On June 2, 2019 Spectrum Pharmaceuticals, Inc. (NasdaqGS: SPPI), a biotechnology company with a primary focus in hematology and oncology, reported integrated analysis results from two Phase 3 clinical trials of ROLONTIS (Press release, Spectrum Pharmaceuticals, JUN 2, 2019, View Source [SID1234536765]). ROLONTIS is a long-acting granulocyte colony-stimulating factor (G-CSF) being studied as a treatment for neutropenia in patients undergoing myelosuppressive cytotoxic chemotherapy.

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The analysis found that integrated efficacy and safety data from the two identically designed Phase 3 trials – ADVANCE and RECOVER – were consistent with results from the individual trials, demonstrating that ROLONTIS was non-inferior to pegfilgrastim in the reduction of duration of severe neutropenia (DSN) in all four cycles of treatment. The summary was presented today during a poster session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2019 Annual Meeting in Chicago.

"These integrated analyses confirm non-inferiority in efficacy and a similar safety profile between eflapegrastim and pegfilgrastim across all cycles of treatment, including a 95 percent confidence interval of the difference in the DSN below zero in favor of ROLONTIS in the first cycle of treatment," said Lee Schwartzberg, M.D., FACP, lead investigator, executive director, University of Tennessee West Cancer Center. "Additionally, the integrated data demonstrated that eflapegrastim provided an absolute risk reduction of severe neutropenia of 6.5 percent compared to pegfilgrastim in Cycle 1. The incidence of febrile neutropenia was low and similar between treatment arms. Adverse events, irrespective of causality and grade, were also similar between the treatment arms. These data strengthen our understanding of the clinical profile of eflapegrastim and help establish it as a possible new supportive care treatment option for patients undergoing myelosuppressive chemotherapy."

Integrated data derived from the two Phase 3 clinical trials, demonstrated that in Cycle 1, the mean DSN±SD was 0.24±0.581 days for ROLONTIS (n=314) and 0.36±0.789 days for pegfilgrastim (n=329), demonstrating non-inferiority (p<0.0001). The non-inferiority of ROLONTIS for DSN was maintained across all four treatment cycles (all p<0.0001). The ROLONTIS arm had an absolute risk reduction of severe neutropenia of 6.5% (95% CI: 0.2%, 13%) versus pegfilgrastim in Cycle 1. Absolute risk reduction was defined as the difference in the percentage of patients who experienced severe neutropenia (ROLONTIS 17.5%; pegfilgrastim 24%). Febrile neutropenia (3.2% vs. 3%; p=NS) and neutropenic complications (5.7% vs. 5.8%; p=NS) were similar between the ROLONTIS and pegfilgrastim arms. Integrated safety data presented today also showed that the adverse events in general, regardless of causality, were not significantly different between the two treatment arms.

"Neutropenia remains a significant complication for people undergoing myelosuppressive chemotherapy, potentially causing hospitalizations and delays in much needed cancer treatment," said Francois Lebel, M.D., F.R.C.P.C., chief medical officer, Spectrum Pharmaceuticals. "ROLONTIS is the first rhG-CSF innovation in over 15 years. The integrated analysis results, which included 643 patients combined, demonstrated reproducible efficacy and an acceptable safety profile. We look forward to potentially providing a new therapy to the patients and physicians managing chemotherapy-induced neutropenia in the near future."

Spectrum Pharmaceuticals is currently working on a revised Biologics License Application (BLA) to submit to the FDA.

About ADVANCE

The ADVANCE trial is a Phase 3, multicenter, randomized, active-controlled, open label trial that enrolled 406 early-stage breast cancer patients, who received docetaxel and cyclophosphamide chemotherapy every 21 days for four cycles. Patients were randomized in a 1:1 ratio to receive ROLONTIS or pegfilgrastim (eflapegrastim n=196; pegfilgrastim n=210). The primary trial endpoint was the DSN (absolute neutrophil counts [ANC] <0.5×109/L) in Cycle 1 of chemotherapy, based on central laboratory assessment of ANC over the 21-day cycle. Secondary endpoints included the DSN in Cycles 2, 3, and 4, time to ANC recovery, depth of ANC nadir and incidence of febrile neutropenia at Cycle 1. Patients with stage I to stage IIIA breast cancer were treated on Day 1 of each of the four cycles with adjuvant/neo-adjuvant docetaxel and cyclophosphamide. On Day 2 of each cycle, patients received a single subcutaneous dose of either eflapegrastim 13.2 mg/0.6 mL (3.6 mg G-CSF) or pegfilgrastim (6 mg) in a 1:1 ratio.

About RECOVER

The RECOVER trial is a Phase 3, multicenter, randomized, active-controlled, open label trial that enrolled 237 breast cancer patients who received docetaxel and cyclophosphamide chemotherapy every 21 days. Patients were randomized in a 1:1 ratio to receive ROLONTIS (n=118) or pegfilgrastim (n=119). The primary trial endpoint was the DSN in Cycle 1 of chemotherapy (absolute neutrophil count [ANC] <0.5×10^9/L), based on central laboratory assessment of ANC over a 21-day cycle. There were a total of four cycles evaluated in this trial. Secondary endpoints included the DSN in Cycles 2, 3, and 4, time to ANC recovery, depth of ANC nadir and incidence of febrile neutropenia at Cycle 1. Patients with stage I to stage IIIA breast cancer were treated on Day 1 of each of the four cycles with adjuvant/neo-adjuvant docetaxel and cyclophosphamide. On Day 2 of each cycle, patients received a single subcutaneous dose of either eflapegrastim 13.2 mg/0.6 mL (3.6 mg G-CSF) or pegfilgrastim (6 mg) in a 1:1 ratio.

On June 2, 2019 Sanofi reported that Pivotal Phase 3 ICARIA-MM trial results demonstrated that isatuximab added to pomalidomide and dexamethasone (isatuximab combination therapy) showed statistically significant improvements compared to pomalidomide and dexamethasone (pom-dex) alone in patients with relapsed/refractory multiple myeloma (RRMM) (Press release, Sanofi, JUN 2, 2019, View Source [SID1234536763]).

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These findings were presented today at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago. Isatuximab is an investigational monoclonal antibody that targets a specific epitope on the CD38 receptor of a plasma cell.

"Isatuximab in combination with pomalidomide and dexamethasone resulted in an impressive 40% reduction in the risk of progression or death compared to pomalidomide and dexamethasone alone," said Paul Richardson, MD, principal investigator and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute. "This outcome is noteworthy because this trial included a particularly difficult-to-treat, relapsed and refractory patient population that was, in my view, highly reflective of real-world practice."

Isatuximab combination therapy showed a statistically significant improvement in progression free survival (HR 0.596, 95% CI 0.44-0.81, p=0.001), and the median progression free survival was longer in the isatuximab combination therapy arm (11.53 months, 95% CI: 8.936 to 13.897) than pom-dex alone (6.47 months, 95% CI: 4.468 to 8.279).

Also of note, isatuximab combination therapy demonstrated a significantly greater overall response rate, compared to pom-dex alone (60% vs. 35%, p<0.0001). In additional analyses, isatuximab combination therapy compared to pom-dex alone showed a treatment benefit consistent across multiple subgroups, including patients 75 years and older, patients with renal insufficiency, and patients who were refractory to lenalidomide. The results presented above were based on an independent review committee assessment.

In addition, the following results favored isatuximab combination therapy:

Isatuximab combination therapy demonstrated significantly higher very good partial response (VGPR) rate compared to pom-dex (31.8% vs. 8.5%, respectively, p<0.0001) and a longer duration of response compared to pom-dex alone (median 13.27 months vs. 11.07 months, respectively). Among patients who achieved a response, isatuximab combination therapy demonstrated faster median time to first response compared to pom-dex alone (35 days vs. 58 days, respectively).
Time to next treatment was longer with isatuximab combination therapy compared to pom-dex alone (median not reached vs. 9.1 months, HR=0.538).
Data at the time of analysis showed a trend towards an overall survival benefit associated with isatuximab combination therapy. Final data on overall survival will be reported when available.

Adverse events (AEs) of Grade >=3 were observed in 86.8% of isatuximab combination therapy patients vs. 70.5% of pom-dex patients. Additionally, isatuximab combination therapy compared to pom-dex showed: 7.2% vs. 12.8% of patients discontinued due to AEs, respectively; 7.9% vs. 9.4% patients died due to AEs, respectively; infections of Grade >=3 were seen in 42.8% vs. 30.2% of patients, respectively; and Grade >=3 neutropenia was seen in 84.9% (febrile 11.8%) vs. 70.1% (febrile 2.0%) of patients, respectively. Infusion reactions were reported in 38.2% (2.6% grade 3-4) of isatuximab combination therapy patients.

First Positive Phase 3 Trial of a Monoclonal Antibody in Combination with Pom-Dex

ICARIA-MM is a pivotal Phase 3 randomized, open-label, multi-center trial evaluating isatuximab in combination with pom-dex versus pom-dex alone in patients with RRMM. The study enrolled 307 patients with RRMM across 96 centers spanning 24 countries. Overall, patients had received a median of three prior lines of anti-myeloma therapies, including at least two consecutive cycles of lenalidomide and a proteasome inhibitor given alone or in combination.

During the trial, isatuximab was administered through an intravenous infusion at a dose of 10mg/kg once weekly for four weeks, then every other week for 28-day cycles in combination with standard doses of pom-dex for the duration of treatment.

Topline results from ICARIA-MM were previously announced in February 2019.

Developing Isatuximab, a Monoclonal Antibody

Isatuximab is an investigational monoclonal antibody (mAb) targeting a specific epitope on the CD38 receptor. It is designed to trigger multiple, distinct mechanisms of action that are believed to directly promote programmed tumor cell death (apoptosis) and immunomodulatory activity. CD38 is highly and uniformly expressed on multiple myeloma cells and is a cell surface receptor target for antibody-based therapeutics in multiple myeloma and other malignancies. The clinical significance of these findings is under investigation.

Isatuximab is being developed by Sanofi and is currently being evaluated in multiple ongoing Phase 3 clinical trials in combination with currently available treatments across the multiple myeloma treatment continuum.

In the second quarter of 2019, the European Medicines Agency (EMA) accepted for review the Marketing Authorization Application and Sanofi filed a Biologics License Application with the U.S. Food and Drug Administration (FDA), both for use of isatuximab in combination with pom-dex for the treatment of certain patients with RRMM.

Isatuximab is also under investigation for the treatment of other hematologic malignancies and solid tumors. Isatuximab is an investigational agent and its safety and efficacy have not been evaluated by the U.S. FDA, the EMA, or any other regulatory authority.

Multiple Myeloma Leads to Significant Disease Burden

Multiple myeloma is the second most common hematologic malignancy[1], affecting more than 138,000[2] people worldwide. Multiple myeloma results in significant disease burden. Patients with multiple myeloma continue to relapse over time making it a difficult to treat and incurable malignancy.

On June 2, 2019 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that it will present updated interim results from a Phase II clinical trial of Puma’s drug neratinib at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2019 Annual Meeting in Chicago. The presentation entitled, "Effect of prophylaxis on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer: Phase II CONTROL trial," will be presented at a poster session on June 2 at 8:00 a.m. CT. A full copy of the poster is available on the Puma Biotechnology website.

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Neratinib was approved by the U.S. Food and Drug Administration (FDA) in July 2017 for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX (neratinib) tablets.

The main adverse event seen to date in clinical trials of neratinib is diarrhea and, more specifically, grade 3 diarrhea. In the Phase III ExteNET trial of neratinib as extended adjuvant treatment of HER2-positive early stage breast cancer that has previously been treated with adjuvant Herceptin, prophylactic use of anti-diarrheal medications was not mandatory. In the trial, 95.4% of the patients experienced all grade diarrhea and 39.8% of the patients experienced grade 3 or higher diarrhea (there was one event of grade 4 diarrhea). The median cumulative duration of grade 3 diarrhea in the ExteNET trial was 5 days and 16.8% of patients who received neratinib in the ExteNET trial discontinued the drug due to diarrhea.

The CONTROL trial is an international, open-label, Phase II study investigating the use of antidiarrheal prophylaxis or dose escalation in the reduction of neratinib-associated diarrhea that has a primary endpoint of the incidence of grade 3 diarrhea.

In the CONTROL trial, patients with HER2-positive early stage breast cancer who had completed trastuzumab-based adjuvant therapy received neratinib daily for a period of one year. The trial initially tested high dose loperamide prophylaxis given for the first 2 cycles (56 days) of treatment (12 mg on days 1-14, 8 mg on days 15-56 and as needed thereafter). The CONTROL trial was then expanded to include four additional cohorts. One cohort received the combination of loperamide and budesonide, the second cohort received the combination of loperamide plus colestipol, the third cohort received colestipol plus loperamide as needed and the fourth cohort did not use any antidiarrheal drugs as mandatory prophylaxis but instead used a dose escalation during the first month of neratinib treatment. Budesonide is a locally acting corticosteroid that Puma believes targets the inflammation identified in a preclinical model of neratinib-induced diarrhea and colestipol is a bile acid sequestrant that Puma believes targets potential bile acid malabsorption that could result from such inflammation. The dose escalation involved treating with neratinib at 120 mg per day for the first week, 160 mg per week for the second week and 240 mg per week starting at week 3 and until the end of treatment.

The interim analysis of the CONTROL trial presented in the poster included a total of 137 patients who received neratinib plus loperamide prophylaxis, 64 patients who received neratinib plus loperamide prophylaxis for 2 cycles and budesonide for 1 cycle, 136 patients who received neratinib plus loperamide prophylaxis for 1 cycle and colestipol for 1 cycle, 104 patients who received colestipol for 1 cycle and loperamide as needed and 60 patients who received the dose escalation regimen of neratinib.

The results of the trial showed that the incidence of grade 3 diarrhea for the 137 patients who received the loperamide prophylaxis was 30.7% and that for the 137 patients in this cohort, 20.4% discontinued neratinib due to diarrhea. The median cumulative duration of grade 3 diarrhea was 3 days.

For the 64 patients who received the combination of loperamide plus budesonide, the results of the trial showed that the incidence of grade 3 diarrhea was 28.1% and that for the 64 patients in this cohort, 10.9% discontinued neratinib due to diarrhea. The median cumulative duration of grade 3 diarrhea was 2.5 days.

For the 136 patients who received the combination of loperamide plus colestipol, the results of the trial showed that the incidence of grade 3 diarrhea was 20.6% and that for the 136 patients in this cohort, 4.4% discontinued neratinib due to diarrhea. The median cumulative duration of grade 3 diarrhea was 3.5 days.

For the 104 patients who received colestipol and loperamide as needed, the results of the trial showed that the incidence of grade 3 diarrhea was 31.7% and that for the 104 patients in this cohort, 6.7% discontinued neratinib due to diarrhea. The median cumulative duration of grade 3 diarrhea was 3 days.

For the 60 patients who received no antidiarrheal drugs as mandatory prophylaxis and dose escalation of neratinib in the first month, the results of the trial showed that the incidence of grade 3 diarrhea was 11.7% and that for the 60 patients in this cohort, 3.3% discontinued neratinib due to diarrhea. The median cumulative duration of grade 3 diarrhea was 2 days.

Further information is provided in Table 1 below:

Table 1: Characteristics of Treatment-Emergent Diarrhea
Neratinib dose
Loperamide + Loperamide + Loperamide escalation +
Loperamide budesonide colestipol prn + colestipol loperamide prn
(n=137) (n=64) (n=136) (n=104) (n=60)
Diarrhea, %
Any grade 79.6 85.9 83.1 95.2 95.0
Grade 1 24.1 25.0 27.9 30.8 43.3
Grade 2 24.8 32.8 34.6 32.7 40.0
Grade 3 30.7 28.1 20.6 31.7 11.7

Diarrhea leading to discontinuation, %

20.4 10.9 4.4 6.7 3.3

Hospitalization (due to diarrhea), %

1.5 0 0 0 0

Discontinuation of study (any cause), %

44.6 20.3 28.7 26.0 13.6

Note: Each patient was counted only once in the highest grade category.
No Grade 4 events reported in the CONTROL study.
Carlos H. Barcenas, MD, MS, Assistant Professor in the Department of Breast Medical Oncology of The University of Texas MD Anderson Cancer Center, said, "We are pleased to see the maturation of the data supporting observations of a reduction in incidence, severity and duration of neratinib-associated diarrhea with loperamide prophylaxis, loperamide plus budesonide prophylaxis or the loperamide plus colestipol prophylaxis. We are pleased to see the initial results of the dose escalation regimen. Along with the continued reduction in the incidence and severity of grade 3 diarrhea with neratinib, diarrhea appears to be early onset, acute, self-limiting and manageable. Not only does the addition of budesonide or colestipol to loperamide prophylaxis appear to greatly improve the tolerability of neratinib, the dose escalation regimen appears as another promising option since there is no mandatory prophylaxis. We look forward to the completion of the dose escalation cohort."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are pleased to see the reductions in the incidence of severe neratinib-related diarrhea in the CONTROL trial when using the antidiarrheal regimens and the dose escalation. The reduction in the discontinuations due to diarrhea are encouraging and appear to represent a marked improvement in tolerability over what was seen in the ExteNET trial."

About HER2-Positive Breast Cancer

Approximately 20% to 25% of breast cancer tumors over-express the HER2 protein. HER2-positive breast cancer is often more aggressive than other types of breast cancer, increasing the risk of disease progression and death. Although research has shown that trastuzumab can reduce the risk of early stage HER2-positive breast cancer returning after surgery, up to 25% of patients treated with trastuzumab experience recurrence.

IMPORTANT SAFETY INFORMATION

NERLYNX (neratinib) tablets, for oral use

INDICATIONS AND USAGE: NERLYNX is a kinase inhibitor indicated for the extended adjuvant treatment of adult patients with early-stage HER2 overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.

CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS:

Diarrhea: Aggressively manage diarrhea occurring despite recommended prophylaxis 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 (≥ 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, weight decreased and urinary tract infection.

To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) and www.NERLYNX.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

DRUG INTERACTIONS:

Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors. When patients require gastric acid reducing agents, use an H2-receptor antagonist or antacid. Separate NERLYNX by at least 3 hours with antacids. Separate NERLYNX by at least 2 hours before or 10 hours after H2-receptor antagonists.
Strong or moderate CYP3A4 inhibitors: Avoid concomitant use.
Strong or moderate CYP3A4 inducers: Avoid concomitant use.
P-glycoprotein (P-gp) substrates: Monitor for adverse reactions of narrow therapeutic agents that are P-gp substrates when used concomitantly with NERLYNX.
USE IN SPECIFIC POPULATIONS:

Lactation: Advise women not to breastfeed.
Please see Full Prescribing Information for additional safety information.

The recommended dose of NERLYNX is 240 mg (six 40 mg tablets) given orally once daily with food, continuously for one year. Antidiarrheal prophylaxis should be initiated with the first dose of NERLYNX and continued during the first 2 months (56 days) of treatment and as needed thereafter.

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 www.NERLYNX.com or 1-855-816-5421.

On June 2, 2019 AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported detailed results from the Phase 3 POLO trial evaluating LYNPARZA tablets as a first-line maintenance monotherapy for patients with germline BRCA-mutated (gBRCAm) metastatic adenocarcinoma of the pancreas (pancreatic cancer) whose disease had not progressed following platinum-based chemotherapy (Press release, Merck & Co, JUN 2, 2019, View Source [SID1234536758]). The results of the trial will be featured today in a press briefing at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago and presented as a late-breaker oral presentation at 1:00 p.m. CDT during the plenary session (Abstract #LBA4). The results will also be published online simultaneously in the New England Journal of Medicine (NEJM).

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Results from the trial showed a statistically-significant and clinically-meaningful improvement in progression-free survival (PFS) for LYNPARZA compared to placebo, reducing the risk of disease progression or death by 47% (HR 0.53 [95% CI 0.35-0.82], p=0.004). The median PFS for patients treated with LYNPARZA was 7.4 months compared to 3.8 months for those on placebo, with more than twice as many patients remaining progression free at both one year (34% on LYNPARZA vs. 15% on placebo) and two years (22% vs. 10%) respectively.

Summary of PFSi,ii

Lynparza (n=92) Placebo (n=62)
Number of patients with event (%)iii 60 (65) 44 (71)
Median (in months) 7.4 3.8
Hazard ratio (95% CI) 0.53 (0.35-0.82)
P-value P=0.004
i Blinded, independent central review
ii Median duration of follow-up for progression was 9.1 months (range, 0 to 39.6) and 3.8 months (range, 0 to 29.8) in the olaparib and placebo arms, respectively
iii Analysis of the primary endpoint was performed at 68% data maturity

José Baselga, executive vice president, Oncology R&D, AstraZeneca said, "These remarkable results raise new hope for a patient population that has seen little progress over the last 20 years. The POLO trial showed that at six months, more than twice as many patients taking LYNPARZA were progression free compared to those on placebo. We are now working with regulatory authorities to bring LYNPARZA to patients as quickly as possible."

Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, "We are encouraged by the results of the POLO trial which showed a considerable reduction in risk of disease progression or death with LYNPARZA for germline BRCA-mutated metastatic pancreatic cancer patients who did not progress on chemotherapy. Currently, less than 3% of metastatic pancreatic cancer patients survive more than five years after diagnosis. The results of this trial reinforce Merck and AstraZeneca’s commitment to develop innovative treatments for cancers with few options."

Dr. Hedy L. Kindler, MD, Co-Principal Investigator of the POLO trial and professor of medicine, University of Chicago Medicine, said, "Despite efforts to identify therapies, targeted or combination treatments to improve patient outcomes, pancreatic cancer remains an area of high unmet need. The results of the POLO trial may open the door to a new era of personalized, biomarker-led care in metastatic pancreatic cancer and reinforces the importance of knowing BRCA status at diagnosis."

The safety and tolerability profile of LYNPARZA in the POLO trial was in line with that observed in prior clinical trials. The most common adverse events (AEs) ≥20% were fatigue/asthenia (60%), nausea (45%), abdominal pain (29%), diarrhea (29%), anemia (28%), decreased appetite (25%) and constipation (23%). The most common ≥ grade 3 AEs were anemia (11%), fatigue/asthenia (5%), decreased appetite (3%), abdominal pain (2%), vomiting (1%) and arthralgia (1%). Around 84% of patients on LYNPARZA remained on the recommended starting dose, while 16% had a dose reduction vs. 97% who remained on the recommended dose with placebo, while 3% had a dose reduction. Additionally, 95% of patients on LYNPARZA continued treatment without an AE-related discontinuation, while 5% had an AE-related discontinuation vs. 98% who continued treatment without an AE-related discontinuation and 2% that had an AE-related discontinuation with placebo.

LYNPARZA is not currently approved by the U.S. Food and Drug Administration (FDA) for gBRCAm pancreatic cancer.

LYNPARZA is currently approved in 64 countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer regardless of BRCA status. It is approved in the U.S. as first-line maintenance treatment in BRCAm advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in 38 countries, including the U.S., countries in the EU, and Japan, for germline BRCAm HER2-negative metastatic breast cancer previously treated with chemotherapy; in the EU this includes locally advanced breast cancer. Regulatory reviews are underway in other jurisdictions for both ovarian cancer and breast cancer.

About POLO

POLO is a Phase 3 randomized, double-blinded, placebo-controlled, multi-center study of LYNPARZA tablets (300 mg twice daily) as maintenance monotherapy vs. placebo. The trial randomized 154 patients with gBRCAm metastatic pancreatic cancer whose disease had not progressed on first-line platinum-based chemotherapy. Patients were randomized (3:2) to receive LYNPARZA or placebo until disease progression. The primary endpoint was PFS and key secondary endpoints include overall survival, time to second disease progression, overall response rate, disease control rate and health-related quality of life.

About Pancreatic Cancer

Pancreatic cancer is the 12th most common cancer worldwide, with 458,918 new cases in 2018 alone. With the worst survival rate of all the most common cancers, it is the seventh leading cause of cancer death, and less than 3% of patients with metastatic disease survive more than five years after diagnosis. Early diagnosis of pancreatic cancer is difficult, as often there are no symptoms until it is too late. Around 80% of patients are diagnosed at the metastatic stage.

There are two types of pancreatic cancer. Exocrine tumors, of which the most common type is pancreatic ductal adenocarcinoma (PDAC), start in the exocrine cells, where enzymes help to digest food. Neuroendocrine tumors start in neuroendocrine cells, which produce hormones, such as insulin, that control different functions of the body.

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 a 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. Inhibition of PARP with LYNPARZA leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. LYNPARZA is being tested in a range of tumor types with defects and dependencies in the DDR.

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 understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types.

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—First-Line Maintenance BRCAm Advanced Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection/influenza/ nasopharyngitis/bronchitis (28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), UTI (13%), thrombocytopenia (11%), and stomatitis (11%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: decrease in hemoglobin (87%), increase in mean corpuscular volume (87%), decrease in leukocytes (70%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease in platelets (35%), and increase in serum creatinine (34%).

ADVERSE REACTIONS—Maintenance Recurrent Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2 were: 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%), decreased appetite (21%), and dyspepsia (20%).

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/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%), mean corpuscular volume elevation (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 metastatic 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 or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C).

Renal Impairment: No adjustment to the starting dose is necessary in patients with mild renal impairment (CLcr=51-80 mL/min) but patients should be monitored closely for toxicity. 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:

First-Line Maintenance BRCAm Advanced Ovarian Cancer

For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients with gBRCAm advanced epithelial ovarian, fallopian tube or primary peritoneal cancer for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Maintenance Recurrent Ovarian Cancer

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.

Advanced gBRCAm ovarian cancer

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.

gBRCAm, HER2-negative metastatic breast cancer

In patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have 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 therapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Please click here for complete Prescribing Information, including Patient Information (Medication Guide).

About the AstraZeneca and Merck Strategic Oncology Collaboration

In July 2017, AstraZeneca and Merck, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialize LYNPARZA, the world’s first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. Working together, the companies will develop LYNPARZA and selumetinib in combination with other potential new medicines and as monotherapies. Independently, the companies will develop LYNPARZA and selumetinib in combination with their respective PD-L1 and PD-1 medicines.

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

On June 2, 2019 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported positive additional results of a prespecified exploratory analysis from the Phase III IMpower150 study, which demonstrated that the combination of Tecentriq (atezolizumab), Avastin (bevacizumab), carboplatin and paclitaxel (chemotherapy) gave patients with chemotherapy-naïve, metastatic non-squamous non-small cell lung cancer (NSCLC), with baseline liver metastases an overall survival (OS) advantage compared with the combination of Avastin and chemotherapy (median OS=13.3 vs 9.4 months; hazard ratio [HR]=0.52; 95% CI: 0.33–0.82) in the intention-to-treat (ITT) population.1 Safety for the Tecentriq, Avastin, and chemotherapy combination appeared consistent with the known safety profiles of the individual medicines, and no new safety signals were identified with the combination (Press release, Hoffmann-La Roche, JUN 2, 2019, View Source [SID1234536754]).

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"We are pleased to present further positive results from the Phase III IMpower150 study that show benefit in people with baseline liver metastases, a population with a worse prognosis for survival", said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "Initial treatment with Tecentriq, Avastin and chemotherapy may represent an important new option for people with baseline liver metastases, as their risk of disease worsening or death was reduced by more than half and 60% responded to the combination treatment".

These data will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting on Sunday, 2 June 2019 at 16:30–18:00 CDT (Abstract #9012).

In December 2018, the US Food and Drug Administration approved Tecentriq in combination with Avastin, carboplatin and paclitaxel for the first-line treatment of adults with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumour aberrations. This approval was based on positive data from Arm B of the Phase III IMpower150 study, which showed that Tecentriq and Avastin plus carboplatin and paclitaxel helped people live significantly longer compared with Avastin plus carboplatin and paclitaxel (median OS=19.2 vs 14.7 months; HR=0.78; p=0.016) in the intention-to-treat wild-type (ITT-WT) population.2

In March 2019, the European Commission also approved and granted marketing authorisation for Tecentriq in combination with Avastin, paclitaxel and carboplatin for the first-line treatment of adults with metastatic non-squamous NSCLC. In people with EGFR-mutant or ALK-positive NSCLC, Tecentriq, in combination with Avastin, paclitaxel and carboplatin, is indicated only after failure of appropriate targeted therapies. This approval was based on positive data from Arm B of the Phase III IMpower150 study, which showed that Tecentriq and Avastin plus carboplatin and paclitaxel helped people live significantly longer compared with Avastin plus carboplatin and paclitaxel (median OS=19.8 vs 14.9 months; HR=0.76; 95% CI: 0.63–0.96; p=0.006) in the ITT population.3

About the IMpower150 study
IMpower150 is a multicentre, open-label, randomised, controlled Phase III study evaluating the efficacy and safety of Tecentriq in combination with chemotherapy (carboplatin and paclitaxel) with or without Avastin in people with stage IV or recurrent metastatic non-squamous NSCLC who had not been treated with chemotherapy for their advanced disease. A total of 1,202 people were enrolled, of whom 1,045 were in the ITT-WT subpopulation, which excluded those people with EGFR and ALK mutations. People were randomised (1:1:1) to receive:

Tecentriq plus carboplatin and paclitaxel (Arm A), or
Tecentriq and Avastin plus carboplatin and paclitaxel (Arm B), or
Avastin plus carboplatin and paclitaxel (Arm C, control arm).
The co-primary endpoints comparing Arms B and C were OS and progression-free survival (PFS), as determined by the investigator using Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) and assessed in the ITT-WT subpopulation. Key secondary endpoints included investigator-assessed PFS, OS and safety in the ITT population. Exploratory analyses included efficacy and safety in people with baseline liver metastases.

A summary of the ITT data for the liver metastases population (a prespecified exploratory subgroup) from the IMpower150 study is included below:1

A survival advantage was observed in people who received Tecentriq in combination with Avastin and chemotherapy, compared with Avastin and chemotherapy alone (median OS=13.3 vs 9.4 months; HR=0.52; 95% CI: 0.33–0.82).
In addition, Tecentriq, Avastin and chemotherapy reduced the risk of disease worsening or death (PFS) by 59%, compared with Avastin and chemotherapy (HR=0.41; 95% CI: 0.26–0.62).
Tecentriq, Avastin and chemotherapy shrank tumours (overall response rate) in 60.8% of people (95% CI: -0.75–40.18) compared with 41.1% of people receiving Avastin and chemotherapy.
The median duration of response for people receiving Tecentriq, Avastin and chemotherapy was 10.7 months (95% CI: 0.21–0.73) compared with 4.6 months for people on Avastin and chemotherapy.
Grade 3–4 treatment-related adverse events occurred in 52.1% and 54.5% of patients with liver metastases in Arm B and Arm C, respectively.
About NSCLC
Lung cancer is the leading cause of cancer death globally.4 Each year 1.76 million people die as a result of the disease; this translates into more than 4,800 deaths worldwide every day.4 Lung cancer can be broadly divided into two major types: NSCLC and small cell lung cancer. NSCLC is the most prevalent type, accounting for around 85% of all cases.5 NSCLC comprises non-squamous and squamous-cell lung cancer, the squamous form of which is characterised by flat cells covering the airway surface when viewed under a microscope.5 Typically, 15–20% of NSCLC cases will also present with liver metastasis, which are difficult-to-treat; these patients have a poorer prognosis, with an approximately 50% increased risk of death.6 In addition, patients with liver metastases are more likely to have other metastases in the body.7

About Tecentriq
Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the activation of T cells. Tecentriq has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers.

In the United States, Tecentriq in combination with nab-paclitaxel is approved for treatment of PD-L1-positive metastatic triple-negative breast cancer; and in combination with Avastin and chemotherapy for the initial treatment of people with metastatic non-squamous NSCLC. Tecentriq is also approved in the United States as an initial treatment for extensive-stage small cell lung cancer (ES-SCLC). In the Europe Union, the non-squamous NSCLC indication includes people with EGFR mutant or ALK genomic tumour aberrations after failure of appropriate targeted therapies. Tecentriq is also approved in the European Union, United States and more than 90 countries for people with previously treated metastatic non-small cell lung cancer (NSCLC) and for certain types of untreated or previously treated metastatic urothelial carcinoma.

About Avastin
Avastin is a prescription-only medicine that is a solution for intravenous infusion. It is a biologic antibody designed to specifically bind to a protein called vascular endothelial growth factor (VEGF) that plays an important role throughout the lifecycle of the tumour to develop and maintain blood vessels, a process known as angiogenesis. Avastin is designed to interfere with the tumour blood supply by directly binding to the VEGF protein to prevent interactions with receptors on blood vessel cells. The tumour blood supply is thought to be critical to a tumour’s ability to grow and spread in the body (metastasise).

About the Tecentriq (atezolizumab) and Avastin (bevacizumab) combination
There is a strong scientific rationale to support the use of Tecentriq plus Avastin in combination. The Tecentriq and Avastin regimen may enhance the potential of the immune system to combat first-line advanced NSCLC. Avastin, in addition to its established anti-angiogenic effects, may further enhance Tecentriq’s ability to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumour infiltration and enabling priming and activation of T-cell responses against tumour antigens.

About Roche in cancer immunotherapy
For more than 50 years, Roche has been developing medicines with the goal to redefine treatment in oncology. Today, we’re investing more than ever in our effort to bring innovative treatment options that help a person’s own immune system fight cancer.

By applying our seminal research in immune tumour profiling within the framework of the Roche-devised cancer immunity cycle, we are accelerating and expanding the transformative benefits with Tecentriq to a greater number of people living with cancer. Our cancer immunotherapy development programme takes a comprehensive approach in pursuing the goal of restoring cancer immunity to improve outcomes for patients.

To learn more about the Roche approach to cancer immunotherapy please follow this link: View Source