On October 7, 2015 Merck and Pfizer reported that the US Food and Drug Administration (FDA) has granted avelumab*, an investigational fully human anti-PD-L1 IgG1 monoclonal antibody, Fast Track designation for the treatment of metastatic Merkel cell carcinoma (MCC), a rare and aggressive type of skin cancer (Press release, Merck KGaA, OCT 7, 2015, View Source [SID:1234507663]).1,2

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This announcement builds on the recent FDA Orphan Drug designation that was granted for avelumab on September 21, 2015 for the treatment of MCC. The Fast Track designation is designed to facilitate the development, and expedite the review, of drugs to treat serious conditions and address an unmet medical need.

"We are pleased that the FDA continues to acknowledge the current high unmet needs for patients with metastatic Merkel cell carcinoma through these recent regulatory designations for avelumab," said Dr. Luciano Rossetti, Head of Global Research & Development at Merck’s biopharmaceutical business, Merck Serono. "We look forward to working closely with the FDA on an expedited review process for avelumab, and we hope to be able to provide a potential new treatment option for patients with this difficult-to-treat cancer in the future."


"We look forward to working with our partners at Merck on the development of avelumab in patients with relapsed and refractory Merkel cell carcinoma," said Dr. Mace Rothenberg, Senior Vice President of Clinical Development and Medical Affairs and Chief Medical Officer for Pfizer Oncology. "Fast Track designation will enable us to coordinate these efforts more closely with the FDA."

The designation relates to the clinical development program for avelumab in metastatic MCC, which includes the Phase II study, JAVELIN Merkel, to assess the safety and efficacy of avelumab in patients with metastatic MCC who have progressed after at least one prior chemotherapy regimen. In this study, the primary endpoint is objective response rate, and secondary endpoints include duration of response, progression-free survival, overall survival and safety. The study, which exceeded its expected enrollment of 84 patients with 88 patients enrolled, is being conducted in sites across Asia Pacific, Australia, Europe and North America.

The clinical development program for avelumab now includes more than 1,000 patients who have been treated across more than 15 tumor types, including breast cancer, gastric/gastroesophageal cancer, head and neck cancer, MCC, mesothelioma, melanoma, non-small cell lung cancer, ovarian cancer, renal cell carcinoma and urothelial (e.g. bladder) cancer.

On October 7, 2015 Nektar Therapeutics (NASDAQ:NKTR) reported that it has submitted an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) for NKTR-214, its lead immuno-oncology candidate. NKTR-214 is a CD122-biased immune-stimulatory cytokine that is designed to stimulate the patient’s own immune system to destroy cancer cells (Press release, Nektar Therapeutics, OCT 7, 2015, View Source [SID:1234507662]).

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The company plans to initiate a Phase 1/2 clinical study by the end of 2015. The study will evaluate the safety, tolerability and efficacy of NKTR-214 in patients with solid tumor malignancies and will include expansion cohorts that will evaluate NKTR-214 both as a single-agent and in combination with a checkpoint inhibitor.

"As a new cytokine with biased receptor activity and an antibody-like dosing schedule, NKTR-214 could emerge as a differentiated immuno-oncology therapy that specifically stimulates T-cell growth to fight cancer," said Stephen Doberstein, PhD, Senior Vice President and Chief Scientific Officer of Nektar. "In preclinical studies with NKTR-214, we not only observed single-agent efficacy in multiple tumor models, but when administered in combination with a checkpoint inhibitor, we see a dramatic immune-educating vaccine-like effect with NKTR-214. We are excited to start our first-in-human study and we expect to have initial data from the dose-escalation phase of the trial by the second half of 2016."

The Phase 1/2 clinical program will be conducted at multiple clinical sites including MD Anderson Cancer Center and Yale Cancer Center. In addition to the Phase 1/2 clinical program, Nektar and MD Anderson will conduct translational research to identify predictive biomarkers that can be used in the future development of NKTR-214.

About NKTR-214
NKTR-214 is a CD122-biased immune-stimulatory cytokine that is designed to preferentially stimulate the expansion and maintenance of CD8-positive effector T cells, which are tumor-killing cells found naturally in the body. CD122, which is also known as the Interleukin-2 (IL-2) receptor beta subunit, is a key signaling receptor that is known to increase the proliferation of CD8-positive effector T cells.1 These tumor-killing cells comprise a key component of the tumor infiltrating lymphocytes that provide cell-mediated anti-tumor effects.1 By biasing activation to the CD122 receptor, NKTR-214 enhances the generation of CD8-positive T cells in the tumor.

In preclinical studies, a single dose of NKTR-214 resulted in an approximate 400-fold AUC exposure within the tumor compared with an equivalent dose of aldesleukin, an existing IL-2 therapy. This increase potentially enables, for the first time, an antibody-like dosing regimen for a cytokine.2

At the Inaugural CRI-CIMT-EATI-AACR Immunotherapy Conference in New York in September 2015, Nektar presented data demonstrating that NKTR-214 induces durable and specific anti-tumor immunity as a single agent and when combined with checkpoint inhibitors in preclinical models. As a single agent, NKTR-214 demonstrated efficacy in multiple preclinical models. In combination with either anti-CTLA4 or anti-PD-1 checkpoint inhibitor therapies, NKTR-214 produced durable anti-tumor immunotherapeutic effects, which persisted long after the termination of dosing. In a preclinical tumor re-challenge study, sequential dosing of anti-CTLA-4 followed by NKTR-214 resulted in durable and complete responses. At 142 days following the final dose, with no additional treatment, the complete responders demonstrated sustained resistance to multiple tumor re-challenges. In highly-resistant established melanoma tumor models, treatment with NKTR-214 resulted in a controlled, sustained and biased T-cell activating signal and a mean ratio of CD8-positive T cells to CD4-positive regulatory T-cells (which can suppress tumor killing) of 450:1 in the tumor infiltrating lympho

On October 7, 2015 Seattle Genetics, Inc. (Nasdaq:SGEN) reported that it has initiated a phase 1/2 clinical trial of ADCETRIS (brentuximab vedotin) in combination with Opdivo (nivolumab) for patients with relapsed or refractory Hodgkin lymphoma (HL) after failure of frontline treatment (Press release, Seattle Genetics, OCT 7, 2015, View Source [SID:1234507658]). The trial is being conducted under a previously announced clinical trial collaboration agreement with Bristol-Myers Squibb Company (NYSE:BMY).

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ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL, which combines the targeting ability of a monoclonal antibody with a highly potent cell-killing agent. Opdivo is 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. A second trial under the collaboration is planned to begin later in 2015 for relapsed or refractory B-cell and T-cell non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL).

"This is the first 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. "The trial supports our strategy to establish ADCETRIS as the foundation of care for CD30-expressing malignancies, and to test novel combinations that could benefit patients. We are executing a broad clinical program with ADCETRIS to potentially expand into earlier lines of therapy and new indications, including the ECHELON-1 trial in frontline Hodgkin lymphoma, the ECHELON-2 trial in frontline mature T-cell lymphoma, the ALCANZA trial in cutaneous T-cell lymphoma and both ongoing and planned trials in diffuse large B-cell lymphoma."

The phase 1/2 open-label trial will enroll relapsed or refractory HL patients who have failed frontline therapy. The primary objective is to assess the safety and antitumor activity of ADCETRIS in combination with Opdivo. After completion of four cycles of combination therapy, patients are eligible to undergo autologous stem cell transplant (ASCT). Patients at high risk of relapse or progression following ASCT will be eligible to receive ADCETRIS in the commercial setting. All patients will be assessed for progression-free survival after ASCT. The trial is being conducted at multiple centers in the United States and is designed to enroll up to approximately 60 patients.

ADCETRIS is not currently approved for the treatment of second-line, transplant eligible HL or for the treatment of NHL other than relapsed systemic anaplastic large cell lymphoma. Opdivo is currently not 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.

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 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.