On Exelixis, Inc. (NASDAQ:EXEL) and Bristol-Myers Squibb Company (NYSE:BMY) reported the initiation of the phase 3 CheckMate 9ER trial to evaluate Opdivo (nivolumab) in combination with CABOMETYX (cabozantinib) tablets, a small molecule inhibitor of receptor tyrosine kinases, or Opdivo and Yervoy (ipilimumab) in combination with CABOMETYX versus sunitinib in patients with previously untreated, advanced or metastatic renal cell carcinoma (RCC). The primary endpoint for the trial is progression-free survival (PFS).

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"There is strong scientific evidence showing that CABOMETYX results in a more immune permissive tumor environment, and we are eager to determine if combining these active agents with complementary and potentially cooperative mechanisms of action has the potential to further improve patient outcomes," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "We are excited to initiate this first clinical trial from our broad development program with Bristol-Myers Squibb looking at the potential of Opdivo in combination with CABOMETYX, with or without Yervoy, in a variety of tumor types."

"While existing therapies have improved outcomes for some patients with advanced or metastatic kidney cancer, high rates of relapse and disease progression demonstrate a need for additional therapeutic options, especially among poor and intermediate risk patients," said Fouad Namouni, M.D., Head of Development, Oncology, Bristol-Myers Squibb. "Combination therapy with agents that target different and complementary pathways—in this case, the combination of immune checkpoint inhibitors and tyrosine kinase inhibitors—may be a potential new approach for these patients."

CheckMate 9ER is an open-label, randomized, multi-national phase 3 trial that aims to enroll approximately 1,014 patients with previously untreated advanced or metastatic RCC. Patients will be randomized 1:1:1 to one of three arms: CABOMETYX and Opdivo; CABOMETYX, Opdivo and Yervoy; or sunitinib. The primary efficacy analysis will compare the doublet combination versus sunitinib and the triplet combination versus sunitinib in intermediate/poor risk patients with RCC.

More information about this trial is available at ClinicalTrials.gov.

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2017 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 percent, with no identified cure for the disease.3 Approximately 30,000 patients in the U.S. and 68,000 globally require treatment.4

The majority of clear cell RCC tumors have lower than normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.5,6 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.7-10 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.6,7

About CABOMETYX

CABOMETYX is the tablet formulation of cabozantinib. Its targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.

CABOMETYX is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.

On April 25, 2016, the FDA approved CABOMETYX tablets for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. On September 9, 2016, the European Commission approved CABOMETYX tablets for the treatment of advanced renal cell carcinoma in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway and Iceland.

On July 10, 2017 BioLineRx Ltd. (NASDAQ/TASE: BLRX), a clinical-stage biopharmaceutical company focused on oncology and immunology, reported that Genentech, a member of the Roche Group, has commenced a Phase 1b/2 study for BL-8040 in combination with atezolizumab (TECENTRIQ), Genentech’s anti-PDL1 cancer immunotherapy agent, evaluating the combination in metastatic pancreatic ductal adenocarcinoma (Press release, BioLineRx, JUL 10, 2017, View Source [SID1234519772]).

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Up to 40 patients are planned to be enrolled in this Phase 1b/2, multicenter, randomized, controlled, open-label study to evaluate the clinical response, safety and tolerability, as well as multiple pharmacodynamic parameters, of BL-8040 in combination with atezolizumab. Initially, patients will receive BL-8040 injections as priming monotherapy for five consecutive days, after which, from day 8, they will receive both BL-8040 and atezolizumab, and continue with multiple treatment cycles for up to two years or until disease progression, clinical deterioration or unacceptable toxicity.

The clinical study collaboration between BioLineRx and Genentech, a member of the Roche Group, is part of MORPHEUS, Roche’s Novel Cancer Immunotherapy Development Platform. MORPHEUS is a phase 1b/2 adaptive platform to assess the efficacy and safety of combination cancer immunotherapies.

Philip Serlin, Chief Executive Officer of BioLineRx, stated, "We are very pleased with the launch of the first clinical study under our cancer immunotherapy collaboration with Genentech. Pancreatic cancer is a very difficult cancer to treat, and both conventional chemotherapy and immunotherapy have failed to demonstrate a significant benefit for these patients. BL-8040 has been shown to have robust mobilization of immune cells, improve the infiltration of T cells into solid tumors, and affect the immunosuppressive tumor micro-environment. We are therefore hopeful that combining atezolizumab with BL-8040 can lead to a significant advancement in the treatment of pancreatic cancer, and of other solid tumors that are difficult to treat. We look forward to the initiation of additional combination studies under this collaboration, all planned for the second half of this year."

BioLineRx is carrying out a larger cancer immunotherapy collaboration with Genentech to conduct several Phase 1b/2 studies investigating BL-8040 in combination with atezolizumab in multiple cancer indications, announced in September 2016.

BL-8040, BioLineRx’s lead oncology platform, is a CXCR4 antagonist that has been shown in clinical trials to be a robust mobilizer of immune cells and to be effective in inducing direct tumor cell death. Additional findings suggest that BL-8040 may be effective in inducing the migration of anti-tumor T cells into the tumor micro-environment, as well as improving the infiltration of T cells into solid tumors. Atezolizumab is a humanized monoclonal antibody designed to bind to PD-L1 in tumor cells and tumor infiltrating immune cells and blocks interactions with the PD-1 and B7.1 receptors. Through this interaction, atezolizumab may enable the activation of T cells, whose migration into the tumor may be enhanced by BL-8040.

About BL-8040

BL-8040 is a short peptide for the treatment of acute myeloid leukemia, solid tumors, and stem cell mobilization. It functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis, metastasis and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. In a number of clinical and pre-clinical studies, BL-8040 has shown robust mobilization of cancer cells from the bone marrow, thereby sensitizing these cells to chemo- and bio-based anti-cancer therapy, as well as a direct anti-cancer effect by inducing cell death (apoptosis). In addition, BL-8040 has also demonstrated robust stem-cell mobilization, including the mobilization of colony-forming cells, T, B and NK cells. BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.

On July 7, 2017 argenx (Euronext & Nasdaq: ARGX), a clinical-stage biotechnology company developing a deep pipeline of differentiated antibody-based therapies for the treatment of severe autoimmune diseases and cancer, reported that its abstract covering the complete data set from its Phase Ib study of ARGX-111 in patients with advanced cancers over-expressing the MET protein was selected as part of the Best of ASCO (Free ASCO Whitepaper) program at the 3rd Singapore Society of Oncology Annual Scientific Meeting in Singapore (Press release, arGEN-X, JUL 7, 2017, View Source [SID1234519763

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The differentiated design of ARGX-111 to enhance killing of advanced tumor cells offers a really exciting approach to treating patients with MET-driven cancers," commented Nicolas Leupin, Chief Medical Officer of argenx. "We are pleased to see preliminary anti-tumor activity and a consistently favorable safety profile, which was the goal of this expansion study. These data offer a compelling path forward to further examine in a Phase 2 study the activity of ARGX-111, which we are looking to strategically partner."

The new data from the Phase Ib study continue to show evidence of anti-tumor activity with
ARGX-111 at all dose levels and across different indications. Partial response and stable disease were observed, respectively, in one and nine of 24 heavily pretreated patients with MET-positive malignancies, both MET-gene-amplified and with MET overexpression. Treatment-emerging adverse events were reported for all patients, but none of the grade 5 toxicities were related to ARGX-111. The poster presented at Best of ASCO (Free ASCO Whitepaper) can be accessed from the "Downloads" section of the argenx website.


About ARGX-111

ARGX-111 was developed for the treatment of patients with certain solid tumors that overexpress c-Met, a receptor associated with tumor growth and metastasis, or tumors that are mesenchymal-epithelial transition factor, or MET, amplified. ARGX-111 employs the SIMPLE AntibodyTM, NHance and POTELLIGENT technologies to drive tissue penetration in the body and to increase its ability to enhance ADCC. ARGX-111 binds to c-Met with high affinity and does not cause dimerization of the c-Met receptor, which differentiates it from other, earlier attempts to direct antibodies against c-Met. Dimerization is a process which can result in receptor activation, undermining the intended therapeutic effect of antibodies blocking hepatocyte growth factor, or HGF, binding to c-Met. By blocking both HGF-dependent and independent c-Met activation, ARGX-111 is able to block c-Met receptor activation which could trigger survival, proliferation and metastasis of tumor cells. In order to further examine the activity of the product candidate in a Phase 2 study, argenx is actively looking for an appropriate collaboration partner.