line MUM patients reflects the potential for a compelling clinical efficacy profile irrespective of haplotype (HLA-A*02:01) status. The partial responses shown in first-line and any-line MUM patients are clinically significant and build on previously-reported results for any-line MUM patients, now with a larger patient data set," said Dr. Marlana Orloff, M.D., Associate Professor, Sidney Kimmel Cancer Center, Jefferson Health.

"The clinical efficacy observed in first-line patients in these interim Phase 2 data presents an opportunity to pursue a front-line strategy and provides a rationale for a potential registration-enabling clinical trial in MUM," said Dr. Matt Maurer, M.D., Vice President, Head of Clinical Oncology and Medical Affairs, IDEAYA Biosciences.

There are currently no FDA approved therapies for GNAQ and GNA11 solid tumors, and current therapies for MUM have relatively low objective response rates and short median progression free survival (PFS), highlighting the high unmet medical need. Approximately 90% of MUM has either a GNAQ or GNA11 mutation that activates the protein kinase C (PKC) signaling pathway. The historical overall response rate (ORR) in MUM clinical trials has generally been reported with an ORR ranging from approximately 0 to 5%, including: pembrolizumab and tebentafusp (each ~5%); MEK inhibitor selumetinib in combination with dacarbazine (~3%); and cMET inhibitor cabozantinib monotherapy (~0%). In addition, the historical median PFS in MUM clinical trials has been reported ranging from approximately 2.0 to 2.8 months, including: tebentafusp (~2.8 months, IMCgp100-102 study); MEK inhibitor selumetinib in combination with dacarbazine (~2.8 months); and cMET inhibitor cabozantinib monotherapy (~2.0 months).

Darovasertib (IDE196) is a small molecule, potential first-in-class protein kinase C (PKC) inhibitor. IDEAYA is evaluating the synthetic lethal combination of darovasertib and crizotinib, a small molecule cMET inhibitor, in MUM and other GNAQ/11 tumors pursuant to a clinical trial collaboration and drug supply agreement with Pfizer.

Clinical Data Update – Darovasertib and Crizotinib Combination in MUM
The interim Phase 2 clinical data update is based on an initial thirty-seven (37) patients enrolled in the darovasertib and crizotinib combination study at the expansion dose of 300mg twice-a-day darovasertib and 200mg twice-a-day crizotinib, as of the data analysis cutoff date of June 26, 2022. Out of the thirty-seven (37) patients enrolled, there were thirty-five (35) evaluable patients and two (2) non-evaluable patients. The two (2) non-evaluable patients were both pretreated and withdrew from the trial prior to the first scan. Neither of the two non-evaluable patients progressed due to disease: one (1) patient withdrew consent and one (1) patient discontinued early due to fatigue. Reported data are preliminary and based on an unlocked database as of the data analyses cutoff date, except one confirmatory scan after the data cutoff date or as otherwise noted. Enrollment in the darovasertib and crizotinib combination expansion dose cohort of the clinical trial is ongoing.

The company observed encouraging clinical activity in Phase 2 clinical trial evaluating darovasertib and crizotinib synthetic lethal combination in metastatic uveal melanoma (MUM) patients in the expansion dose cohort. These investigator-reviewed data by RECIST 1.1 include:

89% of Patients show Tumor Shrinkage in Any-Line MUM: 31 of 35 evaluable patients showed tumor shrinkage as determined by target lesion size reduction
83% Disease Control Rate (DCR) in Any-Line MUM: 29 of 35 evaluable patients showed stable disease or better as determined by target lesion size reduction
50% Overall Response Rate (ORR) in First-Line MUM: 4 of 8 evaluable patients had a confirmed partial response (PR)
31% Overall Response Rate (ORR) in Any-Line MUM: 11 of 35 evaluable patients had a confirmed partial response (PR)
43% of Patients with >30% Tumor Reduction in Any-Line MUM: 15 of 35 evaluable patients observed partial responses with >30% tumor reduction, including 11 confirmed and 4 unconfirmed partial responses
Median Study Follow-Up of 6.5 months for First-Line MUM patients and 7.8 months for Any-Line MUM patients
Median Duration of Response (DOR) in evaluable First-Line MUM patients has not yet been reached and 4 of 4 patients with confirmed PR’s in First-Line MUM remain in response; median DOR in evaluable Any-Line MUM patients has not yet been reached and 7 of 11 patients with confirmed PR’s in Any-Line MUM remain in response
Median Progression Free Survival (PFS) in First-Line MUM patients has not yet been reached and is >5 months in evaluable First-Line MUM patients; median PFS for evaluable Any-Line MUM patients is ~ 5 months
These data provide robust clinical proof-of-concept for the efficacy of the darovasertib and crizotinib synthetic lethal combination treatment.

The darovasertib and crizotinib combination therapy has a manageable adverse event profile in MUM patients (n=37), with a low rate of drug-related serious adverse events (SAE’s). Patients reported predominantly Grade 1 or 2 drug-related adverse events: all patients experienced a drug-related AE, of which 76% were reported as Grade 1 or 2 and 24% were reported as Grade 3. No patients observed Grade 4 or Grade 5 AE’s. One patient discontinued treatment due to a drug-related adverse event.

The potentially addressable patient population for metastatic uveal melanoma is estimated to include over 4,000 patients across US and Europe, based on estimated annual incidence. As an orally-administered small molecule precision medicine therapeutic, with demonstrated anti-tumor activity and manageable adverse event profile, the company considers the darovasertib and crizotinib combination therapy to have the potential to be broadly impactful to the MUM patient population.

IDEAYA is currently targeting to initiate a potential registration-enabling trial in Q1 2023. The company is evaluating first-line MUM as a potential registrational regulatory strategy. As of August 31, 2022, IDEAYA has enrolled 21 first-line MUM patients at the expansion dose of the darovasertib and crizotinib combination study.

Darovasertib – (Neo)Adjuvant Uveal Melanoma and Other Potential Expansion Opportunities
IDEAYA is also evaluating the potential for darovasertib in other oncology indications, including as (neo)adjuvant therapy in primary uveal melanoma (UM), in cMET-driven tumors and in KRAS-mutation tumors.

(Neo)Adjuvant UM represents a significant expansion opportunity for darovasertib – with a potential annual incidence of approximately 8,700 patients aggregate in US and Europe.

The company has observed preliminary proof of concept for potential darovasertib use in the (neo)adjuvant uveal melanoma setting, including responses of the primary orbital tumor. Clinical data reflects an observed tumor shrinkage by investigator review of primary ocular lesions in 5 of 5 (100%) UM or MUM patients treated as monotherapy or in combination with Crizotinib, including preliminary observation of tumor reductions in uvea lesion of two patients after the data cut-off date of August 19, 2022:

a darovasertib monotherapy patient with metastatic disease and an intact primary lesion in the eye observed a reduction of approximately 74% in the eye lesion by PET Standard Uptake Value (SUV) at an initial scan after approximately 2 weeks on therapy, with observed improvement in visual symptoms in the affected eye; this patient remained on therapy for approximately 7 months;
a darovasertib and crizotinib combination patient with metastatic disease and an intact primary lesion in the eye observed tumor shrinkage of approximately 67% by RECIST 1.1 as a contribution to an overall confirmed PR, with improvement in visual symptoms in the affected eye; this patient is continuing on therapy as of approximately 5 months; a second darovasertib and crizotinib combination MUM patient with an intact primary lesion observed a reduction of the ocular lesion based on preliminary scan after the data cut-off date; and
a darovasertib monotherapy neoadjuvant uveal melanoma patient with a primary ocular lesion observed a reduction of approximately 20% by RECIST 1.1 at the first scan after 27 days on therapy, with an observed decrease in ocular vasculature; a second darovasertib monotherapy neoadjuvant UM patient observed a reduction in the primary ocular lesion based on preliminary scan after the data cut-off date; these two patients are enrolled in the NADOM IST and are continuing on therapy as of approximately 1 month.
"I am excited to explore the potential for darovasertib as a (neo)adjuvant approach for the treatment of uveal melanoma patients. The observed clinical experience provides a basis for clinical investigation to evaluate whether darovasertib, can improve current primary treatment paradigms, which typically include radiotherapies and/or enucleation of the eye," said Dr. Marcus Butler, Medical Oncologist, Tumor Immunotherapy Program, Melanoma/Skin Oncology Site Lead at Princess Margaret Cancer Centre in Toronto, Canada, and Ocular Melanoma Physician Task Force of Canada Co-Lead.

IDEAYA is supporting St. Vincent’s Hospital Sydney Limited, which has initiated an Investigator Sponsored Trial, or IST, captioned as the "Neoadjuvant / Adjuvant trial of Darovasertib in Ocular Melanoma" (NADOM) study, to evaluate darovasertib monotherapy in a neo-adjuvant and adjuvant setting in primary UM patients. IDEAYA is targeting initiation of a company-sponsored clinical trial in Q4 2022 to further evaluate darovasertib monotherapy in (neo)adjuvant uveal melanoma, and is evaluating potential near-term clinical endpoints such as vision and organ preservation.

IDEAYA Investor Webcast and Conference Call
IDEAYA will host an investor webcast and conference tomorrow morning, September 12, 2022 at 8:00 am ET, to present darovasertib and crizotinib Phase 2 interim clinical efficacy and tolerability data, as well as clinical landscape, potential registrational strategies and expansion opportunities.

Presenters at the investor webcast and conference call will include Dr. Marlana Orloff, M.D., Associate Professor, Sidney Kimmel Cancer Center, Jefferson Health, and Dr. Marcus Butler, Medical Oncologist, Tumor Immunotherapy Program, Melanoma/Skin Oncology Site Lead at Princess Margaret Cancer Centre in Toronto, Canada, and Ocular Melanoma Physician Task Force of Canada Co-Lead, each of whom are key opinion leaders and clinical investigators. Yujiro S. Hata, President and Chief Executive Officer, and other members of the IDEAYA management team will also present.

IDEAYA’s darovasertib investor webcast presentation, as well as an updated corporate presentation, will be available on the company’s website, at its Investor Relations portal (View Source) in advance of the investor webcast presentation at approximately 6:00 am ET.

Corporate Updates
IDEAYA had cash, cash equivalents and marketable securities of approximately $324 million as of June 30, 2022, which it currently projects will be sufficient to fund its planned operations into 2025.

On September 11, 2022 Amgen (NASDAQ: AMGN) reported detailed results from the global Phase 3 CodeBreaK 200 trial, which showed once-daily oral LUMAKRAS/LUMYKRAS (sotorasib) led to significantly superior progression-free survival (PFS; primary endpoint) and a significantly higher objective response rate (ORR; a key secondary endpoint) in patients with KRAS G12C-mutated non small cell lung cancer (NSCLC), compared with intravenous chemotherapy, docetaxel (Press release, Amgen, SEP 11, 2022, View Source [SID1234619382]). These data will be presented Monday, Sept. 12 at 5:20 p.m. CEST at the Presidential Symposium III session as a late-breaker oral presentation (#LBA5812) during the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 in Paris.

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"The totality of evidence from this study supports LUMAKRAS as an important targeted treatment option for patients with non-small cell lung cancer who harbor the KRAS G12C mutation, and reinforces the critical need for comprehensive biomarker testing for all patients with advanced disease," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "We plan to submit this data to health authorities around the world where LUMAKRAS/LUMYKRAS is conditionally approved, and we look forward to our discussions with regulators."

LUMAKRAS significantly improved PFS as determined by Blinded Independent Central Review (BICR) compared to docetaxel in heavily pre-treated patients (HR, 0.66 [95% CI: 0.51, 0.86]; P = 0.002), and PFS favored LUMAKRAS across all clinically relevant subgroups. The proportion of patients with PFS at one year was 25% for LUMAKRAS versus 10% for docetaxel. LUMAKRAS demonstrated a significantly higher ORR than docetaxel with double the response rates in the LUMAKRAS arm (28% versus 13%, respectively; P < 0.001) and showed consistent benefit across other efficacy secondary endpoints, including improved disease control rate (DCR; 83% versus 60%, respectively). Overall survival (OS; a key secondary endpoint) was not significantly different between treatment arms. The study was not powered to detect a statistical difference in OS, and cross-over from docetaxel to LUMAKRAS was permitted after disease progression.

There were fewer treatment-related adverse events (TRAEs) for LUMAKRAS versus docetaxel. Grade ≥ 3 TRAEs (33% LUMAKRAS; 40% docetaxel) and serious TRAEs (11% LUMAKRAS; 23% docetaxel) were lower with LUMAKRAS compared to docetaxel. The most common TRAEs reported by at least 15% of patients in either treatment group were diarrhea (34% LUMKRAS; 19% docetaxel), fatigue (7% LUMAKRAS; 25% docetaxel), alopecia (1% LUMKARAS; 21% docetaxel), nausea (14% LUMAKRAS; 20% docetaxel) and anemia (3% LUMAKRAS; 18% docetaxel).

"This is the first Phase 3 randomized clinical trial for a KRASG12C inhibitor to show benefit in heavily pre-treated patients who have limited treatment options," said Melissa L. Johnson, M.D., director of Lung Cancer Research, Sarah Cannon Research Institute at Tennessee Oncology and presenting author. "It is encouraging that progression-free survival benefits were consistent across all clinically relevant subgroups, and that sotorasib response rates were more than double compared to docetaxel response rates. This data represents a major advance for the treatment of patients with KRAS G12C-mutated non-small cell lung cancer."

Data from CodeBreaK 200 will be submitted to global regulatory authorities where LUMAKRAS/LUMYKRAS has accelerated approval or conditional marketing authorization. LUMAKRAS is the only KRASG12C inhibitor approved anywhere in the world with approval in 44 markets, including the United States, the European Union, the United Kingdrom and Japan. CodeBreaK 200 is the first randomized, controlled clinical trial for a KRASG12C inhibitor.

About LUMAKRAS/LUMYKRAS (sotorasib)
Amgen took on one of the toughest challenges of the last 40 years in cancer research by developing LUMAKRAS/LUMYKRAS, a KRASG12C inhibitor.1 LUMAKRAS/LUMYKRAS has demonstrated a positive benefit-risk profile with rapid, deep, and durable anticancer activity in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation with a once daily oral formulation.2

Amgen is progressing the largest and broadest global KRASG12C inhibitor development program with unparalleled speed and exploring more than 10 sotorasib combination regimens, with clinical trial sites spanning five continents. To date, over 6,500 patients around the world have received LUMAKRAS/LUMYKRAS through the clinical development program and commercial use.

In May 2021, LUMAKRAS was the first KRASG12C inhibitor to receive regulatory approval with its approval in the U.S., under accelerated approval. LUMAKRAS/LUMYKRAS is also approved in the European Union, Japan, United Arab Emirates, South Korea, Hong Kong, Switzerland, Taiwan, Qatar, and in Australia, Brazil, Canada, Great Britain, Singapore, and Israel under the FDA’s Project Orbis. Additionally, Amgen has submitted MAAs in Argentina, Colombia, Kuwait, Macao, Malaysia, Mexico, Russia, Saudi Arabia, Thailand and Turkey.

LUMAKRAS/LUMYKRAS is also being studied in multiple other solid tumors.3

About Non-Small Cell Lung Cancer and the KRAS G12C Mutation
Lung cancer is the leading cause of cancer-related deaths worldwide, and it accounts for more deaths worldwide than colon cancer, breast cancer and prostate cancer combined.4 Overall survival rates for NSCLC are improving but remain poor for patients with advanced disease, and 5-year survival is only 8% for those with metastatic disease.5

KRAS G12C is the most common KRAS mutation in NSCLC.6 About 13% of patients with NSCLC harbor the KRAS G12C mutation.7 Unmet medical need remains high and treatment options are limited for NSCLC patients with the KRAS G12C mutation whose first-line treatment has failed to work or has stopped working. The outcomes with other approved therapies are suboptimal, with a median progression-free survival of approximately four months following second-line treatment of KRAS G12C-mutated NSCLC.8

About CodeBreaK
The CodeBreaK clinical development program for Amgen’s drug sotorasib is designed to study patients with an advanced solid tumor with the KRAS G12C mutation and address the longstanding unmet medical need for these cancers.

CodeBreaK 100, the Phase 1 and 2, first-in-human, open-label multicenter study, enrolled patients with KRAS G12C-mutant solid tumors.9 Eligible patients must have received a prior line of systemic anticancer therapy, consistent with their tumor type and stage of disease. The primary endpoint for the Phase 2 study was centrally assessed objective response rate. The Phase 2 trial in NSCLC enrolled 126 patients, 124 of whom had centrally evaluable lesions by RECIST at baseline.2 The Phase 2 trial in colorectal cancer (CRC) enrolled 62 patients and results have been published.10

CodeBreaK 200, the global Phase 3 randomized active-controlled study comparing sotorasib to docetaxel in KRAS G12C-mutated NSCLC completed enrollment of 345 patients. Eligible patients had previously treated, locally advanced and unresectable or metastatic KRAS G12C-mutated NSCLC. The primary endpoint is progression-free survival and key secondary endpoints include overall survival, objective response rate, and patient-reported outcomes.11

Amgen also has several Phase 1b studies investigating sotorasib monotherapy and sotorasib combination therapy across various advanced solid tumors (CodeBreaK 101) open for enrollment.12 A Phase 2 randomized study will evaluate sotorasib in patients with stage IV KRAS G12C-mutated NSCLC in need of first-line treatment (CodeBreaK 201).13

For information, please visit www.hcp.codebreaktrials.com.

LUMAKRAS (sotorasib) U.S. Indication
LUMAKRAS is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

LUMAKRAS (sotorasib) Important U.S. Safety Information

Hepatotoxicity

LUMAKRAS can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis.
Among 357 patients who received LUMAKRAS in CodeBreaK 100, hepatotoxicity occurred in 1.7% (all grades) and 1.4% (Grade 3). A total of 18% of patients who received LUMAKRAS had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 6% were Grade 3 and 0.6% were Grade 4. In addition to dose interruption or reduction, 5% of patients received corticosteroids for the treatment of hepatotoxicity.
Monitor liver function tests (ALT, AST and total bilirubin) prior to the start of LUMAKRAS every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop transaminase and/or bilirubin elevations.
Withhold, dose reduce or permanently discontinue LUMAKRAS based on severity of adverse reaction.
Interstitial Lung Disease (ILD)/Pneumonitis

LUMAKRAS can cause ILD/pneumonitis that can be fatal. Among 357 patients who received LUMAKRAS in CodeBreaK 100, ILD/pneumonitis occurred in 0.8% of patients, all cases were Grade 3 or 4 at onset, and 1 case was fatal. LUMAKRAS was discontinued due to ILD/pneumonitis in 0.6% of patients.
Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold LUMAKRAS in patients with suspected ILD/pneumonitis and permanently discontinue LUMAKRAS if no other potential causes of ILD/pneumonitis are identified.
Most Common Adverse Reactions

The most common adverse reactions ≥ 20% were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity and cough.
Drug Interactions

Advise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, dietary and herbal products.
Inform patients to avoid proton pump inhibitors and H2 receptor antagonists while taking LUMAKRAS.
If coadministration with an acid-reducing agent cannot be avoided, inform patients to take LUMAKRAS 4 hours before or 10 hours after a locally acting antacid.
Please see LUMAKRAS full Prescribing Information.

About Amgen Oncology
At Amgen Oncology, our mission to serve patients drives all that we do. That’s why we’re relentlessly focused on accelerating the delivery of medicines that have the potential to empower all angles of care and transform lives of people with cancer.

For the last four decades, we have been dedicated to discovering the firsts that matter in oncology and to finding ways to reduce the burden of cancer. Building on our heritage, Amgen continues to advance the largest pipeline in the Company’s history, moving with great speed to advance those innovations for the patients who need them.

On September 11, 2022 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, reported the presentation of updated findings from the Phase II SUMMIT basket trial of neratinib for HER2 (ERBB2)-mutant, metastatic cervical cancer at the 2022 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, currently taking place in Paris, France (Press release, Puma Biotechnology, SEP 11, 2022, View Source [SID1234619381]). The poster (#559P) entitled, "Neratinib in HER2-mutant, recurrent/metastatic cervical cancer: updated findings from the phase 2 SUMMIT basket trial," was presented by Claire F. Friedman, M.D., Melanoma and Immunotherapy Service, Memorial Sloan Kettering Cancer Center, on September 11 at 11:10 a.m. CEST.

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Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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The Phase II SUMMIT ‘basket’ trial is an open-label, multicenter, multi-national study evaluating the safety and efficacy of neratinib administered daily to patients who have solid tumors with activating, somatic HER2 mutations. The cervical cancer cohort was comprised of 22 patients with persistent, recurrent, or metastatic cervical cancer and a HER2 mutation, as documented by institutional testing at a CLIA/CAP- (or regionally equivalent) certified laboratory. Patients were treated with neratinib monotherapy (240 mg/day); 22 patients (100%) had previously received platinum-based chemotherapy, 16 patients (73%) had prior bevacizumab, and 4 patients (18%) received prior pembrolizumab. Overall, the objective response rate was 18.2% (95% CI: 5.2–40.3%) and the clinical benefit rate was 45.5% (95% CI: 24.4–67.8%), which included 1 patient with a confirmed complete response, 3 patients with confirmed partial responses, and 6 patients with stable disease at equal or greater than 16 weeks. The median progression-free survival was 5.1 months (95% CI: 1.7–7.2 months). Among the 13 patients (59.1%) who had tumors with a highly activating HER2 S310F/Y mutation, 4 had confirmed responses.

The safety profile observed in the neratinib-treated cervical cancer patients was consistent with that reported for neratinib monotherapy in HER2-amplified breast cancer. The most frequently observed treatment-related adverse event was any-grade diarrhea (n=18; 81.8%), which included 5 (22.7%) Grade 3 or higher diarrhea events. Diarrhea was manageable with anti-diarrheal prophylaxis and none of the diarrhea events resulted in dose reduction or treatment discontinuation.

"HER2 mutations are present in 5% of cervical cancers, most commonly in endocervical adenocarcinomas, and HER2 targeted therapy is a potential treatment option for patients whose cancer has grown after standard first lines of treatment, including platinum-based chemotherapy," said Dr. Friedman, an investigator of the study from Memorial Sloan Kettering Cancer Center. "Neratinib treatment has been effective against several HER2-mutant cancers and the observed durable responses and disease control in metastatic patients with HER2-mutant cervical cancer are extremely promising for patients."

Alan H. Auerbach, CEO and President of Puma Biotechnology, added, "We are very pleased to observe that treatment with neratinib led to durable response and effective disease control in patients with aggressive HER2-mutant cervical cancer and that the adverse event of diarrhea could be managed with prophylaxis. Improving the lives of our cancer patients is our foremost goal, and we are pleased to see the benefit that was provided to these patients in the SUMMIT trial."

About Puma Biotechnology

Puma Biotechnology, Inc. is a biopharmaceutical company with a focus on the development and commercialization of innovative products to enhance cancer care. Puma in-licenses the global development and commercialization rights to PB272 (neratinib, oral), PB272 (neratinib, intravenous) and PB357. Neratinib, oral was approved by the U.S. Food and Drug Administration in 2017 for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX (neratinib) tablets. In February 2020, NERLYNX was also approved by the FDA in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. NERLYNX was granted marketing authorization by the European Commission in 2018 for the extended adjuvant treatment of adult patients with early stage hormone receptor-positive HER2-overexpressed/amplified breast cancer and who are less than one year from completion of prior adjuvant trastuzumab-based therapy. NERLYNX is a registered trademark of Puma Biotechnology, Inc.

Further information about Puma Biotechnology may be found at View Source

To help ensure patients have access to NERLYNX, Puma has implemented the Puma Patient Lynx support program to assist patients and healthcare providers with reimbursement support and referrals to resources that can help with financial assistance. More information on the Puma Patient Lynx program can be found at View Source or 1-855-816-5421.

INDICATIONS:

NERLYNX (neratinib) tablets, for oral use, is a kinase inhibitor indicated:

As a single agent, for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer, to follow adjuvant trastuzumab-based therapy.
In combination with capecitabine, for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer, who have received two or more prior anti-HER2 based regimens in the metastatic setting.
IMPORTANT SAFETY INFORMATION Regarding NERLYNX (neratinib) U.S. Indication:

CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS:

Diarrhea: Manage diarrhea through either NERLYNX dose escalation or loperamide prophylaxis. If diarrhea occurs despite recommended prophylaxis, treat with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥ 2 diarrhea that occurs after maximal dose reduction.
Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing Grade 4 liver abnormalities.
Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.
ADVERSE REACTIONS: The most common adverse reactions (reported in ≥ 5% of patients) were as follows:

NERLYNX as a single agent: Diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increased, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased, and urinary tract infection.
NERLYNX in combination with capecitabine: Diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue/asthenia, weight decreased, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distention, renal impairment, and muscle spasms.
To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) or FDA at 1-800-FDA-1088 or View Source

DRUG INTERACTIONS:

Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors. Separate NERLYNX by at least 2 hours before or 10 hours after H2-receptor antagonists. Or separate NERLYNX by at least 3 hours with antacids.
Strong CYP3A4 inhibitors: Avoid concomitant use.
P-gp and moderate CYP3A4 dual inhibitors: Avoid concomitant use.
Strong or moderate CYP3A4 inducers: Avoid concomitant use.
Certain P-gp substrates: Monitor for adverse reactions of P-gp substrates for which minimal concentration change may lead to serious adverse reactions when used concomitantly with NERLYNX.