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SOLO-1 Phase 3 Trial Demonstrates LYNPARZA® (olaparib) Maintenance Therapy Cut the Risk of Disease Progression or Death by 70 Percent in Patients with Newly-Diagnosed, Advanced BRCA-Mutated Ovarian Cancer

On October 21, 2018 AstraZeneca and Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported detailed results from the Phase 3 SOLO-1 trial testing LYNPARZA 300 mg tablets twice daily as a maintenance treatment for patients with newly-diagnosed advanced BRCA-mutated (BRCAm) ovarian cancer who were in complete or partial response following first-line standard platinum-based chemotherapy (Press release, AstraZeneca (Australia), OCT 21, 2018, View Source [SID1234530011]).

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Results of the trial confirm the statistically-significant and clinically-meaningful improvement in progression-free survival (PFS) for LYNPARZA as compared to placebo, reducing the risk of disease progression or death by 70 percent (HR=0.30 [95% CI, 0.23-0.41]; p<0.001). At 41 months of follow-up, the median PFS for patients treated with LYNPARZA was not reached compared to 13.8 months for patients treated with placebo. Of those receiving LYNPARZA, 60.4 percent remained progression-free at 36 months, compared to 26.9 percent of women in the placebo arm. The data were presented at the Presidential Symposium of the ESMO (Free ESMO Whitepaper) 2018 Congress in Munich, Germany and published simultaneously online in the New England Journal of Medicine (NEJM).

Sean Bohen, executive vice president, Global Medicines Development and chief medical officer at AstraZeneca, said, "There is currently a significant unmet need in the treatment of advanced ovarian cancer because 70 percent of women relapse within the first three years after their initial treatment. The remarkable results of the SOLO-1 trial, which showed that 60 percent of women with newly-diagnosed, advanced BRCA-mutated ovarian cancer remained progression-free at three years, highlight the potential of LYNPARZA as a first-line maintenance therapy in this setting."

Dr. Roy Baynes, senior vice president and head of Global Clinical Development, chief medical officer, Merck Research Laboratories, said, "Our collective goal in oncology research is to improve long-term outcomes for people living with cancer. Based on the SOLO-1 trial results, LYNPARZA is the only PARP inhibitor to have demonstrated a significant and clinically-meaningful improvement in reducing the risk of progression or death for newly-diagnosed patients with advanced BRCA-mutated ovarian cancer following platinum-based chemotherapy. We are working with regulatory authorities as quickly as possible to seek approval of LYNPARZA for these patients."

Kathleen Moore, co-principal investigator of the SOLO-1 trial and associate director, Stephenson Cancer Center at The University of Oklahoma, Oklahoma City, Oklahoma, said, "Women with ovarian cancer are often diagnosed with advanced disease, which unfortunately is associated with poor long-term survival rates. The newly-diagnosed setting is our best opportunity to achieve a sustained remission, since once a patient’s ovarian cancer recurs, it is typically incurable. The SOLO-1 results demonstrate the potential of LYNPARZA maintenance therapy earlier in the treatment pathway and reinforce the importance of identifying a patient’s BRCA mutation status at the time of diagnosis – these results could change the way we treat women with advanced BRCA-mutated ovarian cancer."

The SOLO-1 safety profile was in line with that observed in prior clinical trials. The most common adverse events (AEs) ≥ 20 percent were nausea (77%), fatigue (64%), vomiting (40%), anemia (39%) and diarrhea (34%). The most common ≥ Grade 3 AEs were anemia (22%) and neutropenia (8%). Seventy-one percent of patients on LYNPARZA remained on the recommended starting dose. Additionally, 88 percent of patients on LYNPARZA continued treatment without an AE-related discontinuation. Further, 48 percent of patients on LYNPARZA did not have a dose interruption as a result of an AE.

Per SOLO-1 protocol guidelines, patients who demonstrated a complete response (no radiological evidence of disease) at two years stopped treatment with LYNPARZA; patients who demonstrated a partial response and, who in the opinion of the treating physician can derive further benefit from continuous treatment, were treated beyond two years.

AstraZeneca and Merck are exploring additional trials in ovarian cancer, including the ongoing GINECO/ENGOTov25 Phase 3 trial, PAOLA-1. This trial is testing the effect of LYNPARZAin combination with bevacizumab as a maintenance treatment for patients with newly-diagnosed advanced ovarian cancer regardless of their BRCA status. Results are expected during the second half of 2019.

LYNPARZA is a first-in-class poly ADP-ribose polymerase (PARP) inhibitor approved in the U.S. since 2014. LYNPARZA has a broad clinical development program and AstraZeneca and Merck are working together to deliver LYNPARZA as quickly as possible to more patients across multiple cancer types.

LYNPARZA is not currently FDA-approved for advanced BRCAm ovarian cancer treatment in the first-line maintenance setting. LYNPARZA is indicated for the maintenance treatment of recurrent ovarian cancer in response to platinum-based chemotherapy regardless of BRCA mutation status, and for the treatment of advanced ovarian cancer patients with a germline BRCA mutation previously treated with three or more lines of chemotherapy. Physicians should select advanced ovarian cancer patients for therapy based on a FDA-approved companion diagnostic. Please see complete indications below.

Important Safety Information

Contraindications

There are no contraindications for LYNPARZA.

Warnings and Precautions

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals,

LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of

reproductive potential prior to initiating treatment.

Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males

Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

Adverse Reactions—Maintenance Setting

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%).

Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), and decreased appetite (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

Adverse Reactions—Advanced gBRCAm Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue (including asthenia) (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), increase in mean corpuscular volume (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

Adverse Reactions—gBRCAm, HER2-Negative Breast Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in >25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

Drug Interactions

Anticancer Agents: Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using LYNPARZA. If a moderate inducer cannot be avoided, there is a potential for decreased efficacy of LYNPARZA.

Use In Specific Populations

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild hepatic impairment (Child-Pugh classification A). There are no data in patients with moderate or severe hepatic impairment.

Renal Impairment: No adjustment to the starting dose is necessary in patients with mild renal impairment (CLcr=51-80 mL/min). In patients with moderate renal impairment (CLcr=31-50 mL/min), reduce the dose to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

Indications

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

In patients with deleterious or suspected deleterious gBRCAm,human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Please see complete Prescribing Information , including Patient Information (Medication Guide).

About the SOLO-1 Phase 3 Trial

SOLO-1 is a Phase 3, randomized, double-blind, placebo-controlled, multi-center trial to evaluate the efficacy and safety of LYNPARZA tablets (300 mgtwice daily) as maintenance monotherapy compared with placebo in newly-diagnosed patients with advanced BRCA-mutated ovarian cancer following platinum-based chemotherapy. The trial randomized 391 patients with a deleterious or suspected deleterious BRCA1 or BRCA2 mutation who were in clinical complete or partial response following platinum-based chemotherapy. Patients were randomized (2:1) to receive LYNPARZA or placebo for up to two years or until disease progression (at the investigator’s discretion). The primary endpoint was investigator-assessed progression-free survival and key secondary endpoints include time to second disease progression or death, time to first subsequent treatment and overall survival.

About Ovarian Cancer

Approximately 20,000 women in the U.S. are diagnosed with ovarian cancer (including ovarian, fallopian tube and primary peritoneal cancers) each year. Among women in the U.S., it is the ninth most common cancer and the fifth leading cause of cancer death.

The risk of developing ovarian cancer is increased in women with specific inherited genetic abnormalities, including BRCA mutations.

About BRCA Mutations

BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role in maintaining the genetic stability of cells. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

About LYNPARZA (olaparib)

LYNPARZA is the first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Specifically, in vitro studies have shown that LYNPARZA-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.LYNPARZA is being tested in a range of DDR-deficient tumor types.

LYNPARZA, which is being jointly developed and commercialized by AstraZeneca and Merck, has a broad and advanced clinical trial development program, and AstraZeneca and Merck are working together to deliver it as quickly as possible to more patients across multiple cancer types.

Published Late Breaking Abstracts at ESMO 2018: Saturday 20th October


More than 60 Late Breaking Abstracts (LBA’s) are scheduled to be published at this year’s European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (E.S.M.O 2018). Below you will find the 10 published at the sessions on Saturday 20th October, the second day of the conference. For full analysis identifying new technologies, drugs, targets, start-ups etc. we recommend Commercial Interest at E.S.M.O Annual Meeting 2018: Analytical Tool.

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ImmunoGen Presents Initial Data from FORWARD II Expansion Cohort Assessing Mirvetuximab Soravtansine in Combination with KEYTRUDA at ESMO 2018 Congress

On October 20, 2018 ImmunoGen, Inc., (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported initial safety and preliminary anti-tumor activity from the FORWARD II expansion cohort assessing mirvetuximab soravtansine in combination with Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab) (Press release, ImmunoGen, OCT 20, 2018, View Source [SID1234530012]). The data are being presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress, which is being held October 19-23, in Munich, Germany.

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"A high unmet need exists in patients with platinum-resistant ovarian cancer, particularly for heavily pretreated patients, and the goal of this study is to assess whether the addition of a checkpoint inhibitor prolongs the clinical benefit of mirvetuximab soravtansine in later-line patients through concomitant activation of the immune system," said Ursula Matulonis, M.D., Chief, Division of Gynecologic Oncology, Dana-Farber Cancer Institute. "Preliminary activity seen with the mirvetuximab soravtansine and pembrolizumab combination is encouraging, especially when considering other combinations involving pembrolizumab used in this patient population, where recent clinical trials have reported overall response rates below 20 percent."

The data presented at ESMO (Free ESMO Whitepaper) were for 56 patients with platinum-resistant ovarian cancer, of whom 40 have medium or high folate receptor alpha (FRα) expression. Patients had received a median of 3 prior therapies (range 2-7).

The combination of mirvetuximab soravtansine (6 mg/kg adjusted ideal body weight) and pembrolizumab (200 mg, supplied by Merck) demonstrates favorable tolerability and encouraging activity. Adverse events were predominantly mild to moderate (≤ Grade 2), consistent with the known safety profiles of each agent.

Preliminary findings related to activity include:

83% of patients (45/54 with at least one post-baseline scan) experienced tumor shrinkage of target lesions in response to treatment with mirvetuximab soravtansine and pembrolizumab, with more robust reductions observed in patients with tumors expressing FRα at medium or high levels.
Confirmed partial responses (PRs) were observed in 16 patients, with another 9 patients having unconfirmed PRs at the time of data analysis.
In the subset of patients with medium or high FRα expression levels, the confirmed overall response rate (ORR) was 31 percent (95% CI, 17, 48), with a median progression-free survival (PFS) of 5.5 months (95% CI 2.8, 6.3) and a median duration (DOR) of 8.1 months (95% CI 4.2, upper bound not yet reached).
At the time of analysis, the data were immature with 16 patients still on study (all with medium or high FRα expression) and a median follow-up of 8.3 months.
For all patients evaluable for activity, the confirmed ORR was 30 percent (95% CI 18, 44), with a median PFS of 4.2 months (95% CI 2.8, 5.9). The median DOR data of 6.9 months (95% CI 4.2, 8.3) suggest a trend towards improvement over mirvetuximab soravtansine monotherapy.
"The combination of mirvetuximab soravtansine with pembrolizumab continues to demonstrate a favorable tolerability profile in women with platinum-resistant ovarian cancer, with preliminary activity consistent with mirvetuximab monotherapy in heavily pretreated patients," said Anna Berkenblit, M.D., Vice President and Chief Medical Officer of ImmunoGen. "The early duration of response data from the expansion cohort suggest a trend towards improvement over mirvetuximab monotherapy. As the data from this cohort continue to mature, we will use it to guide the further development of this novel combination, as part of our broader strategy to establish mirvetuximab soravtansine as the preferred combination therapy in ovarian cancer."

POSTER PRESENTATION DETAILS

Title: "Mirvetuximab soravtansine, a folate receptor alpha (FRα-targeting antibody-drug conjugate (ADC), with pembrolizumab in platinum-resistant ovarian cancer (PROC): Initial results of an expansion cohort from FORWARD II, a Phase Ib study" (abstract #949P)
Date: October 20, 2018
Time: 12:30 CEST
Lead author: Ursula Matulonis, M.D., Chief, Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, MA
Additional information can be found at www.esmo.org.

About FORWARD II
FORWARD II is a Phase 1b/2 study of mirvetuximab soravtansine in combination with AVASTIN (bevacizumab), or KEYTRUDA (pembrolizumab) in patients with FRα-positive platinum-resistant ovarian cancer, primary peritoneal, or fallopian tube tumors, as well as a combination with carboplatin and a triplet combination of mirvetuximab plus carboplatin and AVASTIN in patients with platinum-sensitive ovarian cancer.

ABOUT MIRVETUXIMAB SORAVTANSINE
Mirvetuximab soravtansine (IMGN853) is the first folate receptor alpha (FRα)-targeting ADC. It uses a humanized FRα-binding antibody to target the ADC specifically to FRα-expressing cancer cells and a potent anti-tumor agent, DM4, to kill the targeted cancer cells.

Innate Pharma announces Phase II results from monalizumab and cetuximab combination in head and neck cancer at the ESMO 2018 Congress

On October 20, 2018 Euronext (Paris: FR0010331421 – IPH), reported updated data from the Phase II trial evaluating the safety and efficacy of the combination of monalizumab and cetuximab (anti-EGFR) in previously treated patients with recurrent and/or metastatic squamous cell carcinoma of the head & neck (R/M SCCHN) (Press release, Innate Pharma, OCT 20, 2018, View Source [SID1234530305]). The data will be discussed today at the ESMO (Free ESMO Whitepaper) 2018 Congress in Munich, Germany, by Professor Jérôme Fayette, Medical Oncologist at the Centre Léon Bérard Lyon, France. Monalizumab is a first-in-class checkpoint inhibitor targeting NKG2A inhibitory receptors expressed on tumor-infiltrating cytotoxic CD8 T lymphocytes and NK cells.

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"These results confirm the emerging clinical activity reported earlier this year at AACR (Free AACR Whitepaper)." commented Pierre Dodion, Chief Medical Officer of Innate Pharma. "This successfully executed study provides the rationale to advance our clinical program and to further investigate the potential benefits of this innovative and differentiated combination in patients who received both prior platinum-based chemotherapy and PD-1/L1 blockers. These patients represent a population with a high unmet medical need."

As of August 31, 2018, a total of 40 patients with R/M SCCHN were evaluable for safety and efficacy. The highest dose tested for monalizumab in the dose-escalation part of the study (10 mg/kg every 2 weeks) was given in combination with the approved dose and schedule of cetuximab in the Phase II cohort expansion. All patients enrolled had been previously treated with platinum-containing regimens.

In the study evaluating the combination of monalizumab and cetuximab the overall response rate was 27.5% (by RECIST) including 1 confirmed complete response (2.5%) and 10 partial responses (25%). Disease control rate at 24 weeks (DCR) was 35%. Median progression-free survival (PFS) and overall survival (OS) reached 5.0 and 10.3 months, respectively. In addition, there were 3 (18%) responders among the 17 patients who had been previously treated with PD-1/L1 antibodies.

"These data show a response rate and durability of response that are of high interest across the totality of patients. The clinical results are supported by a strong preclinical dataset that demonstrated the synergy between the two components of this non-PD-1/L1 combination therapy," commented Professor Jérôme Fayette, Investigator of the study. "Currently approved PD-1/L1 therapies have shown overall response rates of 13-16% in patients with head and neck cancer in the second-line setting. Almost half of the patients in the study were previously treated with immunotherapy, and achieving responses in this subpopulation with no treatment option is exciting. In today’s treatment landscape, there is much potential to explore other treatment paradigms that provide alternatives especially to non-responding PD-1/L1 patients."

best change

Among the 40 patients enrolled in the cohort expansion, the safety findings were consistent with previously presented data at AACR (Free AACR Whitepaper) 2017 and 2018, with no additional safety concerns compared to monalizumab or cetuximab given alone. The majority of adverse events (AE) were of Grade 1-2 severity, rapidly reversible and easily manageable. No infusion-related reactions or treatment-related deaths occurred. The most frequent AEs (skin disorders) described with cetuximab were not potentiated by the combination with monalizumab.

The poster is available in the monalizumab section on Innate Pharma’s website.

A KOL call with Dr Cohen, Prof. of Medicine at the Hospital of the University of Pennsylvania, Associate Director of Clinical Research, Abramson Cancer Center Philadelphia and the lead investigator of the study, will be held

Monday, October 22, at 4pm CEST (10am ET)

Dial in numbers:

France and International: +33 (0)1 72 72 74 03 US only: +1 646 722 4916

PIN code: 69616804#

TESARO Announces Data Presentations at ESMO 2018 Congress

On October 20, 2018 TESARO, Inc. (NASDAQ: TSRO), an oncology-focused biopharmaceutical company, today summarized updated Phase 1 GARNET data of TSR-042 (anti-PD-1 antibody) in patients with recurrent or advanced microsatellite instability high (MSI-H) endometrial cancer presented during the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (Press release, TESARO, OCT 20, 2018, View Source [SID1234529996]). Blinded, pooled interim safety data from the Phase 3 PRIMA trial of niraparib in patients with first-line ovarian cancer regardless of biomarker status were also presented in a poster discussion session and additional data from the QUADRA trial of niraparib for treatment of late-line ovarian cancer beyond BRCAmut were presented in a poster display.

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"The updated results from GARNET presented at ESMO (Free ESMO Whitepaper) demonstrate robust clinical activity of TSR-042 in patients with MSI-H endometrial tumors," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "In addition, blinded, pooled interim safety data from the ongoing PRIMA study of niraparib as maintenance therapy in first line ovarian cancer demonstrated a favorable tolerability profile for niraparib when dosed according to a patient’s weight and platelet count compared to a fixed starting dose. These prospective data confirmed that adverse events are reduced for patients starting niraparib at an individualized dose, including a reduction in symptomatic events that are particularly meaningful to patients. We look forward to announcing top-line results for the PRIMA study in late 2019."

TSR-042 (anti-PD-1 antibody)

GARNET: Efficacy data indicates robust activity of TSR-042 in patients with MSI-high endometrial cancer
GARNET is a multicenter, open-label, Phase 1 dose-escalation study designed to assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity of TSR-042 in patients with advanced solid tumors. The weight-based dose escalation and fixed-dose safety portions of the GARNET study have been completed. The ongoing cohort expansion portion of GARNET is evaluating TSR-042 at a dose of 500 milligrams every 3 weeks (Q3W) for the first 4 cycles, and 1000 milligrams every 6 weeks (Q6W) thereafter in four cohorts: MSI-H endometrial cancer, MSI-H non-endometrial cancer, MSS endometrial cancer and non-small cell lung cancer (NSCLC). Data presented at ESMO (Free ESMO Whitepaper) included safety and efficacy data from the cohort of patients with MSI-H endometrial cancer.

At the time of data cutoff, 35 patients with MSI-H endometrial cancer had received treatment with TSR-042. Among the 25 patients with MSI-H endometrial cancer who had at least one post-baseline tumor assessment, one had a complete response and 12 had partial responses (including 1 unconfirmed response) by immune related RECIST (irRECIST) criteria (ORR 52%). Twelve of the 13 responses are ongoing (92%), including three patients with partial responses who have thus far received over 60 weeks of treatment with TSR-042. Three additional patients (12%) had stable disease. Median duration of response was not reached.

Preliminary safety findings among the 35 MSI-H endometrial patients indicate TSR-042 is generally well-tolerated. Grade ≥3 treatment-related treatment-emergent adverse events (TEAEs) were reported in 4 out of 35 patients (11.4%).

The data support the unique and convenient dose of TSR-042 of 500 mg Q3W for the first 4 doses, then 1000 mg Q6W thereafter. At this dose, TSR-042 maintained serum concentrations required to retain maximum receptor occupancy throughout the dosing cycle.

The GARNET study is intended to support a Biologics License Application (BLA) submission to the U.S. Food and Drug Administration (FDA) in 2019.

ZEJULA (niraparib)

PRIMA: Prospective validation of individualized niraparib dose regimen based on patient baseline body weight & platelet counts; Rates of adverse events in blinded, pooled patient groups decreased with individualized starting dose compared to fixed starting dose
PRIMA is a double-blind, randomized Phase 3 study designed to evaluate niraparib versus placebo as maintenance therapy in first-line ovarian cancer patients. Platinum responsive patients were initially randomized 2:1 to start niraparib at 300 mg once-daily or placebo and the protocol was subsequently amended to require an individualized starting dose of 200 mg once-daily in patients with baseline weight <77kg or platelet count <150K/μL and 300 mg in all other patients. The trial remains blinded for efficacy and safety.

Among the 727 patients dosed on the study, 480 patients were treated with a fixed 300 mg starting dose of niraparib or placebo and 247 patients were treated with an individualized dose of 300 mg or 200 mg of niraparib based on weight and platelet count or placebo. The findings presented were from evaluable patients with ≥30 days of safety data from blinded pooled niraparib and placebo and indicate improved tolerability with niraparib at the individualized starting dose. TEAEs grade ≥ 3 were lower (36%) in the individualized dosing group (pooled niraparib and placebo) as compared with the group that received a fixed starting dose of 300 mg of niraparib or placebo (52.7%). There were fewer dose reductions and dose discontinuations in patients treated with the individualized starting dose compared with the fixed starting dose. TEAEs leading to treatment discontinuation remained low for both groups at 7.9% for the fixed starting dose and 5.3% for the individualized starting dose group.

The rates of hematologic toxicities of all grades, including grade ≥ 3, were lower with introduction of an individualized starting dose. Grade ≥3 non-hematologic toxicities (nausea, vomiting, fatigue, hypertension, and insomnia) decreased with an individualized starting dose.

QUADRA: Clinical benefit of niraparib treatment demonstrated in late-line ovarian cancer setting, including patients with platinum resistant and refractory disease
Late line ovarian cancer represents a high unmet medical need and efficacy of cytotoxic chemotherapy is limited in patients with heavily-pretreated ovarian cancer. Previous studies have shown meaningful activity of other PARP inhibitors in the late-line treatment of ovarian cancer only in populations with BRCA mutations. QUADRA, a single arm study, was conducted to assess the activity of ZEJULA monotherapy in the fourth-line or later treatment of patients with ovarian cancer, regardless of platinum sensitivity or biomarker status.

Niraparib treatment demonstrated durable clinical activity in late-line (≥ 4th line) patients with BRCAmut tumors, with an ORR of approximately 30%, including patients with platinum-sensitive, -resistant, and -refractory disease, and a median duration of response of 9.2 months. The clinical benefit rate (CBR; CR+PR+SD) at 16 weeks and 24 weeks were 56% and 38%, respectively. A gradient of clinical activity based on platinum sensitivity was demonstrated in the BRCAmut patient population, with greatest activity demonstrated in patients with platinum-sensitive disease (ORR 39%), mOS was not reached (95% CI 19, NE). However, even patients with platinum-resistant and platinum-refractory disease experienced benefit from niraparib treatment with ORR of 33% and 19%, and mOS of 26.0 and 23.3 months, respectively.

Clinical benefit of niraparib extended beyond patients with BRCA mutations in this late-line setting. Patients with non-BRCAmut/HRDpos platinum-sensitive disease had an ORR of 20%. In total, the biomarker-driven population (BRCAmut regardless of platinum status and non-BRCAmut HRDpos platinum-sensitive patients) included 98 patients with ORR of 26%, mDOR of 8.3 months, and a mOS of 23.3 months.

The safety profile in the QUADRA treatment study was consistent with the safety profile observed in the NOVA maintenance population.

Details of TESARO’s poster presentations are as follows (all times local):

ZEJULA (niraparib)

Saturday, October 20, 2018, 9:15 AM – 10:45 AM; Lecture time: 9:59 AM

A prospective evaluation of tolerability of niraparib dosing based upon baseline body weight (wt) and platelet (plt) count: Blinded pooled interim safety data from the PRIMA Study

Poster Discussion, Abstract: 941PD, Location: ICM – Room 13, Poster Displayed: Hall B4

Saturday, October 20, 2018, 12:30 PM – 1:30 PM

QUADRA: A phase 2, open-label, single-arm study to evaluate niraparib in patients with relapsed ovarian cancer in 4th or later line of therapy: results from the BRCAmut subset

Poster Session, Abstract: 944P, Location: Hall A3

Saturday, October 20, 2018, 12:30 PM – 1:30 PM

OVARIO: A single-arm, open-label phase 2 study of maintenance therapy with niraparib + bevacizumab in patients with advanced ovarian cancer after response to frontline platinum-based chemotherapy

Poster Session, Abstract: 999TiP, Location: Hall A3

Saturday, October 20, 2018, 12:30 PM – 1:30 PM

Real world occurrence of top three clinical-trial reported adverse events of PARP inhibitor niraparib maintenance therapy in platinum-sensitive recurrent ovarian cancer, a national retrospective observational study of a 200 mg/day starting-dose cohort

Poster Session, Abstract: 986P, Location: Hall A3

Saturday, October 20, 2018, 12:30 PM – 1:30 PM

Brain metastases in primary ovarian cancer: real-world data

Poster Session, Abstract: 946P, Location: Hall A3

TSR-042 (anti-PD-1)

Saturday, October 20, 2018, 9:15 AM – 10:45 AM; Lecture time: 9:15 AM

Preliminary safety, efficacy, and PK/PD characterization from GARNET, a phase 1 clinical trial of the anti–PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced MSI-H endometrial cancer

Poster Discussion, Abstract: 935PD, Location: ICM – Room 13, Poster displayed: Hall B4

Niraparib is marketed in the United States and Europe under trade name ZEJULA.

About ZEJULA (Niraparib)
ZEJULA (niraparib) is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated in the United States and in the EU for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. In preclinical studies, ZEJULA concentrates in the tumor relative to plasma, delivering greater than 90% durable inhibition of PARP 1/2 and a persistent antitumor effect. Important Safety Information Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), including some fatal cases, was reported in 1.4% of patients receiving ZEJULA vs 1.1% of patients receiving placebo in Trial 1 (NOVA), and 0.9% of patients treated with ZEJULA in all clinical studies. The duration of ZEJULA treatment in patients prior to developing MDS/AML varied from <1 month to 2 years. All patients had received prior chemotherapy with platinum and some had also received other DNA damaging agents and radiotherapy. Discontinue ZEJULA if MDS/AML is confirmed.

Hematologic adverse reactions (thrombocytopenia, anemia and neutropenia) have been reported in patients receiving ZEJULA. Grade ≥3 thrombocytopenia, anemia and neutropenia were reported in 29%, 25%, and 20% of patients receiving ZEJULA, respectively. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, in 3%, 1%, and 2% of patients, respectively. Do not start ZEJULA until patients have recovered from hematological toxicity caused by prior chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically thereafter. If hematological toxicities do not resolve within 28 days following interruption, discontinue ZEJULA, and refer the patient to a hematologist for further investigations.

Hypertension and hypertensive crisis have been reported in patients receiving ZEJULA. Grade 3-4 hypertension occurred in 9% of patients receiving ZEJULA vs 2% of patients receiving placebo in Trial 1, with discontinuation occurring in <1% of patients.
ZEJULA can cause fetal harm and females of reproductive potential should use effective contraception.

In clinical studies, the most common adverse reactions (Grades 1-4) in ≥10% of patients included: thrombocytopenia (61%), anemia (50%), neutropenia (30%), leukopenia (17%), palpitations (10%), nausea (74%), constipation (40%), vomiting (34%), abdominal pain/distention (33%), mucositis/stomatitis (20%), diarrhea (20%), dyspepsia (18%), dry mouth (10%), fatigue/asthenia (57%), decreased appetite (25%), urinary tract infection (13%), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation (10%), myalgia (19%), back pain (18%), arthralgia (13%), headache (26%), dizziness (18%), dysgeusia (10%), insomnia (27%), anxiety (11%), nasopharyngitis (23%), dyspnea (20%), cough (16%), rash (21%) and hypertension (20%).

Common lab abnormalities (Grades 1-4) in ≥25% of patients included: decrease in hemoglobin (85%), decrease in platelet count (72%), decrease in white blood cell count (66%), decrease in absolute neutrophil count (53%), increase in AST (36%) and increase in ALT (28%). Please see full U.S. prescribing information, including additional important safety information, available at www.zejula.com.

About GARNET
The ongoing Phase I GARNET trial is evaluating TSR-042 as monotherapy in patients with advanced solid tumors. GARNET included a weight-based dose escalation study (Part 1) and a fixed-dose safety study (Part 2A), both of which have been completed. Results of these studies were used to determine the recommended Phase 2 dose (RP2D; 500 mg Q3W for the first 4 cycles then 1000 mg Q6W). The study is now enrolling patients with MSI-H endometrial cancer, MSI-H non-endometrial cancer, MSS endometrial cancer, and NSCLC into four large expansion cohorts.

About TSR-042

TSR-042 is an investigational humanized anti-programmed death (PD)-1 monoclonal antibody that binds with high affinity to the PD-1 receptor and effectively blocks its interaction with the ligands PD-L1 and PD-L2. TSR-042 is the only anti-PD-1 therapy administered as monotherapy every 3 weeks for 4 doses then every 6 weeks thereafter. TSR-042 was developed as part of the collaboration between TESARO and AnaptysBio, Inc. This collaboration was initiated in March of 2014, and is focused on the development of monospecific antibody drugs targeting PD-1, TIM-3 (TSR-022), and LAG-3 (TSR-033), in addition to a bi-specific antibody drug candidate targeting PD-1/LAG-3 (TSR-075).