On December 23, 2015 Exelixis, Inc. (NASDAQ:EXEL) reported that it has completed the submission of its rolling New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for cabozantinib as a treatment for patients with advanced renal cell carcinoma (RCC) who have received one prior therapy (Press release, Exelixis, DEC 23, 2015, View Source [SID:1234508634]). Exelixis has requested Priority Review as part of the NDA filing.

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In August 2015, the FDA granted Breakthrough Therapy designation to cabozantinib for this potential advanced RCC indication. Breakthrough Therapy designation can expedite the development and review of drugs that are intended to treat serious or life-threatening diseases, and for which preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. Drugs that receive Breakthrough Therapy designation may benefit from the involvement of FDA senior leadership in the review process, rolling submission, and other benefits. Prior to receiving Breakthrough Therapy designation, cabozantinib received Fast Track designation for its potential advanced RCC indication in April 2015.

"Completing the submission of our rolling New Drug Application brings us closer to our goal of improving the treatment options for patients with advanced kidney cancer," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "Following the release of positive top-line results from our phase 3 pivotal trial in July, the Exelixis team worked expeditiously to complete the U.S. regulatory filing by year end. We look forward to continuing to work with the FDA team during the review process."

The NDA submission is based on results of METEOR, a phase 3 pivotal trial comparing cabozantinib to everolimus in patients with advanced RCC who experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor. In July 2015, Exelixis announced top-line results from METEOR demonstrating that the trial had met its primary endpoint of improving progression-free survival; compared with everolimus, cabozantinib was associated with a 42% reduction in the rate of disease progression or death. These data were later presented at the European Cancer Congress in September 2015 and concurrently published in The New England Journal of Medicine.

In the European Union, Exelixis aims to complete its Marketing Authorization Application (MAA) in early 2016. The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recently granted accelerated assessment to cabozantinib for advanced RCC. As a result, when filed, the company’s MAA may be eligible for a 150-day review, versus the standard 210 days (excluding clock stops when information is requested from CHMP).

Cabozantinib is currently marketed in capsule form under the brand name COMETRIQ in the United States for the treatment of progressive, metastatic medullary thyroid cancer (MTC), and in the European Union for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. COMETRIQ is not indicated for patients with RCC. In the METEOR trial, and all other cancer trials currently underway, Exelixis is investigating a tablet formulation of cabozantinib distinct from the COMETRIQ capsule form. The tablet formulation of cabozantinib is the subject of the NDA for advanced RCC.

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2015 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; however, the five-year survival rate for patients with advanced or late-stage metastatic RCC is under 10 percent, with no identified cure for the disease.3

Until the introduction of targeted therapies into the RCC setting a decade ago, treatments for metastatic RCC had historically been limited to cytokine therapy (e.g., interleukin-2 and interferon). In the second and later-line settings, which encompass approximately 17,000 drug-eligible patients in the U.S. and 37,000 globally,4 two small-molecule therapies and a checkpoint inhibitor have been approved for the treatment of patients who have received prior VEGF receptor TKIs. The currently approved small-molecule agents have shown little differentiation in terms of efficacy and have demonstrated only modest progression-free survival benefit in patients refractory to sunitinib, a commonly-used first-line therapy.

The majority of clear cell RCC tumors exhibit down-regulation of von Hippel-Lindau (VHL) protein function, either due to gene inactivation or epigenetic silencing, resulting in a stabilization of the hypoxia-inducible transcription factors (HIFs) and consequent up-regulation of VEGF, MET and AXL.5 The up-regulation of VEGF may contribute to the angiogenic nature of clear cell RCC, and expression of MET or AXL may be associated with tumor cell viability, a more invasive tumor phenotype and reduced overall survival. 6 Up-regulation of MET and AXL in clear cell RCC has also been shown to occur in response to treatment with VEGF receptor TKIs in preclinical models, indicating a potential role for MET and AXL in the development of resistance to these therapies.7

About Cabozantinib

Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGF receptors, AXL and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis and maintenance of the tumor microenvironment.

Cabozantinib, marketed under the brand name COMETRIQ, is currently approved by the U.S. Food and Drug Administration for the treatment of progressive, metastatic medullary thyroid cancer (MTC).

The European Commission granted COMETRIQ conditional approval for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Similar to another drug approved in this setting, the approved indication states that for patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.

Important Safety Information, including Boxed WARNINGS

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

Serious and sometimes fatal gastrointestinal perforations and fistulas occur in COMETRIQ-treated patients.
Severe and sometimes fatal hemorrhage occurs in COMETRIQ-treated patients.

COMETRIQ treatment results in an increase in thrombotic events, such as heart attacks.

Wound complications have been reported with COMETRIQ.

COMETRIQ treatment results in an increase in hypertension.

Osteonecrosis of the jaw has been observed in COMETRIQ-treated patients.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES) occurs in patients treated with COMETRIQ.

The kidneys can be adversely affected by COMETRIQ. Proteinuria and nephrotic syndrome have been reported in patients receiving COMETRIQ.

Reversible Posterior Leukoencephalopathy Syndrome has been observed with COMETRIQ.

Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

COMETRIQ can cause fetal harm when administered to a pregnant woman.

Adverse Reactions – The most commonly reported adverse drug reactions (≥25%) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Please see full U.S. prescribing information, including Boxed WARNINGS, at www.COMETRIQ.com/downloads/Cometriq_Full_Prescribing_Information.pdf

Please refer to the full European Summary of Product Characteristics for full European Union prescribing information, including contraindication, special warnings and precautions for use at www.sobi.com once posted.

On December 23, 2015 Seattle Genetics, Inc. (Nasdaq: SGEN) and Bristol-Myers Squibb (NYSE:BMY) reported that the companies have initiated a phase 1/2 clinical trial of ADCETRIS (brentuximab vedotin) in combination with Opdivo (nivolumab) for patients with CD30-expressing relapsed or refractory B-cell and T-cell non-Hodgkin lymphomas (NHL), including diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) (Press release, Bristol-Myers Squibb, DEC 23, 2015, View Source [SID:1234508633]).

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This is the second of two trials being conducted under a previously announced clinical trial collaboration agreement between Bristol-Myers Squibb Company and Seattle Genetics. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a marker expressed on Hodgkin lymphoma (HL) and several types of NHL, which combines the targeting ability of a monoclonal antibody with a highly potent cell-killing agent. Recent preclinical data suggest that ADCETRIS causes immunogenic cell death of tumor cells, providing rationale for combination with Opdivo, a human antibody that targets and inhibits the programmed death receptor-1 (PD-1), resulting in T-cell activation. Opdivo is part of a new class of cancer immunotherapy treatments known as checkpoint inhibitors, which are designed to harness the body’s own immune system in fighting cancer by targeting distinct regulatory components of the immune system.

"This is the second corporate-sponsored clinical trial to evaluate ADCETRIS combined with a checkpoint inhibitor to determine if the combination can improve patient outcomes," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "This study is a part of a broad development program that includes more than 70 ongoing clinical trials evaluating ADCETRIS in multiple lines of therapy for Hodgkin and non-Hodgkin lymphoma and as part of novel combinations that could result in improved clinical benefit with manageable safety profiles. Our goal is to establish ADCETRIS as the foundation of care for CD30-expressing lymphomas."

The phase 1/2 open-label, multi-center, clinical trial is designed to evaluate the safety, tolerability and antitumor activity of ADCETRIS in combination with Opdivo in patients with relapsed or refractory CD30-expressing NHL. The study will consist of a phase 1 dose evaluation portion followed by a single-arm phase 2 portion that will expand enrollment to treat disease-specific cohorts with relapsed or refractory DLBCL, PTCL or CTCL at the recommended dose level and treatment schedule. The primary endpoints are safety, tolerability and objective response rate of the combination of ADCETRIS with Opdivo. The secondary endpoints include duration of response, complete response rate with the combination regimen, duration of complete response, progression-free survival and overall survival. The trial is being conducted at multiple centers in the United States, Canada and Europe and is designed to enroll approximately 120 patients.

"Bristol-Myers Squibb continues to strengthen its industry-leading development program for Opdivo and its rapidly expanding hematology portfolio," said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. "We are pleased to collaborate with Seattle Genetics on clinical research that focuses on novel combination regimens in areas of serious unmet need."

In addition to the two ongoing Opdivo combination trials under the collaboration with Bristol-Myers Squibb, ADCETRIS is being evaluated in more than 70 ongoing clinical trials including the ECHELON-1 phase 3 trial in frontline HL, the ECHELON-2 phase 3 trial in frontline mature T-cell lymphoma and the ALCANZA phase 3 trial in CTCL. Opdivo is being evaluated either as monotherapy or in combination with other therapies in some of the hardest-to-treat hematologic cancers, including multiple myeloma, chronic myelogenous leukemia, and Hodgkin and non-Hodgkin lymphomas including follicular and DLBCL. Opdivo has Breakthrough Therapy designation for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant and brentuximab vedotin.

ADCETRIS is not currently approved for frontline treatment or for the treatment of NHL other than relapsed systemic anaplastic large cell lymphoma (sALCL). Opdivo is not currently approved for the treatment of lymphoma.

About ADCETRIS (Brentuximab Vedotin)

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells. CD30 is a member of the tumor necrosis factor receptor (TNFR) superfamily. In HL, CD30 may be involved in tumor cell proliferation by interacting with immune cells in the tumor microenvironment.

ADCETRIS for intravenous injection has received approval from the FDA for three indications: (1) regular approval for the treatment of patients with classical HL after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (2) regular approval for the treatment of classical HL patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (3) accelerated approval for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for the sALCL indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Health Canada granted ADCETRIS approval with conditions for relapsed or refractory HL and sALCL.

ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive HL following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. ADCETRIS has received marketing authorization by regulatory authorities in more than 55 countries. See important safety information below.

Seattle Genetics and Takeda Pharmaceutical Company Limited (Takeda) are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

About Opdivo

Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide. Opdivo is the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in more than 40 countries including the United States, Japan, and in the European Union.

About Lymphoma

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: HL and NHL. HL is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell generally expresses CD30. NHL is further categorized into indolent (low-grade) or aggressive, including DLBCL. DLBCL is the most common type of NHL.

On December 22, 2015 Merrimack Pharmaceuticals, Inc. (Nasdaq: MACK) reported it filed an amendment to its ongoing Phase 2 clinical study of MM-121 (seribantumab) in patients with heregulin-positive non-small cell lung cancer (NSCLC) with the U.S. Food and Drug Administration (FDA) (Press release, Merrimack, DEC 22, 2015, View Source [SID:1234508631]). The amendment includes a change in primary endpoint to overall survival to enable a potential registration opportunity for MM-121.

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"We believe MM-121 has the potential to address the pervasive clinical problem of resistance in cancer. This amendment is intended to accelerate development of this new treatment option for heregulin-positive non-small cell lung cancer patients who are resistant to standard-of-care therapies," said Robert Mulroy, Merrimack’s President and CEO. "The financing we announced today will allow us to independently advance and retain sole ownership of MM-121. In light of this amendment, we are focusing the development of MM-121 on this indication."

MM-121 is a fully human monoclonal antibody targeting ErbB3. The ongoing clinical study in NSCLC is an open-label, biomarker-selected randomized study of MM-121 in combination with docetaxel or pemetrexed compared to docetaxel or pemetrexed alone, in patients with heregulin-positive, locally advanced or metastatic NSCLC. Three prior Phase 2 clinical studies demonstrated that a subset of biomarker positive patients treated with MM-121 had a statically significant reduction in the risk of progression, with hazard ratios in a range of 0.26 – 0.37.

"We are pleased with investigator enthusiasm for the trial, which highlights the high unmet medical need in metastatic non-small cell lung cancer. Consistent with our previous Phase 2 study, more than half of the patients screened to date have been biomarker positive," said Akos Czibere, M.D., Ph.D., MM-121 Global Development Lead at Merrimack. "Amending this study design is a significant step forward in the development path for MM-121 in non-small cell lung cancer, where there is an urgent need for novel, biomarker-directed therapies to help patients battle drug resistance. We look forward to advancing this therapy and providing a potential new treatment option for this patient population."

Under the filed amendment, Merrimack expects to enroll approximately 280 heregulin-positive patients who will be randomized (2:1) to receive MM-121 plus the investigator’s choice of docetaxel or pemetrexed, or the investigator’s choice of docetaxel or pemetrexed alone. Eligible patients for the study must have failed prior treatment with no more than three lines of therapy for locally advanced or metastatic disease and, where applicable, prior PDL1 therapy. The amended primary endpoint of the study will be overall survival. Secondary endpoints include progression free survival, objective response rate, safety and quality of life measures. Merrimack continues to open study sites in the United States, Canada, Asia and Europe. With this updated study design, Merrimack expects survival data in 2018.

About MM-121 (Seribantumab)

MM-121 is Merrimack’s wholly owned, fully human monoclonal antibody that targets ErbB3, a cell surface receptor that is activated by the ligand heregulin. Heregulin-driven ErbB3 signaling has been implicated as a mechanism of tumor growth and resistance to targeted, cytotoxic and anti-endocrine therapies. When used in the combination setting, MM-121 is designed to block ErbB3 signaling in order to enhance the anti-tumor effect of a combination therapy partner.

Merrimack is pursuing this Phase 2 study based on encouraging results from a broad MM-121 Phase 2 program which identified heregulin mRNA expression as a potential prognostic factor of poor response to standard-of-care therapy across multiple cancers. The results also indicated that patients with heregulin-positive tumors experienced a longer time to progression when they received a combination of MM-121 with their standard-of-care therapy as compared to patients who received the standard therapy alone. Across the three different standard-of care combination regimens, a consistent safety profile demonstrated a modest but tolerable increase in adverse events. An extensive translational component of the MM-121 clinical program was designed to establish clinically meaningful biomarkers that were initially identified using Merrimack’s systems biology approach and preclinical studies