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Ipsen and Exelixis announce phase 3 trial results of cabozantinib demonstrating significant overall survival benefit in patients with previously treated advanced hepatocellular carcinoma

On January 16, 2018 Ipsen (Euronext:IPN; ADR:IPSEY) and Exelixis, Inc. (NASDAQ:EXEL) reported detailed results of the pivotal phase 3 CELESTIAL trial in patients with previously treated advanced hepatocellular carcinoma (HCC), which will be presented in a late-breaking oral session at the 2018 ASCO (Free ASCO Whitepaper)-GI Symposium being held in San Francisco, January 18-20, 2018 (Press release, Ipsen, JAN 16, 2018, View Source [SID1234523152]). In CELESTIAL, cabozantinib provided a statistically significant and clinically meaningful improvement versus placebo in overall survival (OS), the trial’s primary endpoint, at the planned second interim analysis (prespecified critical p value £ 0.021) for the population of second- and third-line patients enrolled in this study. Median OS was 10.2 months with cabozantinib versus 8.0 months with placebo (HR 0.76, 95 percent CI 0.63-0.92; p=0.0049). Median progression-free survival (PFS) was more than doubled, at 5.2 months with cabozantinib and 1.9 months with placebo (HR 0.44, 95 percent CI 0.36-0.52; p<0.0001). Objective response rates per RECIST 1.1 were 4 percent with cabozantinib and 0.4 percent with placebo (p=0.0086). Disease control (partial response or stable disease) was achieved by 64 percent of the cabozantinib group compared with 33 percent of the placebo group.

In a subgroup analysis of patients whose only prior therapy for advanced HCC was sorafenib (70 percent of patients in the study), median OS was 11.3 months with cabozantinib versus 7.2 months with placebo (HR 0.70, 95 percent CI 0.55-0.88). Median PFS in the subgroup was 5.5 months with cabozantinib versus 1.9 months with placebo (HR 0.40, 95 percent CI 0.32-0.50). Adverse events were consistent with the known safety profile of cabozantinib.

Ghassan K. Abou-Alfa, M.D., Memorial Sloan Kettering Cancer Center, New York and lead investigator on CELESTIAL, will present detailed findings, including analyses of OS and PFS in various patient subgroups, during Oral Abstract Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract, which begins at 2:15 p.m. PT on Friday, January 19, 2018.

"Patients with advanced hepatocellular carcinoma often have a poor prognosis and limited treatment options following prior systemic therapy," said Dr. Abou-Alfa. "The clinically significant benefits in both overall survival and progression-free survival shown in the CELESTIAL trial suggest that, if approved, cabozantinib could become an important addition to the treatment landscape for these patients."

"We are excited by the potential benefit cabozantinib may offer to patients with previously treated advanced hepatocellular carcinoma," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "Given the worldwide prevalence of advanced hepatocellular carcinoma, there is a continued urgency to bring new treatment options to this patient population. We look forward to submitting our supplemental New Drug Application to the FDA for cabozantinib in the first quarter of 2018, and to further advancing our mission to help cancer patients recover stronger and live longer."

Alexandre Lebeaut, M.D., Executive Vice-President, R&D, Chief Scientific Officer, Ipsen, said: " Patients diagnosed with advanced hepatocellular carcinoma urgently need new treatment options. The positive results of the pivotal phase 3 CELESTIAL trial are encouraging for both physicians and patients, and we have committed to file in the first half of 2018 a variation of the initial application to the EMA and other relevant regulatory agencies. "

The most common (≥10 percent) grade 3 or 4 adverse events in the cabozantinib group compared to the placebo group were palmar-plantar erythrodysesthesia (17 percent vs. 0 percent), hypertension (16 percent vs. 2 percent), increased aspartate aminotransferase (12 percent vs. 7 percent), fatigue (10 percent vs. 4 percent), and diarrhea (10 percent vs. 2 percent). Treatment-related grade 5 adverse events occurred in six patients in the cabozantinib group (hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism and hepatorenal syndrome) and in one patient in the placebo group (hepatic failure). Sixteen percent of patients in the cabozantinib arm and three percent of patients in the placebo arm discontinued treatment due to treatment-related adverse events.

Webcast for the Financial Community

Ipsen and its partner Exelixis will host a live briefing event for the financial community to discuss data presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO-GI). The webcast event will be held following the closing of the ASCO (Free ASCO Whitepaper)-GI day’s sessions on Friday, January 19, 2018, beginning at 9:30 p.m. EST / 6:30 p.m. PST (local San Francisco time). During the briefing, Exelixis and Ipsen management, along with an invited guest, will discuss and provide context for the cabozantinib clinical data presented earlier that day at the Symposium. Ipsen previously announced that detailed results from the CELESTIAL trial will be the subject of a late-breaking oral presentation at ASCO (Free ASCO Whitepaper)-GI. CELESTIAL is a randomized, double-blind, placebo-controlled study of cabozantinib versus placebo in patients with advanced hepatocellular carcinoma who have received prior treatment with sorafenib.

To access the webcast link, log onto www.exelixis.com and proceed to the News & Events / Event Calendar page under the Investors & Media heading. Please connect to the company’s website at least 15 minutes prior to the presentation to ensure adequate time for any software download that may be required to listen to the webcast. Alternatively, please call 855-793-2457 (domestic) or 631-485-4921 (international) and provide the conference call passcode 2478857 to join by phone. A webcast replay will be archived on www.exelixis.com for one year. A telephone replay will also be available until 11:59 p.m. EST on January 26, 2018. Access numbers for the telephone replay are: 855-859-2056 (domestic) and 404-537-3406 (international); the passcode is 2478857.

About the CELESTIAL Study

CELESTIAL is a randomized, double-blind, placebo-controlled study of cabozantinib in patients with advanced HCC conducted at more than 100 sites globally in 19 countries. The trial was designed to enroll 760 patients with advanced HCC who received prior sorafenib and may have received up to two prior systemic cancer therapies for HCC and had adequate liver function. Enrollment of the trial was completed in September 2017. Patients were randomized 2:1 to receive 60 mg of cabozantinib once daily or placebo and were stratified based on etiology of the disease (hepatitis C, hepatitis B or other), geographic region (Asia versus other regions) and presence of extrahepatic spread and/or macrovascular invasion (yes or no). No cross-over was allowed between the study arms during the blinded treatment phase of the study.

The primary endpoint for the trial is OS, and secondary endpoints include objective response rate and PFS. Exploratory endpoints include patient-reported outcomes, biomarkers and safety.

Based on available clinical trial data from various published trials conducted in the second-line setting of advanced HCC, the CELESTIAL trial design assumed a median OS of 8.2 months for the placebo arm. A total of 621 events provide the study with 90 percent power to detect a 32 percent increase in median OS (HR = 0.76) at the final analysis. Two interim analyses were planned and conducted at approximately 50 percent and 75 percent of the planned 621 events. At the first interim analysis conducted by the independent data monitoring committee the observed hazard ratio was 0.71 and the p-value was 0.0041, which did not cross the stopping boundary for the first interim analysis (p ≤ 0.0037).

On October 16, 2017, Ipsen announced that the independent data monitoring committee recommended that the trial be stopped for efficacy following review of the second planned interim analysis, as the trial had met its primary endpoint of OS (prespecified critical p value £ 0.021).

Array BioPharma to Present Updated Phase 3 BEACON CRC Safety Lead-In Results of the Combination of Encorafenib, Binimetinib and Cetuximab in BRAF-Mutant Colorectal Cancer at the 2018 Gastrointestinal Cancers Symposium

On January 16, 2018 Array BioPharma Inc. (Nasdaq: ARRY) reported the upcoming presentation of updated safety results and clinical activity from the safety lead-in of the Phase 3 BEACON CRC trial evaluating the triplet combination of encorafenib, a BRAF inhibitor, binimetinib, a MEK inhibitor and cetuximab, an anti-EGFR antibody, in patients with BRAF-mutant colorectal cancer (CRC) (Press release, Array BioPharma, JAN 16, 2018, View Source;p=RssLanding&cat=news&id=2326690 [SID1234523136]). These data will be presented at the 2018 Gastrointestinal Cancers Symposium (ASCO GI) in San Francisco, California.

BEACON CRC SAFETY LEAD-IN

Title:

Abstract #627: BEACON CRC Study Safety Lead-in (SLI) in Patients With BRAFV600E Metastatic Colorectal Cancer (mCRC): Efficacy and Tumor Markers

Presenter:

Eric Van Cutsem, M.D., University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium

Date:

Saturday, January 20

Times:

7:00 am – 7:55 am PT and 12:30 pm – 2:00 pm PT

Updated data on the safety and tolerability profile of the triplet combination and measures of efficacy, including mPFS, ORR, duration of response, as well as tumor marker data, will be available as part of the presentation on January 20. The presentation will be available as a PDF from the Publications section of the Array website starting January 20.

Array’s BEACON CRC Phase 3 trial safety lead-in abstract published on January 16 contains previously presented safety and clinical activity data, as well as new data on changes in tumor markers.

About Encorafenib and Binimetinib
BRAF and MEK are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma and colorectal cancer. Encorafenib is a late-stage small molecule BRAF inhibitor and binimetinib is a late-stage small molecule MEK inhibitor, both of which target key enzymes in this pathway. Encorafenib and binimetinib are being studied in clinical trials in advanced cancer patients, including the Phase 3 BEACON CRC trial and the Phase 3 COLUMBUS trial.

The U.S. Food and Drug Administration (FDA) is currently reviewing the New Drug Applications (NDAs) to support use of the combination of encorafenib and binimetinib for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma. The FDA set a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2018 for both applications. In addition, the European Medicines Agency (EMA) is reviewing the Marketing Authorization Applications for encorafenib and binimetininb.

Encorafenib and binimetinib are investigational medicines and are not currently approved in any country.

Array BioPharma has exclusive rights to encorafenib and binimetinib in the U.S. and Canada. Array has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Asia and Latin America. The BEACON CRC trial is being conducted with support from Pierre Fabre and Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

Context Therapeutics Announces the Acquisition of Apristor™ (Onapristone XR)

On January 6, 2018 Context Therapeutics, a biopharma company dedicated to developing new medicines for patients with hormone responsive cancers, reported that it has acquired worldwide rights to Apristor (Onapristone XR) (Press release, Context Therapeutics, JAN 16, 2018, View Source [SID1234523265]). Onapristone has been extensively studied and has established efficacy in two Phase 2 metastatic breast cancer clinical trials. In these trials, meaningful clinical benefit and response rates were seen in 120 metastatic breast cancer patients, 101 of whom were actively progressing on Tamoxifen before Onapristone treatment initiation. Onapristone has been studied in over 200 patients, and it was well tolerated with no drug-related serious adverse events.

Martin Lehr, CEO of Context stated: "We are excited to advance the development of Apristor and to potentially provide a mechanistically novel option for patients diagnosed with metastatic breast cancer. Unfortunately, the median life expectancy of a woman diagnosed with metastatic breast cancer is approximately three years. In the United States alone 40,000 women die each year as a result. These women deserve better, and we are committed to improving their treatment and removing the fear that comes along with this diagnosis."

Apristor blocks the binding of progesterone, a carcinogen, to the progesterone receptor (PR). Up to 70% of metastatic breast cancers express PR and are said to be PR+. If approved, Apristor would provide physicians with a novel product that could be used in combination with standard of care agents targeting the estrogen receptor or as a monotherapy.

Context made a one-time payment to Arno Therapeutics in exchange for the worldwide rights to Apristor. Apristor is a new chemical entity and is protected by a robust patent estate that should provide exclusivity through at least 2034.

Scott Applebaum, President of Context stated: "Context has taken a big leap forward and is now a clinical-stage company. This transformation is consistent with our mission of discovering, developing, and commercializing treatments for hormone-responsive cancers. We are building a world-class global clinical trial organization to bring Apristor to market as fast as possible. In addition, we have an Apristor fast-follower program for progesterone receptor-mediated diseases and continue to advance our preclinical Sigma1 program."

First Patient Dosed in a Phase 2 Trial with Transgene’s TG4010 + Nivolumab + Chemotherapy for the First-Line Treatment of Lung Cancer (NSCLC)

On January 16, 2018 Transgene (Paris:TNG) (Euronext Paris: TNG), a biotechnology company that designs and develops virus-based immunotherapies, reported the dosing of the first patient in the Phase 2 trial evaluating TG4010 in combination with Opdivo (nivolumab) and chemotherapy as a first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC) with low or no expression of PD-L1 by the tumor cells (Press release, Transgene, JAN 16, 2018, View Source [SID1234523195]).

The Phase 2 clinical trial is exploring the tolerability and efficacy of the combination regimen of Transgene’s TG4010, an investigational active immunotherapy against MUC1 tumor-associated antigen, with Bristol-Myers Squibb’s immune checkpoint inhibitor, Opdivo (nivolumab), which acts by overcoming immune suppression, and standard platinum doublet chemotherapy.
This multi-center single-arm trial will enroll up to 39 patients (without EGFR activating mutations or ALK-rearrangements), both in the USA and Europe. The trial has objective tumor responses rate (ORR) as primary endpoint. The study will also assess the safety and tolerability of the regimen together with other efficacy and immunological parameters. The first results are expected in H2 2018.
More information on the trial can be found on clinicaltrial.gov (NCT03353675).
This trial is conducted by Transgene under a clinical collaboration agreement with Bristol-Myers Squibb, which is supplying nivolumab (see press release dated April 25, 2017).

"Advanced lung cancer remains a devastating disease, in particular for patients whose tumors express low or undetectable levels of PD-L1. We are excited to start a trial that combines our active immunotherapy TG4010, with nivolumab and chemotherapy as a first-line treatment" said Maud Brandely, Chief Medical Officer of Transgene. "We believe that this trial could confirm the promising efficacy data that we previously obtained with TG4010 in combination with chemotherapy, and show that the triple regimen could be an attractive treatment option in this patient population."

Elisabeth Quoix, M.D., Head of the Department of Pulmonology at the University Hospital of Strasbourg, and coordinating investigator of the trial, added: "The three complementary mechanisms of action of TG4010, nivolumab and chemotherapy are believed to enhance the immune cellular response and lead to an increase in antitumor activity. This combination regimen aims at achieving a higher response rate, and ultimately an improvement in the survival rate in advanced-stage NSCLC patients."

The combination of TG4010 immunotherapy and chemotherapy has demonstrated significant efficacy in terms of increased response rate, progression-free survival and overall survival in a randomized, double-blind, placebo-controlled Phase 2b trial in first-line treatment of patients with advanced non-squamous NSCLC (Quoix et al. Lancet Oncol. 2015).

About TG4010
TG4010 is an active immunotherapy that has been designed to express the coding sequences of the MUC1 tumor-associated antigen and the cytokine, Interleukin-2 (IL2). It is based on a modified Vaccinia virus (MVA), and has been shown to induce an immune response against MUC1 expressing tumors, such as non-small cell lung cancer (NSCLC). Its mechanism of action and excellent safety profile make TG4010 a very suitable candidate for combinations with other therapies, including immune checkpoint inhibitors and chemotherapy. The combination of TG4010 immunotherapy and chemotherapy has demonstrated significant efficacy in terms of progression-free survival and overall survival in patients with advanced stage NSCLC (Quoix et al. Lancet Oncol. 2015).
TG4010 is being investigated in combination with nivolumab (ICI) for the 2nd-line treatment of advanced NSCLC (NCT02823990) and for 1st-line treatment of NSCLC in combination with nivolumab and chemotherapy in patients whose tumors express low or undetectable levels of PD-L1 (NCT03353675).

About Non-Small Cell Lung Cancer
Lung cancer is one of the most common malignancies worldwide with an estimated 1.8 million new cases annually. It is also a leading cause of cancer-related deaths, accounting for an estimated 1.6 million deaths in 2012 (Source: GLOBOCAN 2012). Advanced lung cancer remains one of the cancer types with the worst prognosis (five-year survival rate for advanced NSCLC of less than 5%), underlining the still unmet need in this disease despite recent progress.