On January 27, 2016 Radius Health, Inc. (Nasdaq:RDUS) reported that it has entered into a worldwide clinical collaboration with Novartis Pharmaceuticals (NYSE:NVS) to evaluate the safety and efficacy of combining investigational agent RAD1901, a novel oral selective estrogen receptor degrader (SERD), with investigational agent LEE011 (ribociclib)*, a cyclin-dependent kinase (CDK) 4/6 inhibitor(Press release, Radius, JAN 27, 2016, View Source [SID:1234508873]). Preclinical studies of RAD1901 have shown consistent and robust single agent anti-tumor activity in multiple wild type and ESR1-mutant breast cancer models and tumor regression when combined with targeted agents such as CDK 4/6 inhibitors in pre-clinical models. The parties also intend to conduct pre-clinical studies to evaluate the effects of RAD1901 in combination with BYL719 (alpelisib), an investigational phosphoinositide 3-kinase (PI3K) inhibitor, with the goal of initiating future clinical trials.

"We are pleased to begin work with Novartis to explore the potential clinical benefits of RAD1901 in combination with these promising investigational agents for breast cancer, the second most common cancer in the world and the most prevalent cancer in women," said Robert Ward, President and Chief Executive Officer of Radius Health. "This collaboration will evaluate the potential of combination therapies to generate improved clinical results, as compared to single agents alone, and to address the needs of these underserved patient populations."

Under the agreement, Radius and Novartis will each contribute resources and supply compound material necessary for the studies to be conducted under the collaboration and will share third party out-of-pocket research and development expenses. The agreement is non-exclusive and each party will solely own all rights to any invention or discovery solely related to its respective product and/or compound. The parties will jointly own all data and inventions related to the combination use of investigational drug RAD1901 with investigational drugs LEE011, BYL719 or another compound arising under the collaboration.

*LEE011 was developed by the Novartis Institutes for BioMedical Research in collaboration with Astex Pharmaceutica

On January 27, 2016 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that it initiated a clinical trial to evaluate a novel combination therapy of Genentech’s investigational cancer immunotherapy atezolizumab (MPDL3280A; anti-PD-L1) and rociletinib for the treatment of advanced EGFR-mutant non-small cell lung cancer (NSCLC) (Press release, Clovis Oncology, JAN 27, 2016, View Source [SID:1234508872]). Rociletinib is the Company’s novel, oral targeted covalent (irreversible) mutant-selective inhibitor of EGFR in development for the treatment of NSCLC in patients with initial activating EGFR mutations, as well as the dominant resistance mutation T790M.

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The Phase 1b/2 trial of rociletinib in combination with atezolizumab, which is sponsored by Clovis, is designed to assess the safety and activity of the combination in patients with activating EGFR mutation-positive (EGFRm) advanced or metastatic NSCLC. The Phase 1b portion of the trial will evaluate the safety, tolerability and pharmacokinetics of the combination in this population. The Phase 2 portion of the trial will evaluate the activity of the combination in two subgroups of patients with EGFR-mutant advanced or metastatic NSCLC: those who have not previously received an EGFR tyrosine kinase inhibitor (TKI) or chemotherapy, and those who have progressed on a prior EGFR TKI. T790M-negative and T790M-positive patients will be enrolled in the Phase 1b portion of the trial and in the Phase 2 portion of the trial in the subgroup of patients who have progressed on a prior EGFR TKI. While patients’ tumors are not required to express PD-L1 to enroll in the study, PD-L1 expression will be assessed in archival and/or fresh tissue as part of the study.

The University of California in Los Angeles (UCLA) is the first site to initiate the trial, with the first patient expected to be enrolled within a few weeks. Additional patients will begin to enroll in sites throughout the U.S. and E.U., and initial safety and tolerability results from the study are expected at the World Conference on Lung Cancer in the fall of 2016.

"We are pleased to be enrolling patients at UCLA to explore this combination therapy for advanced EGFR-mutant non-small cell lung cancer patients, for whom additional treatment options are needed," said Dr. Jonathan Goldman, Director, Clinical Trials in Thoracic Oncology, Associate Director of Drug Development at UCLA and Principal Investigator. "We obviously hope to see meaningful synergy and patient benefit by combining the effects of immuno-oncology with a targeted therapy."

"I am excited to explore this combination with rociletinib to determine if we can bring the promise of long-term benefit of PD-L1 inhibitors seen in other lung cancer sub-types to those patients with mutant EGFR driven tumors", said Professor Jean-Charles Soria, Professor of Medicine and Medical Oncology at Paris University XI, Cancer Specialist at Gustav Roussy and lead Principal Investigator.

Currently, rociletinib is under review by the U.S. Food and Drug Administration and European Medicines Agency.

"Rociletinib’s activity and safety profile observed in our monotherapy trials suggest that rociletinib may be an attractive agent for combination use," said Patrick Mahaffy, President and CEO of Clovis Oncology. "We are committed to exploring the potential of rociletinib both as monotherapy and in combination to help patients with lung cancer who may benefit."

About Rociletinib

Rociletinib is the company’s novel, oral, targeted covalent (irreversible) mutant-selective inhibitor of EGFR in development for the treatment of NSCLC in patients with initial activating EGFR mutations, as well as the dominant resistance mutation T790M. Data from both the pivotal, single-arm TIGER-X and TIGER-2 clinical trials served as the basis for the U.S. and EU regulatory submissions for the treatment of advanced mutant EGFR T790M-positive lung cancer. Rociletinib was granted Breakthrough Therapy designation by the FDA in May 2014.

About Lung Cancer and EGFR Mutations

Lung cancer is the most common cancer worldwide with 1.35 million new cases annually, with NSCLC accounting for almost 85 percent of all lung cancers. NSCLC progresses rapidly with a five-year survival rate in advanced NSCLC patients of less than five percent. EGFR activating mutations occur in approximately 10 to 15 percent of NSCLC cases in Caucasian patients and approximately 30 to 35 percent in East Asian patients. These patients often experience significant tumor response to erlotinib, afatinib and gefitinib, which are first- and second-generation EGFR inhibitors. However, most patients ultimately progress on these therapies, with approximately 60 percent of patients developing acquired resistance from a second, "gatekeeper" mutation, T790M.

On January 27, 2016 ImmunoCellular Therapeutics, Ltd. ("ImmunoCellular") (NYSE MKT: IMUC) reported it has entered into a sponsored research agreement with Eduardo Davila, PhD, Associate Professor of Microbiology and Immunology at the University of Maryland School of Medicine, and the University of Maryland, Baltimore (Press release, ImmunoCellular Therapeutics, JAN 27, 2016, View Source [SID:1234508866]). The agreement includes three projects, which together have the potential to improve the efficacy of dendritic cell, T-cell, and combination immunotherapies for cancer and lead to enhancements to both of ImmunoCellular’s dendritic cell and Stem-to-T-cell platforms.

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The first of three projects evaluates certain immune modulators that could enhance T-cell killing of tumor cells. These small molecule modulators have been shown preclinically to be capable of increasing tumor antigen expression while simultaneously decreasing expression of ligands, such as PD-L1 and PDL2, which decrease T-cell activity. This technology applies directly to both ImmunoCellular platforms.

The second project explores the combination of engineered killer T-cells and dendritic cell immunotherapies on tumor killing. These T-cells embody a novel engineering technology that potentially amplifies their cytotoxic, proliferative, and cytokine-producing properties toward tumor antigens. Combining these engineered T-cells with ImmunoCellular’s dendritic cell immunotherapies could lead to enhanced tumor cell killing.

The third project tests novel peptide configurations for use with dendritic cell immunotherapies to potentially induce enhanced T-cell responses.

Dr. Davila is the Program Leader for the Tumor Immunology and Immunotherapy Program within the University of Maryland Marlene and Stewart Greenebaum Cancer Center Program. As such, he collaborates with both basic and clinical research investigators to understand the immune regulation of malignant disease and translate this knowledge into the development of novel diagnostic, preventative and treatment regimens.

"ImmunoCellular’s research and early development strategy is to complement and enhance our dendritic cell and Stem-to-T-cell technology platforms and create potent cell-based cancer immunotherapeutic clinical candidates and combinations," said Steven Swanson, PhD, ImmunoCellular Senior Vice President, Research. "The research projects we are undertaking with Dr. Davila align well with this strategy and have the potential to lead to platform technology enhancements and new clinical programs."

"With this agreement and with other related research underway, we are systematically delivering on our goal to build a leading cancer immunotherapy company. We are pleased with the enhanced position we are establishing in the dendritic cell and T-cell cancer immunotherapy space," said Andrew Gengos, ImmunoCellular Chief Executive Officer.

On January 27, 2016 Boehringer Ingelheim reported the results of the LUX-Lung 7 trial. Superiority in progression-free survival and time to treatment failure was demonstrated with second-generation EGFR-directed therapy afatinib, versus first-generation gefitinib in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) with common EGFR mutations (del19 or L858R)(Press release, Boehringer Ingelheim, JAN 27, 2016, View Source [SID:1234508865]).1

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The Phase IIb trial met two of its co-primary endpoints of progression-free survival (PFS) by independent review and time to treatment failure (a measure of time between start, and discontinuation of treatment for any reason).1 The LUX-Lung 7 trial results will be presented today at the 14th Annual British Thoracic Oncology Group (BTOG) Conference in Dublin, Ireland. Data for the third co-primary endpoint, overall survival (OS), are not yet mature and will be presented in the future.

Results from the LUX-Lung 7 trial showed that afatinib significantly reduced the risk of lung cancer progression by 27% versus gefitinib.1 The improvement in PFS became more pronounced over time, with a significantly higher proportion of patients alive and progression-free at 18 months (27% vs 15%) and 24 months (18% vs 8%), showing a greater long-term benefit to using afatinib versus gefitinib.1 In addition to superior PFS, patients on afatinib had a significantly longer time on treatment: risk of treatment failure reduced by 27%, versus gefitinib.1 Significantly more patients had an objective tumour response (a clinically meaningful decrease in tumour size) with afatinib when compared to gefitinib (70% vs 56%), with a median duration of response of 10.1 months and 8.4 months, respectively.1 The improvement in PFS with afatinib was consistent across most pre-defined clinical subgroups, including gender, age, race and EGFR mutation type.1

LUX-Lung 7 lead investigator Professor Keunchil Park, director of Innovative Cancer Medicine Institute (ICMI) at Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea commented, "LUX-Lung 7 is the first global trial directly comparing two EGFR-directed therapies and the results demonstrate the benefits of second-generation inhibitor afatinib, compared to first-generation drug, gefitinib, in first-line therapy. These results provide important guidance on the choice of first-line treatment for patients with EGFR mutation-positive lung cancer."

Adverse events (AEs) observed in the LUX-Lung 7 trial were consistent with the known safety profiles of both treatments. Treatment with both afatinib and gefitinib was generally tolerable, leading to an equally low rate of treatment-related discontinuation in both arms (6.3%).1 The overall frequency of serious AEs was similar for both (afatinib: 44.4% vs gefitinib: 37.1%); the most common grade ≥3 related AEs with afatinib were: diarrhea (12.5%) and rash/acne (9.4%), and with gefitinib: aspartate aminotransferase (AST)/alanine aminotransferase (ALT) increase (8.8%) and rash/acne (3.1%).1 Drug-related interstitial lung disease was reported for four patients on gefitinib and no patients on afatinib.1

"LUX-Lung 7 is the second positive head-to-head trial of afatinib versus first-generation EGFR TKIs in lung cancer, showing that first- and second-generation EGFR targeted agents are not the same," said Dr Mehdi Shahidi, Medical Head, Solid Tumour Oncology, Boehringer Ingelheim. "Interestingly, the progression-free survival difference observed in the LUX-Lung 7 trial became more prominent over time so that by 24 months the rate of patients who were free of cancer growth was more than doubled with afatinib."

About the LUX-Lung 7 trial
LUX-Lung 7 is the first global, head-to-head trial comparing second- and first-generation EGFR-directed therapies (afatinib and gefitinib respectively) for patients with EGFR mutation-positive NSCLC who received no prior treatment. The Phase IIb trial included 319 patients with advanced stage NSCLC harbouring common EGFR mutations (del19 or L858R). The trial’s co-primary endpoints were PFS by independent review, time to treatment failure and OS; and the secondary endpoints included objective response rate, disease control rate, tumour shrinkage, patient-reported outcomes and safety.

Results: compared to gefitinib, afatinib significantly improved:

PFS (HR=0.73; 95% CI, 0.57‒0.95; p=0.0165; median: 11.0 months [afatinib] versus 10.9 months [gefitinib])
Time to treatment failure (HR=0.73; 95% CI, 0.58‒0.92; p=0.0073; median: 13.7 months [afatinib] versus 11.5 months [gefitinib])
Objective Response Rate (70% vs 56%, p=0.0083)

Afatinib is approved in more than 60 countries for the first-line treatment of distinct types of EGFR mutation-positive NSCLC (under the brand names: GIOTRIF / GILOTRIF). Approval of afatinib in this indication was based on the primary endpoint of PFS from the LUX-Lung 3 clinical trial where afatinib significantly delayed tumour growth when compared to standard chemotherapy.2 In addition, afatinib is the first treatment to have shown an OS benefit for patients with specific types of EGFR mutation-positive NSCLC compared to chemotherapy.3 A significant OS benefit was demonstrated independently in the LUX-Lung 3 and 6 trials for patients with the most common EGFR mutation (exon 19 deletions; del19) compared to chemotherapy.3