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

On June 2, 2019, Corvus Pharmaceuticals presented the corporate presentation (Presentation, Corvus Pharmaceuticals, JUN 2, 2019, View Source [SID1234536804]).

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On June 2, 2019 Amgen (NASDAQ: AMGN) reported new data from Phase 1 studies evaluating investigational bispecific T cell engager (BiTE) molecules were presented at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Press release, Amgen, JUN 2, 2019, View Source;p=RssLanding&cat=news&id=2400287 [SID1234536742]). Data presented included updated investigational AMG 420 safety and efficacy results in patients with relapsed and/or refractory multiple myeloma (R/R MM), as well as initial results from the investigational AMG 212 (pasotuxizumab) first-in-human trial in patients with metastatic castration-resistant prostate cancer (mCRPC). BiTE technology is a targeted immuno-oncology platform that is designed to engage patients’ own T cells to a tumor-specific antigen, activating the cytotoxic potential of T cells.

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"Our BiTE immuno-oncology platform offers unique versatility, with the potential to treat various tumors through targeting tumor-associated antigens," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "As a leader in the development of targeted immuno-oncology therapies, we continue to investigate and advance more than a dozen BiTE molecules across a broad range of hematologic malignancies and solid tumors. These data at the ASCO (Free ASCO Whitepaper) Annual Meeting reinforce the potential of BiTE technology for patients with difficult-to-treat cancers like multiple myeloma and prostate cancer."

ASCO Annual Meeting Abstract #8007: Evaluation of AMG 420, An Anti-BCMA Bispecific T Cell Engager (BiTE) Immunotherapy, In R/R Multiple Myeloma (MM) Patients: Updated Results of a First-in-Human (FIH) Phase 1 Dose-Escalation Study

Updated results from a Phase 1, first-in-human dose-escalation trial of investigational AMG 420, a B-cell maturation antigen (BCMA)-targeting BiTE molecule, in patients with R/R MM were shared during an oral presentation at the ASCO (Free ASCO Whitepaper) Annual Meeting. This abstract was also selected for inclusion in the Best of ASCO (Free ASCO Whitepaper) educational program. The objectives of the study included assessment of the safety, tolerability and anti-tumor activity of AMG 420 per International Myeloma Working Group 2006 Uniform Response Criteria for Multiple Myeloma. In the study, 42 patients with R/R MM who had progression after at least two prior lines of treatment (including a proteasome inhibitor and an immunomodulatory imide drug) received AMG 420 at varying doses [0.2 to 800 µg/day (d)]. Of the doses tested in this study, 400 µg/d was the maximum tolerated dose (MTD).

As of the latest readout, AMG 420 induced clinical responses in 13 of 42 patients across the dosing cohorts. Of the six patients that achieved a minimal residual disease (MRD)-negative complete response (CR), five were treated at the 400 µg/d dose. In addition, at the 400 µg/d dose, one patient achieved a very good partial response, and one achieved a partial response. The overall response rate at 400 µg/d was 70 percent (7/10). The median duration of response was nine months (range 5.8-13.6 months). Median time to response was one month, with 11 of 13 patients responding in the first cycle.

Serious adverse events (AEs) were reported in 19 patients (45 percent). Sixteen required hospitalization and four had prolonged hospitalization. No grade 3 or 4 central nervous system toxicities were observed. Serious AEs occurring in more than one patient included infections (n=13) and peripheral polyneuropathy (n=2). Treatment-related serious AEs included polyneuropathy (n=2, both grade 3) and edema (n=1, grade 3). Grade 3 cytokine release syndrome (CRS) was seen in one patient. Two patients died during the study from AEs not considered treatment-related: one patient died from acute respiratory distress due to concurrent flu and aspergillosis, and the second patient died from liver failure secondary to a viral infection during the course of treatment.

"These updated results presented at the ASCO (Free ASCO Whitepaper) Annual Meeting showed that AMG 420 at the 400 µg/d dose was efficacious with no new safety concerns in heavily pre-treated patients with relapsed and/or refractory multiple myeloma," said Max S. Topp, M.D., professor, University Hospital of Wuerzburg, Germany, and AMG 420 clinical study investigator. "Based on these results, we recommend AMG 420 at the 400 µg/d dose for further investigation."

ASCO 2019 Abstract #5034: Phase 1 Study of Pasotuxizumab (BAY 2010112), a PSMA-targeting BiTE (Bispecific T Cell Engager) Immunotherapy for Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Initial results from a Phase 1 dose-escalation study of investigational AMG 212 (pasotuxizumab, formerly known as BAY 2010112), in patients with mCRPC who are refractory to standard therapy were presented in a poster at the ASCO (Free ASCO Whitepaper) Annual Meeting. AMG 212 is an investigational BiTE molecule which is designed to target prostate-specific membrane antigen (PSMA), a promising target in mCRPC. In the trial, 16 patients with mCRPC were enrolled into five dosing cohorts, with a target dose range of 5 to 80 µg/d delivered by continuous intravenous infusion. The primary objective was to determine safety and MTD and secondary objectives included pharmacokinetics (PK), biomarkers and tumor response. Antitumor activity as indicated by decline in serum level of prostate-specific antigen (PSA) was dose dependent. PSA decreases of ≥ 50 percent occurred in three patients (n=1 each in 20 µg/d, 40 µg/d and 80 µg/d cohorts). One long-term responder was treated for 14 months (40 µg/d) and one for 19.4 months (80 µg/d). The latter patient showed a complete regression of soft-tissue metastases and marked regression of bone metastases, as well as a significant and durable improvement in disease-related symptoms. Recruitment in the trial was stopped before MTD was reached to facilitate initiation of a new study sponsored by Amgen.

"Metastatic castrate-resistant prostate cancer is considered a heterogenous disease and despite advances made over the last few years, the majority of patients face a poor outlook1," said Horst-Dieter Hummel, M.D., University Hospital of Wuerzburg, Germany, and AMG 212 clinical study investigator. "In the first clinical study investigating the potential of a BiTE molecule in solid tumors, AMG 212 showed clinical activity, including two long-term responders. We look forward to studying AMG 212 further in this patient population."

The most common drug-related AEs were fever (94 percent, n=15) and chills (69 percent, n=11). A drug-related serious AE (fatigue) was reported in one patient. CRS was reported for three patients (19 percent); two were grade 2 and one was grade 3. No grade 5 AEs occurred.

Additional Updates on Amgen’s BiTE Immuno-Oncology Platform at ASCO (Free ASCO Whitepaper) 2019
Amgen continues to investigate the BiTE immuno-oncology platform across a broad range of solid and hematologic malignancies with the goal of enhancing patient experience and therapeutic potential. Amgen is investigating more than a dozen BiTE molecules across a range of solid and hematologic malignancies, with an additional two trials-in-progress being presented at the ASCO (Free ASCO Whitepaper) Annual Meeting.

During poster sessions, researchers shared information on the studies of AMG 596, an investigational BiTE molecule targeting epidermal growth factor receptor variant III (EGFRvIII) in glioblastoma (GBM), and AMG 757, an investigational BiTE molecule targeting delta-like ligand 3 (DLL3) in small-cell lung cancer (SCLC). GBM and SCLC are both aggressive and difficult-to-treat forms of cancer where there is a significant unmet medical need for patients.

Forty-three percent of GBM tumors test positive for amplification or mutation of the EGFR, the most common of which is the EGFRvIII gain-of-function mutation.2 A Phase 1, first-in-human, open-label, sequential dose-escalation and dose-expansion study is ongoing for investigational AMG 596, evaluating its safety, tolerability, and PK and pharmacodynamics in patients with EGFRvIII-postive glioblastoma. The study is expected to enroll 82 patients in two groups: one with recurrent GBM and a second in newly diagnosed patients in the maintenance treatment phase following standard of care treatment.

DLL3 is an inhibitory ligand of notch receptors that is expressed in most SCLC tumors but minimally expressed in normal tissues.3 An ongoing open-label, ascending, multiple-dose, Phase 1 study is evaluating investigational AMG 757 in adult patients with SCLC which has progressed or recurred after at least one platinum-based chemotherapy regimen. Primary objectives are to evaluate safety and tolerability and to determine the MTD or recommended Phase 2 dose. Secondary objectives are to characterize PK and evaluate preliminary anti-tumor activity.

For more information on these and other ongoing clinical trials, visit www.AmgenTrials.com.

Amgen Webcast Investor Meeting
Amgen will host a webcast investor meeting at ASCO (Free ASCO Whitepaper) 2019 on Monday, June 3 at 6:30 p.m. CT. David M. Reese, M.D., executive vice president of Research and Development at Amgen, along with members of Amgen’s clinical development team and clinical investigators, will participate at the investor meeting to discuss Amgen’s oncology program and data presented at ASCO (Free ASCO Whitepaper) 2019.

Live audio of the conference call will be broadcast over the internet simultaneously and will be available to members of the news media, investors and the general public.

The webcast, as with other selected presentations regarding developments in Amgen’s business given at certain investor and medical conferences, can be accessed on Amgen’s website, www.amgen.com, under Investors. Information regarding presentation times, webcast availability and webcast links are noted on Amgen’s Investor Relations Events Calendar. The webcast will be archived and available for replay for at least 90 days after the event.

About BiTE Technology
BiTE (Bispecific T cell engager) technology is a targeted immuno-oncology platform that is designed to engage patients’ own T cells to any tumor-specific antigen, activating the cytotoxic potential of T cells with the goal of eliminating detectable cancer. The BiTE immuno-oncology platform has the potential to treat different tumor types through tumor-specific antigens. The BiTE platform has the goal of off-the-shelf solutions, which have the potential to make innovative T cell treatment available to all providers when their patients need it. Amgen is advancing more than a dozen BiTE molecules across a broad range of solid and hematologic malignancies, further investigating BiTE technology with the goal of enhancing patient experience and therapeutic potential.

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 AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) reported detailed results from the Phase III POLO trial at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, US (Abs #LBA4) (Press release, AstraZeneca, JUN 2, 2019, View Source [SID1234536743]). Results are today also published in The New England Journal of Medicine (NEJM).

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The POLO trial tested Lynparza (olaparib) tablets as 1st-line maintenance monotherapy for patients with germline BRCA-mutated (gBRCAm) metastatic adenocarcinoma of the pancreas (pancreatic cancer) whose disease had not progressed following standard-of-care platinum-based 1st-line chemotherapy.

Results from the trial showed a statistically-significant and clinically-meaningful improvement in progression-free survival (PFS) for Lynparza vs. placebo, improving the time without disease progression by a median of 7.4 months for patients treated with Lynparza vs. 3.8 months for those on placebo (HR 0.53 [95% CI, 0.35-0.82], p=0.004). More than twice as many patients showed no disease progression both at one year (34% on Lynparza vs. 15% on placebo) and two years (22% vs. 10%, respectively).

José Baselga, Executive Vice President, Oncology R&D, said: "These unprecedented results raise new hope for patients that have seen little progress over a long period of time. From as early as six months after initiation, more than twice as many patients taking Lynparza lived without progression of their disease compared to those on placebo and we are now working with regulatory authorities to bring Lynparza to patients as quickly as possible."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD 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 MSD and AstraZeneca’s commitment to develop innovative treatments for cancers with few options."

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 personalised, biomarker-led care in metastatic pancreatic cancer and reinforces the importance of knowing BRCA status at diagnosis."

Kaplan-Meier estimates of PFS by blinded, independent central review

From The New England Journal of Medicine, Golan T, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer, Jun 2 [Epub ahead of print] Copyright © 2019 Massachusetts Medical Society. Reprinted with permission from the Massachusetts Medical Society.

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%), diarrhoea (29%), anaemia (28%), decreased appetite (25%) and constipation (23%). The most common ≥ grade 3 AEs were anaemia (11%), fatigue/asthenia (5%), decreased appetite (3%), abdominal pain (2%), vomiting (1%) and arthralgia (1%). AEs led to dose interruption in 16% of patients on Lynparza while 5% of patients discontinued treatment.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, is approved for multiple indications in advanced ovarian cancer and metastatic breast cancer and has been used in over 20,000 patients worldwide.

About POLO

POLO is a Phase III randomised, double-blinded, placebo-controlled, multicentre trial of Lynparza tablets (300mg twice daily) as maintenance monotherapy vs. placebo. The trial randomised 154 patients with gBRCAm metastatic pancreatic cancer whose disease had not progressed on 1st-line platinum-based chemotherapy. Patients were randomised (3:2) to receive Lynparza or placebo until disease progression. The primary endpoint was PFS and key secondary endpoints included 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,1 with 458,918 new cases in 2018 alone.1 With the worst survival rate of all the most common cancers,2 it is the 4th leading cause of cancer death,3 and less than 3% of patients with metastatic disease survive more than five years after diagnosis.4 Early diagnosis of pancreatic cancer is difficult, as often there are no symptoms until it is too late.5 Around 80% of patients are diagnosed at the metastatic stage.6

There are two types of pancreatic cancer. Exocrine tumours, of which the most common type is pancreatic ductal adenocarcinoma (PDAC),7 start in the exocrine cells, where enzymes help to digest food. Neuroendocrine tumours start in neuroendocrine cells, which produce hormones, such as insulin,6 that control different functions of the body.

About BRCA mutations

Breast cancer susceptibility genes 1/2 (BRCA1 and BRCA2) are human genes that produce proteins responsible for repairing damaged DNA and play an important role 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

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2. 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 PARP-dependent tumour types with defects and dependencies in the DDR.

Lynparza is currently approved in over 60 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 US, Canada and Brazil as 1st-line maintenance treatment of BRCAm advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in nearly 40 countries, including the US 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.

Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

About the AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise 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.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.