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

On June 2, 2019 Celgene Corporation (NASDAQ: CELG) reported the first clinical results evaluating iberdomide (CC-220) in combination with dexamethasone in patients with relapsed and refractory multiple myeloma from the ongoing phase 1/2 CC-220-MM-001 study during an oral presentation at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Celgene, JUN 2, 2019, View Source [SID1234536749]).

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The results included preliminary safety and efficacy data from the ongoing multicenter, open-label, dose-escalation study, which aims to determine the maximum tolerated dose and the recommended phase 2 dose of iberdomide in combination with dexamethasone. Iberdomide is Celgene’s proprietary cereblon E3 ligase modulator (CELMoD) compound with enhanced tumoricidal and immune stimulatory effects demonstrated in preclinical studies. The phase 1/2 study is expected to enroll approximately 300 participants.

"Nearly half a million people globally are affected by multiple myeloma, a cancer of plasma cells. The management of patients with late relapsed or refractory multiple myeloma continues to be challenging due to the complex nature of the disease’s pathophysiology. Despite the introduction of newer agents, patients continue to experience disease relapse therefore new therapeutic options are needed for patients who have failed multiple prior treatments," said Sagar Lonial, MD, Chief Medical Officer at Winship Cancer Institute of Emory University. "The early data on iberdomide in combination with dexamethasone in these heavily pretreated patients show promising activity, and we look forward to advancing our understanding of this combination’s potential in this patient population."

As of April 2019, 66 patients at a median age of 65 received the iberdomide plus dexamethasone combination, with iberdomide being administered in 8 incremental doses ranging from 0.3 mg to 1.3 mg. Escalating doses of iberdomide were given on days 1 through 21 in combination with dexamethasone (40 mg; 20 mg in patients older than 75) on days 1, 8, 15, and 22 of each 28-day cycle. Patients had a median of five prior multiple myeloma treatment regimens, which could have included stem cell transplant, immunomodulatory drugs including lenalidomide and pomalidomide, proteasome inhibitors and daratumumab.

Grade 3-4 adverse events (AE) reported included neutropenia (29%), infection (26%), anemia (24%), thrombocytopenia (12%), pulmonary embolism (1.5%) and peripheral sensory neuropathy (1.5%). Six patients (9%) discontinued treatment due to adverse events.

Of the 66 patients who received the iberdomide plus dexamethasone combination, 59 were evaluable for response. The overall response rate was 32% (19/59), with 29% (17/59) achieving a partial response and two patients achieving a very good partial response.

Patients (n=51) who were refractory to IMiD compounds, which included lenalidomide and pomalidomide, had an overall response rate of 35% (18/51) with 33% (17/51) of patients achieving a partial response and one patient achieving a very good partial response. Further, patients who were refractory to both daratumumab and pomalidomide (n=27) had an overall response rate of 29% (8/27), with 25% (7/27) achieving a partial response and one patient achieving a very good partial response. Maximum tolerated dose and the recommended phase 2 dose have not yet been determined.

"While we have made tremendous progress in treating multiple myeloma, there is still a significant need for new options to address the heterogeneous nature of the disease. We are focused on exploring the potential of our next generation CELMoD compounds to help fill this gap," said Dr. Alise Reicin, President, Global Clinical Development for Celgene. "The preliminary clinical activity and favorable safety data observed with the combination of iberdomide and dexamethasone are encouraging, particularly in patients who have failed multiple lines of therapy including patients who were refractory to lenalidomide, pomalidomide and/or daratumumab."

The phase 1/2 study is also evaluating iberdomide as monotherapy and in combination with daratumumab or bortezomib or carfilzomib. Iberdomide is investigational and has not been approved in any country.

About Iberdomide (CC-220)

Iberdomide is an investigational cereblon E3 ligase modulator (CELMoD) compound that induces degradation of transcription factors Aiolos and Ikaros, thereby inhibiting growth of myeloma cells in vitro. In pre-clinical models, iberdomide has demonstrated ability to destroy tumor cells, stimulate an immune response, overcome resistance to immunomodulatory drugs, and synergize with dexamethasone, daratumumab and bortezomib.

About CC-220-MM-001

The open-label phase 1/2 CC-220-MM-001 dose escalation study (NCT02773030) seeks to determine the maximum tolerated dose and recommended phase 2 dose of iberdomide (CC-220) as monotherapy and in combination with dexamethasone, as well as further evaluate safety and preliminary efficacy in patients with relapsed/refractory multiple myeloma. The study consists of a dose-escalation portion (Part 1) as well as an expansion of these two cohorts at the recommended phase 2 dose to further evaluate safety and estimate preliminary efficacy (Part 2). The study also seeks to establish the maximum tolerated dose and recommended phase 2 dose of iberdomide when administered in combination with daratumumab or bortezomib or carfilzomib.

About Multiple Myeloma

Multiple myeloma is a life-threatening blood cancer that is characterized by tumor proliferation and suppression of the immune system.1 It is a rare but deadly disease – more than 32,000 new cases will be diagnosed in the United States in 2019, and approximately 13,000 deaths will occur in 2019, representing about 2.1% of all cancer-related deaths.2 The typical multiple myeloma disease course includes periods of symptomatic myeloma followed by periods of remission, and eventually, the disease becomes refractory (nonresponsive).

On June 2, 2019 BerGenBio ASA (OSE: BGBIO) a clinical-stage biopharmaceutical company developing novel, selective AXL kinase inhibitors for multiple cancer indications, reported updated data from its Phase II clinical trial (BGBC008, NCT03184571) with bemcentinib and Merck’s anti-PD-1 therapy KEYTRUDA (pembrolizumab) in patients with advanced non-small cell lung cancer (NSCLC) at the 2019 annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, Illinois (31 May – 4 June 2019) (Press release, BerGenBio, JUN 2, 2019, View Source [SID1234536748]).

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At data cut off, 35 out of 46 enrolled patients were evaluable; 58% were AXL +ve, and 53% were PD-L1 negative (<1%TPS), and a further 39% were PD-L1 (1-49% TPS). An objective response rate of 40% was achieved in AXL +ve patients, irrespective of the patients PD-L1 score; and an overall response rate of 29% was achieved. The median survival rate of 12.2 months was observed at the time of data cut-off, significantly surpassing what has been shown historically in second line treatment with PD-1 inhibitor monotherapy.

The combination treatment of bemcentinib and pembrolizumab was overall well-tolerated; the most common adverse events included transaminase increase (35%), fatigue (30%), and diarrhoea (26%). No grade 5 treatment related adverse events were reported and all events were reversible.

Principal investigator Enriqueta Filip, Vall d’Hebron University Hospital, Barcelona
" Following the rapid uptake of checkpoint inhibitors in first-line lung cancer therapy, treatment options for NSCLC cancer patients that have not responded to anti-PD-1 therapies such as KEYTRUDA represent a significant unmet medical need. These data, which suggest that combination therapy with bemcentinib has the potential to enhance patient responses to these novel agents, particularly in patients with no or limited expression of PD-L1, is a very significant and encouraging development."

Richard Godfrey, Chief Executive Officer of BerGenBio, commented: "The clinical activity we are presenting here today surpasses what has been shown historically in previously-treated, PD-L1 low patients on PD-1 inhibitor monotherapy, and supports the hypothesis that AXL is implicated in the failure of anti-PD-L1 therapies. Further investigation is warranted and having recently extended the trial to include patients showing disease progression on checkpoint inhibitors, we will continue to test this hypothesis and look forward to providing further updates during 2019."

-END–

About NSCLC
It is estimated that more than 230,000 new cases of lung cancer have been diagnosed in the US in 2018 and it is the leading cause of cancer deaths. 65% of non-small cell lung cancers (NSCLC) are of adenocarcinoma pathology. Although various treatments exist for NSCLC, they are often curtailed by acquired resistance to therapy and immune evasion. Novel treatments overcoming these mechanisms in NSCLC are urgently required.

About the BGBC008 trial
The BGBC008 trial is a Phase II open-label study of bemcentinib in combination with KEYTRUDA (pembrolizumab) in previously treated patients with advanced adenocarcinoma of the lung, run at centres in the US, UK, Spain and Norway. The objective of the trial is to determine the anti-tumour activity of this novel drug combination and responses will be correlated with biomarker status (including AXL kinase and PD-L1 expression).

Patients eligible for participation in Cohort A must have progressed on or after prior therapy excluding immunotherapy whereas patients in Cohort B will be actively progressing on a therapy regimen containing an anti-PD(L)-1 therapy.

Both cohorts follow a two-stage design, Cohort A has previously successfully progressed into the second stage after meeting its first efficacy endpoint. Cohort B will evaluate advancement into stage 2 after 13 patients have been assessed for response.

For more information please access trial NCT03184571 at www.clinicaltrials.gov.

On June 2, 2019 AstraZeneca has reported three-year overall survival (OS) results from the Phase III PACIFIC trial of Imfinzi (durvalumab) in unresectable, Stage III non-small cell lung cancer (NSCLC) during the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, AstraZeneca, JUN 2, 2019, View Source [SID1234536744]).

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These latest results show a durable and sustained OS benefit in patients with unresectable, Stage III NSCLC who had not progressed following concurrent chemoradiation therapy (CRT), a previous standard-of-care (SoC) treatment. The OS rate was 57% at three years for patients receiving Imfinzi vs. 43.5% for placebo following concurrent CRT. Median OS was not yet reached with the Imfinzi arm vs. 29.1 months for placebo.

Dave Fredrickson, Executive Vice President, Oncology Business Unit said: "These findings for Imfinzi are another example of our focus on bringing long-term survival benefits to patients who still have a chance of being cured. These three-year survival results further establish the PACIFIC regimen as the standard of care for these patients, and we are optimistic this survival trend will continue as we move towards the five-year landmark in this curative-intent setting."

Results build on the primary two-year OS analysis that was published in The New England Journal of Medicine in September 2018 and demonstrated a significant OS benefit for treatment with Imfinzi vs. placebo after CRT, regardless of PD-L1 expression. The primary analysis showed Imfinzi reduced the risk of death by 32% (HR 0.68, [99.73% CI, 0.47-0.997], p=0.0025).

With the additional year of follow up, the latest results for Imfinzi showed consistent and durable efficacy, maintaining a 31% reduction in the risk of death vs. placebo after CRT (HR 0.69, [95% CI 0.55-0.86]).

Jhanelle Gray, MD, Director of Clinical Research in the Thoracic Oncology Department at Moffitt Cancer Center in Tampa, Florida, and an investigator in the PACIFIC trial, said: "In the past, patients with unresectable, Stage III non-small cell lung cancer faced five-year survival rates of only 15% to 30%. It is remarkable to see that more than half of patients treated with the PACIFIC regimen remain alive at three years, an important milestone that raises the bar for treatments in this curative-intent setting."

The safety and tolerability profile for Imfinzi was consistent with the results reported at the time of the previous OS analysis. Among patients receiving Imfinzi, the most common adverse events (AE) (greater than or equal to 20% of patients) vs. placebo were cough (35.2% vs. 25.2%), fatigue (24.0% vs. 20.5%), dyspnoea (22.3% vs. 23.9%) and radiation pneumonitis (20.2% vs. 15.8%). 30.5% of patients experienced a grade 3 or 4 AE with Imfinzi vs. 26.1% with placebo, and 15.4% of patients discontinued treatment due to AEs with Imfinzi vs. 9.8% of patients on placebo.

Building on PACIFIC

AstraZeneca has several ongoing trials focused on testing Imfinzi in earlier stages of NSCLC (Stages I-III) in potentially-curative settings. The Phase III PACIFIC-2 trial design, presented today at the ASCO (Free ASCO Whitepaper) Annual Meeting, is evaluating Imfinzi given concurrently with CRT in patients with unresectable, Stage III NSCLC. In the Phase II PACIFIC-6 trial, Imfinzi is being tested in the same population following sequential chemotherapy and radiation therapy.

Additional trials assess Imfinzi in the neoadjuvant setting (prior to other treatments) in Stage II and III NSCLC patients (AEGEAN) and in the adjuvant setting (following the primary treatment) in Stage I to III (BR.31). The Phase III PACIFIC-4 trial is testing Imfinzi in unresected Stage I and II NSCLC patients following definitive stereotactic body radiation therapy (SBRT).

AstraZeneca is also testing novel combinations with Imfinzi in two Phase II platform trials in both unresectable, Stage III disease (COAST) and in resectable Stage I-III disease starting before surgery (NeoCOAST), to help find solutions for NSCLC patients not benefiting from currently-available therapies.

Immuno-Oncology trials in early-stage non-small cell lung cancer (NSCLC)

Trial name

Phase

Population

Trial arms

Stages I-III

PACIFIC-4

Phase III

Unresected, Stage I/II NSCLC

Imfinzi monotherapy vs. placebo following definitive SBRT

AEGEAN

Phase III

Resectable, Stage II and III NSCLC, neoadjuvant (incl. EGFR/ALK positive)1

SoC chemotherapy + Imfinzi vs. SoC chemotherapy + placebo followed by surgery

ADJUVANT BR.312

Phase III

Completely resected, Stage Ib-IIIa NSCLC (incl. EGFR/ALK positive)1

Placebo vs. Imfinzi monotherapy

NeoCOAST

Phase II

Resectable, Stage I-IIIA NSCLC

Imfinzi in combination with potential new medicines vs. Imfinzi monotherapy followed by surgery

COAST

Phase II

Unresectable, Stage III NSCLC following concurrent CRT

Imfinzi in combination with potential new medicines vs. Imfinzi monotherapy

Stage III

PACIFIC-2

Phase III

Unresected, Stage III NSCLC

Concurrent CRT + placebo vs. concurrent CRT + Imfinzi

PACIFIC-5

Phase III

Unresected, Stage III NSCLC (ex US global trial, China focus)

Placebo following concurrent CRT vs. Imfinzi following concurrent CRT

PACIFIC-6

Phase II

Unresectable, Stage III NSCLC

Imfinzi following sequential CRT

1. EGFR = epidermal growth factor receptor, ALK = anaplastic lymphoma kinase
2. BR.31 is an externally-sponsored research study led by the Canadian Cancer Trials Group (CCTG)

Imfinzi is approved for the treatment of unresectable, Stage III non-small cell lung cancer in more than 45 countries, including the US, EU and Japan, based on the Phase III PACIFIC trial. Since the first approval in February 2018, more than 20,000 patients in this setting have been treated with Imfinzi.

About PACIFIC

The PACIFIC trial is a Phase III, randomised, double-blinded, placebo-controlled, multi-centre trial of Imfinzi as treatment in ‘all-comer’ patients (i.e. regardless of PD-L1 status) with unresectable, Stage III (locally-advanced) NSCLC whose disease has not progressed following platinum-based chemotherapy and radiation therapy (CRT).

The trial is being conducted in 235 centres across 26 countries involving 713 patients. The primary endpoints of the trial are progression-free survival (PFS) and OS, and secondary endpoints include landmark PFS and OS, objective response rate, and duration of response.

About Stage III NSCLC

Stage III (locally-advanced) NSCLC is commonly divided into three sub-categories (IIIA, IIIB and IIIC), defined by how much the cancer has spread locally and the possibility of surgery.1 Stage III disease is different from Stage IV disease, when the cancer has spread (metastasised) to distant organs, as Stage III is currently treated with curative intent.1,2

Stage III NSCLC represents approximately one-third of NSCLC incidence and was estimated to affect nearly 200,000 patients in the top-eight countries (China, France, Germany, Italy, Japan, Spain, UK, US) in 2015.3,4 The majority of Stage III NSCLC patients are diagnosed with unresectable tumours.5 No new treatments beyond chemoradiation therapy, followed by active surveillance to monitor for progression, have been available to patients for decades.6-9

About Imfinzi

Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is approved for unresectable, Stage III NSCLC in more than 45 countries including the US, in the EU, and Japan based on the Phase III PACIFIC trial. Imfinzi is also approved for previously-treated patients with advanced bladder cancer in the US, Canada, Brazil, Australia, Israel, India, United Arab Emirates, Qatar, Macau and Hong Kong.

As part of a broad development programme, Imfinzi is also being tested as a monotherapy and in combination with tremelimumab, an anti-CTLA4 monoclonal antibody and potential new medicine, as a treatment for patients with NSCLC, small cell lung cancer, bladder cancer, head and neck cancer, liver cancer, cervical cancer, biliary tract cancer and other solid tumours.
About AstraZeneca in lung cancer

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage clinical development for the treatment of different forms of lung cancer spanning several stages of disease, lines of therapy and modes of action. We aim to address the unmet needs of patients with EGFR-mutated tumours as a genetic driver of disease, which occur in 10-15% of NSCLC patients in the US and EU and 30-40% of NSCLC patients in Asia, with our approved medicines Iressa (gefitinib) and Tagrisso (osimertinib), and ongoing Phase III trials FLAURA, ADAURA and LAURA as well as the Phase II exploratory combination trials SAVANNAH and ORCHARD.10-12

Our extensive late-stage Immuno-Oncology programme focuses on lung cancer patients without a known genetic mutation which represents up to 50% of all patients with lung cancer. Imfinzi (durvalumab), an anti-PDL1 antibody, is in development as monotherapy (Phase III trials ADJUVANT BR.31, PACIFIC-4, PACIFIC-5, and PEARL) and in combination with tremelimumab and/or chemotherapy (AEGEAN, PACIFIC-2, NEPTUNE, POSEIDON, ADRIATIC and CASPIAN Phase III trials).

About AstraZeneca’s approach to Immuno-Oncology (IO)

IO is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. Our IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumour immune suppression. We believe that IO-based therapies offer the potential for life-changing cancer treatments for the clear majority of patients.

We are pursuing a comprehensive clinical-trial programme that includes Imfinzi (anti-PDL1) as monotherapy and in combination with tremelimumab (anti-CTLA4) in multiple tumour types, stages of disease, and lines of therapy, using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient. In addition, the ability to combine our IO portfolio with small, targeted molecules from across our Oncology pipeline, and from our research partners, may provide new treatment options across a broad range of tumours.

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.