On June 4, 2018 AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., US (Merck: known as MSD outside the US and Canada) reported data, which showed clinical improvement in median radiologic progression-free survival (rPFS) with Lynparza (olaparib) in combination with abiraterone compared to abiraterone monotherapy, a standard of care, in metastatic castration-resistant prostate cancer (mCRPC) (Press release, AstraZeneca, JUN 4, 2018, View Source [SID1234527133]). Lynparza is being jointly developed and commercialised by AstraZeneca and MSD.

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The results of Study 08, a randomised, double-blinded, multi-centre Phase II trial, comparing Lynparza in combination with abiraterone (n=71) to abiraterone monotherapy (n=71) in patients with previously-treated mCRPC, regardless of homologous recombination repair (HRR) mutation status, were presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, US, 1-5 June 2018 as a "Best of ASCO (Free ASCO Whitepaper) presentation" and were published online today in the Lancet Oncology. The primary endpoint was rPFS. Secondary endpoints included time to second progression or death (PFS2), overall survival (OS) and health-related quality of life.

Noel Clarke, Professor of Urological Oncology, Christie NHS Foundation Trust, Manchester, UK, said: "This is the first time we have seen an improvement with the use of a PARP inhibitor in combination with abiraterone in patients with metastatic castration-resistant prostate cancer and this effect may be independent of HRR status. The data suggest this therapeutic combination may be a promising new treatment approach for this aggressive disease."

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "A previous trial demonstrated improvements in response rates with Lynparza monotherapy in metastatic castration-resistant patients with HRR mutations. The Study 08 combination data suggests that regardless of their mutation status, men with metastatic castration-resistant prostate cancer may potentially benefit from Lynparza in combination with abiraterone."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "There is a significant unmet medical need for patients with metastatic castration-resistant prostate cancer as they are a high-risk group with limited treatment options. Lynparza is the first PARP inhibitor to demonstrate activity in combination with standard-of-care treatment in prostate cancer. These data from Study 08 represent another important milestone in the clinical development of Lynparza."

Median rPFS was 13.8 months with Lynparza and abiraterone compared to 8.2 months with abiraterone alone (HR 0.65; 95% CI 0.44-0.97; p=0.034). Median PFS2 was 23.3 months vs 18.5 months (HR 0.79; 95% CI 0.51–1.21). Median OS was 22.7 months with combination treatment versus 20.9 months with abiraterone alone (HR 0.91; 95% CI 0.60–1.38). Pre-specified exploratory subgroup analyses demonstrated an rPFS improvement in patients, regardless of HRR status (see Table 1). Study 08 was not powered for subgroup analyses, PFS2 and OS.

The safety profile of Lynparza and abiraterone was generally manageable, with no detrimental effect on quality of life compared to abiraterone alone. Grade ≥3 adverse events (AEs), serious AEs and treatment discontinuations due to AEs were more frequent with combination treatment than abiraterone alone (54% and 28%; 34% and 18%; 30% and 10%, respectively). The most common grade ≥3 AEs in the combination arm were anaemia (21%), pneumonia (6%) and myocardial infarction (6%). Serious cardiovascular events occurred in seven patients in the combination group and one patient in the abiraterone group.

In addition to Study 08, other studies are underway to explore the potential of Lynparza as a monotherapy for HRR-mutated mCRPC, including PROfound, which is testing Lynparza monotherapy vs. enzalutamide or abiraterone in patients with previously-untreated mCRPC. Additional trials are planned to explore Lynparza in combination for the treatment of mCRPC regardless of HRR status. Lynparza was granted Breakthrough Therapy Designation by the US Food and Drug Administration in 2016 for the treatment of BRCA-mutated or ATM-gene-mutated mCRPC.

Lynparza is a first-in-class PARP inhibitor approved for advanced ovarian cancer and metastatic breast cancer and has been used in over 20,000 patients. Lynparza has the broadest and most-advanced clinical trial development programme and AstraZeneca and MSD are working together to deliver Lynparza as quickly as possible to more patients across multiple cancer types, including prostate and pancreatic cancers.

NOTES TO EDITORS
About Study 08

Study 08 was a global, randomised, double-blinded, multi-centre Phase II trial of 142 patients, assessing the efficacy and safety of Lynparza tablets (300mg twice daily) and abiraterone tablets (4 x 250mg once daily) (n=71) compared to matched placebo and abiraterone tablets (4 x 250mg once daily) (n=71) in patients with metastatic castration-resistant prostate cancer (mCRPC), regardless of HRR status. Prednisone/prednisolone (5mg BID) was administered to patients in both treatment arms.

Patients in Study 08 had previously received docetaxel for mCRPC. Prior to enrolment, patients had received no more than two lines of chemotherapy.

The primary endpoint was radiologic progression-free survival (rPFS) (time from randomisation to radiologic progression or death). rPFS is increasingly used in clinical trials of mCRPC as a clinically-meaningful endpoint focusing on the impact of treatment on the disease progression to areas where spread of prostate cancer is common, notably soft tissue and bone.

Secondary endpoints included time to second progression or death, overall survival and health-related quality of life.

About metastatic castration-resistant prostate cancer (mCRPC)

Prostate cancer is the second-most common cancer in men, with an estimated 1.6 million new cases diagnosed worldwide in 2015 and is associated with a significant mortality rate.[i] Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.[ii] mCRPC occurs when prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.ii Approximately 10-20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these will have metastases at the time of CRPC diagnosis.[iii] Of men with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.iii Despite an increase in the number of available therapies for men with mCRPC, five-year survival is only 28%.iii

About Lynparza

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

Lynparza, which has the broadest clinical development programme of any PARP inhibitor, is being tested in a range of DDR-deficient tumour types, and is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

On June 4, 2018 OncoSec Medical Incorporated (OncoSec) (NASDAQ:ONCS), a company developing intratumoral cancer immunotherapies, reported the presentation of a Trials in Progress poster at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting taking place in Chicago, IL (Press release, OncoSec Medical, JUN 4, 2018, View Source [SID1234527149]).

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Titled, Trial in Progress, A Phase 2 Study of Intratumoral pIL-12 Plus Electroporation In Combination With Intravenous Pembrolizumab In Patients With Stage III/IV Melanoma Progressing on Either Pembrolizumab or Nivolumab Treatments (PISCES/KEYNOTE-695), the poster provides an update on OncoSec’s global, multi-center, registration-directed open-label Phase 2b clinical trial, assessing the Company’s investigational therapy, (intratumoral pIL-12 [tavokinogene telseplasmid] delivered with electroporation) ("tavo" or "ImmunoPulse IL-12"), and the approved anti-PD-1 therapy pembrolizumab, in patients with unresectable metastatic melanoma who have progressed or are progressing on an anti-PD-1 therapy.

PISCES/KEYNOTE-695, a phase 2b, Simon 2-stage multicenter study of tavo in combination with intravenous KEYTRUDA, will enroll approximately 48 patients with histological diagnosis of melanoma with progressive locally advanced or metastatic disease defined as Stage III or Stage IV. Stage 1 of the study will enroll 23 patients. The primary endpoint will be the Best Overall Response Rate (BORR).

Numerous sites in the U.S., Australia, and Canada are open and enrolling patients. The Company anticipates that enrollment in stage 1 will be completed by the third quarter 2018.

"Despite the addition of immunotherapy and targeted therapies, disease progression continues to occur in a significant percentage of advanced melanoma patients," said OncoSec Chief Clinical and Regulatory Officer, Sharron Gargosky, Ph.D. "We are pleased with our progress as we continue to enroll patients in the KEYNOTE-695 trial, which is evaluating the tolerability and efficacy of pembrolizumab plus tavo in Stage III/IV melanoma patients who have progressed or are progressing on approved checkpoint inhibitors."

The Company’s prior Phase 2 combination study of tavo and pembrolizumab (OMS-102) in 22 patients unlikely to respond to anti-PD-1 therapy demonstrated a 50% best overall response rate and a 41% complete response rate. In addition, the trial showed a 57% progression free survival (PFS) rate at 15 months (median PFS not yet reached) and 100% (11/11) duration of response. In clinical studies to date, tavo has demonstrated a favorable safety profile and has been well tolerated.

PISCES/KEYNOTE-695 is the second combination study conducted with tavo and pembrolizumab and, if successful, could form the basis for a BLA under the accelerated approval pathway.

Tavo has received both Orphan Drug and Fast-Track Designation by the U.S. Food & Drug Administration.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

ImmunoPulse is a registered trademark of OncoSec Medical Incorporated.

To learn more about the trial, visit www.oncosec.com. Additional details can also be found at www.clinicaltrials.gov via NCT03132675.

About PISCES/KEYNOTE-695 (Anti-PD-1 IL-12 Stage III/IV Combination Electroporation Study)
PISCES/KEYNOTE-695 is a global, multicenter phase 2b, open-label trial of intratumoral plasma encoded IL-12 (tavokinogene telseplasmid or "tavo") delivered by electroporation in combination with intravenous pembrolizumab in patients with stage III/IV melanoma who have progressed or are progressing on either pembrolizumab or nivolumab treatment. The Simon 2-stage study of intratumoral tavo plus electroporation in combination with pembrolizumab will enroll approximately 48 patients with histological diagnosis of melanoma with progressive locally advanced or metastatic disease defined as Stage III or Stage IV. The primary endpoint will be the Best Overall Response Rate (BORR).

About Metastatic Melanoma1
Melanoma is a type of skin cancer that begins in skin cells called melanocytes. As the cancer progresses, melanoma becomes more difficult to treat once it spreads beyond the skin, such as the lymphatic system (metastatic disease). Given its occurrence young individuals, the potential years of life lost to melanoma can be higher when compared with other cancers. Although melanoma is a rare form of skin cancer, it accounts for over 75% of skin cancer deaths. The American Cancer Society estimates that approximately 87,000 new melanoma cases and 10,000 deaths from the disease will occur in the United States in 2017. Additionally, the World Health Organization estimates that approximately 132,000 new cases of melanoma are diagnosed around the world every year.

On June 4, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that the phase 3 ENLIVEN study showed a statistically significant 39 percent overall response rate (ORR) at week 25 based upon central review of MRI scans using Response Evaluation Criteria in Solid Tumors, version 1.1 (the primary endpoint) for patients treated with oral pexidartinib compared to no tumor response among patients who received placebo (P<0.0001) (Press release, Daiichi Sankyo, JUN 4, 2018, View Source [SID1234527165]). Patients enrolled in the trial were those with tenosynovial giant cell tumor (TGCT) for whom surgery would be associated with potentially worse function or severe morbidity. After a median six month follow-up (longest 17 months), no responders in the ENLIVEN study had progressed. The data will be presented during an oral abstract session on Monday, June 4, 2018 between 8:24 AM – 8:36 AM CDT (Abstract 11502) at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago.

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"Current treatment options for TGCT are largely limited to surgery in order to remove as much of the tumor as possible. Despite the best surgical intervention, the recurrence rate of diffuse TGCT is high and the disease may advance to the point where surgery is no longer an option," said William D. Tap, MD, lead investigator of the study and Chief of the Sarcoma Medical Oncology Service at Memorial Sloan Kettering Cancer Center in New York City. "Pexidartinib may offer a relevant treatment option for patients with TGCT, which is associated with severe morbidity or functional limitations, and for which surgery is not recommended."

Pexidartinib is an investigational, oral small molecule that potently inhibits CSF1R (colony stimulating factor-1 receptor), a primary growth driver of abnormal cells in the synovium that cause TGCT.

In the ENLIVEN study, hepatic toxicities were more frequent with pexidartinib versus placebo (AST or ALT ≥3X ULN: 33 percent, total bilirubin ≥2X ULN: 5 percent, N=61). Eight patients discontinued pexidartinib due to hepatic adverse events (AEs); four were serious nonfatal AEs with increased bilirubin, one lasting ~7 months. In non-TGCT development studies using pexidartinib, two severe liver toxicity cases (one required liver transplant, one was associated with death) were observed.

Other AEs noted in ENLIVEN >10 percent and more common with pexidartinib included hair color changes, pruritus, rash, vomiting, abdominal pain, constipation, fatigue, dysgeusia, facial edema, peripheral edema, periorbital edema, decreased appetite and hypertension.

Secondary efficacy endpoints demonstrated that patients treated with pexidartinib had a 56 percent overall response rate (ORR) by Tumor Volume Score (TVS), compared to no response in patients who received placebo (P<0.0001). Clinically meaningful improvement versus placebo was observed in other secondary efficacy endpoints, including range of motion (+15% vs +6%, P=0.0043), PROMIS physical function (+4.1 vs -0.9, P=0.0019), and worst stiffness (-2.5 vs -0.3, P<0.0001). There was also a nonsignificant improvement in pain response (31% vs 15%).

"We are encouraged by the results from the ENLIVEN study and we look forward to submitting an NDA to the U.S. FDA and engaging European regulators for review of pexidartinib," said Gideon Bollag, PhD, CEO, Plexxikon, a member of the Daiichi Sankyo Group."

About the ENLIVEN Study

ENLIVEN, a double-blind, randomized, global multi-cener, pivotal phase 3 study, evaluated pexidartinib in patients with symptomatic advanced TGCT for whom surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. The first part of the study, the double-blind phase, enrolled 120 patients who were randomized (1:1) to receive either pexidartinib or placebo at 1000 mg/d for 2 weeks followed by 800 mg/d for 22 weeks in order to evaluate the efficacy and safety of pexidartinib versus placebo. The primary endpoint of the study was the percentage of patients achieving a complete or partial response after 24 weeks of treatment (Week 25), as assessed with centrally-read MRI scans using RECIST 1.1 criteria. Key secondary endpoints included range of motion, response by tumor volume score, PROMIS physical function, stiffness and measures of pain reduction.

After completing the first part of the study, patients randomized to either pexidartinib or placebo were eligible to take part in the second part of ENLIVEN, a long-term, open-label part where patients could continue to receive or start to receive pexidartinib. In October 2016, following two reported cases of serious, non-fatal liver toxicity in the ENLIVEN study, the data monitoring committee (DMC) recommended that patients receiving placebo in the first part of the study should no longer be eligible to start pexidartinib in the second part of the study. A total of 120 patients who were enrolled prior to the DMC recommendation continued with the study according to the revised protocol.

About TGCT (PVNS/GCT-TS)

Tenosynovial giant cell tumor (TGCT), previously referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS), is a rare, usually non-cancerous tumor that affects the synovium-lined joints, bursae, and tendon sheaths, resulting in swelling, pain, stiffness and reduced mobility in the affected joint or limb.1,2 It has been estimated that the incidence of TGCT is 11 to 50 cases per million, based on studies from three countries.3-5 Patients are commonly diagnosed in their 20s to 50s,and depending on the type of TGCT, women can be up to twice as likely to develop a tumor as men.6,7

Primary treatment of TGCT includes surgery to remove the tumor. However, in patients with a diffuse form where the tumor can wrap around bone, tendons, ligaments and other parts of the joint, it is more difficult to remove and may require multiple surgeries or joint replacement, eventually advancing to the point where surgical resection is no longer an option and amputation may be considered. It is estimated that the rate of recurrence for diffuse TGCT can be 20 to 55 percent.8

About Pexidartinib

Pexidartinib is an investigational, novel, oral small molecule that potently inhibits CSF1R (colony stimulating factor-1 receptor), which is a primary growth driver of abnormal cells in the synovium that cause TGCT. Pexidartinib also inhibits c-kit and FLT3-ITD. Pexidartinib was discovered by Plexxikon Inc., the small molecule structure-guided R&D center of Daiichi Sankyo.

Pexidartinib has been granted Breakthrough Therapy Designation for the treatment of patients with pigmented villonodular synovitis (PVNS) or giant cell tumor of tendon sheath (GCT-TS), where surgical resection may result in potentially worsening functional limitation or severe morbidity and Orphan Drug Designation for PVNS/GCT-TS by the U.S. Food and Drug Administration (FDA). Pexidartinib also has received Orphan Designation from the European Commission for the treatment of TGCT. Pexidartinib is not approved by the FDA or any other regulatory agency worldwide as a treatment for any indication. Safety and efficacy have not been established.

On June 4, 2018 Oncolytics Biotech Inc. (TSX: ONC) (NASDAQ: ONCY), currently developing REOLYSIN (pelareorep), an intravenously delivered immuno-oncolytic virus turning cold tumors hot, reported a key poster presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting (Press release, Oncolytics Biotech, JUN 4, 2018, View Source [SID1234527183]). The meeting takes place from June 1 – 5, 2018 at McCormick Place, Chicago, IL.

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"These results demonstrate that pelareorep promotes the expression of gene signatures predictive of a response to immunotherapy in breast cancer and hepatocellular carcinoma." said Matt Coffey, President and CEO of Oncolytics Biotech. "The tumor inflammation promoting effects in breast cancer models provide a compelling explanation for the significant overall survival benefit in hormone receptor positive metastatic breast cancer patients in our phase 2, IND 213, study and we believe this will continue to drive interest in our breast cancer program."

Highlights of the poster include:

• Pelareorep promotes expression of gene signatures that are predictive of response to checkpoint inhibitors in select cell lines
• HCC – hepatocellular carcinoma
• HR+ BC – hormone receptor positive breast cancer
• Pronounced tumor inflammatory effects of pelareorep in HR+ BC cells may explain the prominent increase in overall survival in a previous phase 2 randomized clinical study in HR+ mBC patients treated with pelareorep and may render this large breast cancer population susceptible to conventional immunotherapy regimes
• Results warrant further investigation of pelareorep in combination with checkpoint inhibitors

Presenter & Lead Author: Grey A. Wilkinson PhD, Oncolytics Scientist, Translational Medicine
Presentation Title: Pelareorep to promote the expression of a IFN-gamma-related gene signature that predicts response to checkpoint blockade therapy
Session Title: Developmental Therapeutics – Immunotherapy
Location: McCormick Place: Hall A
Abstract number: 3089
Poster Board #: 303
Date/Time: 6/4/2018; 8:00 AM-11:30 AM

The complete poster can be found online on the company website at View Source

About REOLYSIN/Pelareorep

REOLYSIN, also known as pelareorep, is a non-pathogenic, proprietary isolate of the unmodified reovirus: a first-in-class intravenously delivered immuno-oncolytic virus for the treatment of solid tumors and hematological malignancies. The compound induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses to treat a variety of cancers.

On June 4, 2018 PharmaMar (MSE:PHM) reported new data on the recurrent small-cell lung cancer patients cohort of the phase II basket study with lurbinectedin as a single agent, will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting, being held from the 1st to the 5th of June in Chicago (Press release, PharmaMar, JUN 4, 2018, View Source [SID1234527118]).

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The multicenter, phase II trial is assessing the safety and efficacy of lurbinectedin in different solid tumors. Among these, small-cell lung cancer, recurrent after one chemotherapy prior line, began by recruiting 15 patients, and later increased to 100 after observing 5 responses in the first 15 patients. The primary endpoint of the study is to measure the overall response rate, also evaluating other secondary objectives such as the duration of response, progression free survival, overall survival, along with the safety profile.

PharmaMar will present the results of the 61 evaluated patients out of the 72 patients recruited so far in the abstract titled "Efficacy and safety of lurbinectedin (PM1183, Zepsyre) in small-cell lung cancer (SCLC): results from a phase 2 study" (abstract#8570). An ORR of 39.3% was seen in these patients.

The median duration of response was 6.2 months and the median overall survival was 12 months.
With respect to the safety profile, the most common adverse event was myelosuppression: 39% of the patients’ registered grade 3/4 neutropenia and 9% had febrile neutropenia. No toxic deaths have been recorded.

"The patients included in this study with small-cell lung cancer are responding favorably to the treatment with lurbinectedin as a single agent. We have observed that this molecule is active in this group of patients, however, we look forward to having more information once recruitment has finalized and we can evaluate all the patients", said Dr. Arturo Soto, Director of Clinical Development at the Oncology Business Unit of PharmaMar.

The studies that will be presented during the congress are available at View Source

About lurbinectedin
Lurbinectedin is a compound under clinical investigation. It is an inhibitor of RNA polymerase II. This enzyme is essential for the transcription process that is over-activated in tumors with transcription addiction