On July 6, 2015 Boehringer Ingelheim reported The Lancet Oncology has published results from the LUX-Lung 8 trial (NCT01523587) (Press release, Boehringer Ingelheim, JUL 6, 2015, View Source [SID:1234506178]).

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LUX-Lung 8 is the largest, prospective Phase III head-to-head trial directly comparing two EGFR-directed treatments. Afatinib* was tested versus erlotinib, an approved and recommended treatment in this setting according to international guidelines, in advanced squamous cell carcinoma (SCC) of the lung progressing after treatment with first-line platinum-based chemotherapy.1 Treatment options for SCC of the lung are limited and this type of lung cancer is associated with a poor prognosis, with less than 5% of patients with advanced SCC surviving for five years or longer.2,3

While afatinib is not yet approved for use in patients with SCC, the study showed that treatment with afatinib, an irreversible ErbB Family Blocker, resulted in superior progression-free survival (PFS, primary endpoint) and overall survival (OS, key secondary endpoint) compared to erlotinib in this patient population.1

Dr. Mehdi Shahidi, Medical Head, Solid Tumour Oncology, Boehringer Ingelheim commented: "The ErbB family of receptors plays an important role in the development of squamous cell carcinoma of the lung, and is a valid therapeutic target for this type of cancer. The broader and irreversible ErbB blockade of afatinib may explain the superiority shown in LUX-Lung 8 over erlotinib, an EGFR inhibitor already approved in this setting. We are pleased with the publication of LUX-Lung 8 data in The Lancet Oncology and based on the improvement in overall survival with the use of afatinib, we are in the process of preparing regulatory submissions."

Previously reported data demonstrated that the LUX-Lung 8 study met its primary endpoint as afatinib significantly improved PFS compared to erlotinib.1 In addition, afatinib extended OS of patients to a median of 7.9 months compared to 6.8 months on erlotinib, reducing the risk of death by 19%.1 In an updated PFS analysis, performed at the time of the OS analysis, patients treated with afatinib had a median PFS of 2.6 months compared to 1.9 months for erlotinib.4 More patients reported an improvement in overall well-being/quality of life with afatinib compared to erlotinib and the rate of severe adverse events was similar between the two treatment arms with differences observed in the incidence of certain adverse events.1 See the online publication for full details.

On July 6, 2015 Ignyta reported a clinical collaboration with the University of California, San Francisco (UCSF), under which UCSF will study entrectinib in a proof-of-concept clinical trial in cancer patients with metastatic melanoma that is positive for activating alterations to NTRK1/2/3 (encoding TrkA/TrkB/TrkC) or ROS1 (Press release, Ignyta, JUL 6, 2015, View Source [SID:1234506174]).

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"We are excited to collaborate with UCSF, a world-renowned academic research institution," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "The focus on melanoma in this study will complement the broader range of indications on which we are focused in our own clinical trials, and we expect the findings to accelerate our understanding of the potential role of entrectinib in treating patients with NTRK-positive and ROS1-positive cancers."

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Under the terms of the collaboration agreement, Ignyta will contribute $1 million toward the funding of the clinical trial, as well as per-patient fees based on enrollment of NTRK-positive or ROS1-positive patients and their participation in the trial. Ignyta will also provide UCSF with sufficient supply of entrectinib for use in the clinical trial. In addition to the safety and efficacy data from the trial, UCSF will provide Ignyta with tumor samples and genetic sequencing data for patients screened for inclusion in the trial for further genomic analysis.

The study is a multicenter, open label umbrella trial designed by UCSF to obtain proof-of-concept data in patients with metastatic melanoma that is positive for molecular alterations in specific tyrosine kinase receptors. UCSF will exclusively use entrectinib for patients enrolled in the clinical trial having activating molecular alterations to NTRK1/2/3 or ROS1.

About Entrectinib

Entrectinib is a novel, orally available, selective tyrosine kinase inhibitor targeting tumors that harbor activating alterations to NTRK1/2/3 (encoding TrkA/ TrkB/TrkC), ROS1 or ALK.

In June 2015, Ignyta announced interim results from two Phase 1 clinical trials of entrectinib: the ALKA-372-001 study and the STARTRK-1 study, which is the first of the "Studies of Tumor Alterations Responsive to Targeted Receptor Kinase" inhibition. Both trials were designed to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose, as well as preliminary anti-cancer activity, of single agent entrectinib in patients with solid tumors with the relevant molecular alterations: NTRK1 (encoding TrkA), ROS1 or ALK for ALKA-372-001 and NTRK1/2/3 (encoding TrkA/TrkB/TrkC), ROS1 or ALK for STARTRK-1.

As of the May 1, 2015 data cut-off for the presentation, the findings showed:

A total of 67 patients with a range of solid tumors had been dosed across both clinical trials;

Entrectinib was well tolerated, with no treatment-related serious adverse events. Other safety findings included:
In the ALKA-372-001 study, two Grade 3 treatment-related adverse events were observed: fatigue and muscle weakness, each of which subsided with dose reduction. The most frequent adverse events were paresthesia, nausea, myalgia, asthenia, dysgeusia, and vomiting;

In the STARTRK-1 study, three Grade 3 treatment-related adverse events were observed: neutropenia, which resolved with dose reduction, and two dose-limiting toxicities of reversible cognitive impairment and fatigue, both of which resolved upon study drug interruption. The most frequent adverse events were fatigue, dysgeusia, constipation, nausea, and paresthesia;

Pharmacokinetic measurements showed dose-proportional increases across the daily dosing regimens evaluated, with a half-life compatible with once-daily dosing;

The body surface area (BSA)-based recommended Phase 2 dose was determined to be 400 mg/m2 once per day (QD); both studies are continuing in order to determine a fixed daily dose regimen;

11 patients across both clinical trials met the company’s expected Phase 2 eligibility criteria, which include:
Presence of NTRK1/2/3, ROS1 or ALK fusions, as opposed to other types of molecular alterations (e.g., SNPs, amplifications, deletions);
ALK inhibitor and/or ROS1 inhibitor naïve; and
Treatment at or above the recommended Phase 2 dose of 400 mg/m2;

The response rate in the 11 patients that met these criteria across both studies was 91% (10 of 11 responses as assessed by the clinical sites), with 9 patients remaining on study treatment with durable responses of up to 16 treatment cycles. The responses included:
3 of 3 responses in patients with NTRK1/2/3 fusions, including patients with non-small cell lung cancer (NSCLC), colorectal cancer and acinic cell cancer;
5 of 6 responses, including one complete response, in patients with ROS1 fusions, all of which were in NSCLC; and
2 of 2 responses in patients with ALK fusions, including one NSCLC patient and one patient with another solid tumor.

On July 6, 2015 Janssen Biotech reported the opening of a daratumumab expanded access program (EAP) for eligible U.S. patients (Press release, Johnson & Johnson, JUL 6, 2015, View Source [SID:1234506170]).

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Daratumumab is an investigational human anti-CD38 monoclonal antibody being evaluated in clinical trials as a treatment for people with multiple myeloma. The multicenter, open-label EAP is available to multiple myeloma patients who are refractory to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) or who have received three or more prior lines of therapy, including a PI and an IMiD. This is referred to as "double refractory" multiple myeloma, which occurs when a patient’s disease has become resistant to at least two of the most commonly utilized and active classes of anti-myeloma agents.

"We understand that heavily pre-treated or double refractory patients are in immediate need of new treatment options," said Craig Tendler, M.D., Vice President, Late Development and Global Medical Affairs, Oncology, Janssen. "Through a research collaboration with the Multiple Myeloma Research Foundation, or MMRF, we have broadened our network of sites and sped site activation. Our goal is to provide timely access to daratumumab for multiple myeloma patients who may benefit while its application is under review with the U.S. Food and Drug Administration. MMRF’s significant experience in multiple myeloma research and innovation has helped to accelerate our efforts to meet this urgent patient need."

In the U.S., EAPs are conducted as clinical trials and designed to make investigational medicines available for patients with serious or life-threatening illnesses who are ineligible for ongoing interventional trials and have exhausted currently available treatment options.

Up to 40 medical centers in the U.S. will enroll patients in the daratumumab EAP. The MMRF played a key role in identifying sites geographically distributed across the U.S. and opening sites for enrollment.

"While we work urgently each day to find solutions for all who are fighting multiple myeloma, our most critical focus is for those individuals whose multiple myeloma has relapsed and often have few or no active treatment options," said Walter M. Capone, Chief Executive Officer and President of the MMRF. "In collaboration with pharmaceutical and biotech companies, the FDA, leading research institutions both within our wholly-owned subsidiary, the Multiple Myeloma Research Consortium and beyond, the MMRF is relentless in advancing the most promising science and accelerating the development of new, innovative multiple myeloma therapies. Our work together with Janssen on this important EAP is a perfect example of our mission in action, helping patients in every way possible, particularly at times of intense need."

On May 1, 2013, daratumumab received Breakthrough Therapy Designation from the FDA for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a PI and an IMiD, the current standards of care, or who are double refractory to a PI and an IMiD. On June 5, 2015, Janssen announced it had initiated the rolling submission of its Biologics License Application (BLA) for daratumumab to the FDA for the treatment of this set of multiple myeloma patients. A rolling submission allows the company to submit portions of the regulatory application to the FDA as they are completed.[i] The regulatory submission for daratumumab will be primarily supported by data from the Phase 2 MMY2002 (SIRIUS) monotherapy study announced in May 2015 at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), along with additional data from four other studies, including the Phase 1/2 GEN501 monotherapy study.

About the daratumumab Expanded Access Program Protocol
The daratumumab expanded access program (EAP) is for U.S. patients 18 years of age or older who are double refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) or who have received three or more prior lines of therapy, including a PI and an IMiD, who may benefit from treatment with daratumumab prior to its potential U.S. Food and Drug Administration (FDA) approval. The EAP has specific inclusion and exclusion criteria for patients to be considered for enrollment in the program, and patients must not be eligible for another daratumumab study. Interested patients should contact their physician to discuss whether they may be a candidate for daratumumab through the EAP. Additional information about the expanded access protocol can be found on clinicaltrials.gov (NCT02477891).

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.[ii] Multiple myeloma is the third most common blood cancer in the U.S., following only leukemia and lymphoma.[iii] Approximately 26,850 new patients will be diagnosed with multiple myeloma, and approximately 11,240 people will die from the disease in the U.S. in 2015.[iv] Globally, it is estimated that 114,251 people will be diagnosed and 80,019 will die from the disease.[v] While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.[vi]

About daratumumab
Daratumumab is an investigational human IgG1k monoclonal antibody (mAb) that binds with high affinity to the transmembrane ectoenzyme, CD38, on the surface of multiple myeloma cells. It induces rapid tumor cell death through diverse mechanisms of action. Five Phase 3 clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin’s lymphoma. In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement which granted Janssen an exclusive license to develop, manufacture and commercialize daratumumab. With the exception of one study sponsored globally by the French multiple myeloma cooperative group, Intergroupe Francophone du Myelome (IFM), Janssen is the global sponsor of all current and future clinical studies for daratumumab.

On July 6, 2015 Oncolytics Biotech reported that Dr. Devalingam Mahalingam of the Cancer Therapy and Research Centre, University of Texas Health Science Centre San Antonio, made a poster presentation at the ESMO (Free ESMO Whitepaper) World Congress on Gastrointestinal Cancer (Press release, Oncolytics Biotech, JUL 6, 2015, View Source [SID:1234506168]).

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The poster, titled "Oncolytic Virus Therapy in Pancreatic Cancer: Clinical Efficacy and Pharmacodynamic Analysis of REOLYSIN in Combination with Gemcitabine in Patients with Advanced Pancreatic Adenocarcinoma," covers final results from the Company’s REO 017 Phase 2 study.

"These data suggest that this drug combination can increase median overall survival, as well as generate an approximate two-fold increase in one-year survival rates, and a five-fold increase in two-year survival rates when compared to gemcitabine therapy alone as seen in historical data," said Dr. Matt Coffey, COO of Oncolytics. "The observation of clear overall survival (OS) benefit combined with apparent limited impact on progression free survival (PFS) is increasingly becoming characteristic of immune-based therapeutic treatments. We are incorporating this finding into both our new and existing studies to ensure we follow OS where possible."

Highlights of the data presented include:

A survival analysis for 33 patients showing a median progression free survival (PFS) of four months and median overall survival (OS) of 10.2 months;
Data showing one- and two-year survival rates of 45% and 24%, respectively; and
An analysis demonstrating upregulation of immune checkpoint marker PD-L1 in post treatment tumours suggesting the potential to combine oncolytic viral therapy with anti-PD-L1 inhibitors in future trials.

Of the 29 patients evaluable for clinical response, one patient had a partial response (PR), 23 had stable disease (SD) and five had progressive disease as their best response. This translated into a clinical benefit rate (CBR) (complete response (CR) + PR + SD) of 83%.

"This is the second cancer where we have confirmed that PD-L1 is upregulated in target tumors following our collaborators initial observations of PD-L1 upregulation in glioblastoma," said Dr. Brad Thompson, President and CEO of Oncolytics. "We are currently analyzing archived samples from other completed studies and current samples from ongoing studies to determine if this is a common effect to most cancers. A systemic viral therapy that generally led to upregulation of PD-L1 would allow increased use of anti PD-L1 drugs in cancers where there is insufficient PD-L1 to make therapy possible."

REO 017 is a U.S. Phase 2, single-arm clinical trial using intravenous administration of REOLYSIN in combination with gemcitabine (Gemzar) in chemotherapy-naïve patients with advanced or metastatic pancreatic cancer. Eligible patients were treated with gemcitabine at 800 mg/m2 on days 1 and 8, and REOLYSIN at 1×1010 TCID50 administered IV on days 1, 2, 8 and 9 every 3 weeks. Tumor assessment was performed every two cycles. The trial enrolled 33 evaluable patients (34 total) using a one sample, two-stage design. In the first stage, 17 patients were to be enrolled, and best response noted. If three or more responses were observed (defined as CR, PR, or SD for 12 weeks or more) among the 17 patients, the study would enroll an additional 16 patients for a total of at least 33 evaluable patients. As previously disclosed, this initial endpoint was met after six evaluable patients were enrolled. The primary objective of the trial was to determine the CBR of intravenous multiple doses of REOLYSIN in combination with gemcitabine in patients with advanced or metastatic pancreatic cancer. The secondary objectives were to determine PFS, and to determine the safety and tolerability of REOLYSIN when administered in combination with gemcitabine.

A copy of the poster presentation will be available on the Oncolytics website at: View Source