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Clovis Oncology Enters into Oncology Clinical Trial Collaboration with GlaxoSmithKline

On November 17, 2014 Clovis Oncology reported that they have entered into a clinical trial collaboration with GlaxoSmithKline to evaluate a novel combination therapy targeting mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) (Press release Clovis Oncology, NOV 17, 2014, View Source;p=RssLanding&cat=news&id=1990475 [SID:1234500975]). The Phase 1/2 trial of rociletinib given in combination with trametinib is planned to start in 1H 2015. The trial is designed to assess the safety and activity of the combination in patients with EGFR mutant NSCLC who were previously treated with an EGFR tyrosine kinase inhibitor (TKI).

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"We have seen significant activity in EGFR mutant NSCLC patients treated with rociletinib monotherapy, and so an important next step in our research is to examine rociletinib in combination with other targeted therapies that may also impact acquired resistance to EGFR inhibitors," said Lecia V. Sequist, MD, MPH, Massachusetts General Hospital Cancer Center and Associate Professor of Medicine at Harvard Medical School and the lead investigator for this combination study.

"As we continue to see compelling activity for rociletinib single-agent therapy at our selected dose, we look forward to exploring combination trials in both T790M-positive and T790M-negative patients," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "We believe that given the tolerability profile of rociletinib, particularly its lack of cutaneous toxicity, it may be a good candidate for combination therapy with trametinib, and other relevant targeted therapies. We intend to announce additional combination studies over the next few months."

All patients with EGFR mutant NSCLC eventually develop resistance to EGFR TKI therapy and T790M is the primary resistance mutation, occurring in 60 percent of patients treated with first- and second-generation EGFR inhibitors. Rociletinib targets the activating mutations of EGFR (L858R and Del19) and the T790M mutation, and has demonstrated encouraging clinical activity and tolerability in Phase 1/2 studies of patients with EGFR mutant NSCLC.

Another mechanism of acquired resistance in EGFR mutant NSCLC is through the activation of the mitogen-activated protein kinase (MAPK) pathway. Trametinib is an orally active inhibitor of mitogen-activated protein kinase (MEK), which plays a key role in downstream MAPK pathway signaling, and it thereby inhibits growth factor-mediated signaling and cellular proliferation. Trametinib as a single agent has been approved by the FDA for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test.

In preclinical models of T790M+ EGFR mutant NSCLC, acquired resistance to T790M inhibitors can occur through MAPK pathway activation, and the combination of rociletinib and trametinib has been shown to restore MAPK pathway suppression, resulting in increased anti-tumor activity.

This clinical trial is designed to test the hypothesis that the combination of two oral drugs targeting different cellular growth pathways, both often active in EGFR mutant NSCLC, will lead to augmented clinical benefit. Rociletinib is the core drug of the combination, and trametinib will be titrated in to first assess safety and then explore efficacy. Extensive tumor sampling will be performed to enable detailed molecular characterization of each patient’s tumor load, together with pharmacodynamic assessment of pathway inhibition. Integration of clinical data with molecular tumor data, both on and off drug(s), will enable robust understanding of observed clinical outcomes.

Deciphera Pharmaceuticals Presents Data on Altiratinib (DCC-22701) that Demonstrated Inhibition of Tumor Growth and Invasion in Bevacizumab Resistant Glioblastoma

On November 17, 2014 Deciphera Pharmaceuticals reported the presentation of preclinical data that demonstrated that altiratinib (DCC-2701) inhibited tumor growth and invasion in a bevacizumab resistant glioblastoma mouse model (Press release Deciphera Pharmaceuticals, NOV 17, 2014, View Source [SID:1234500972]). Altiratinib, a kinase inhibitor that targets multiple selected kinases MET, TIE2, VEGFR2 and TRK, is currently in Phase 1 clinical development for the treatment of invasive solid tumors and received Orphan Drug Status from the U.S. Food and Drug Administration for the treatment of glioblastoma. The data on altiratinib were presented at the 19th Annual Scientific Meeting and Education Day of The Society for Neuro-Oncology held November 13-16, 2014, in Miami.

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"Altiratinib is differentiated in its ability to inhibit MET and TRK kinases while also providing balanced inhibition of the tumor microenvironment within a single oral therapeutic," said Michael D. Taylor, PhD, Deciphera’s President and Chief Executive Officer. "This balanced inhibitory profile demonstrates the power of Deciphera’s switch pocket technology to design advanced kinase inhibitor therapies to simultaneously block multiple cancer signaling mechanisms in the tumor cell and the tumor microenvironment to prevent growth and spread of cancer."
"These data demonstrated that altiratinib inhibited tumor growth and invasion both in vitro and in vivo. Based on these results, we believe the combination of altiratinib and anti-VEGF therapy may provide a new strategy to overcome antiangiogenic therapy resistance and prolong overall survival in patients with glioblastoma," said John F. de Groot MD, Associate Professor, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center and presenting author. "We look forward to further exploring the potential of altiratinib in refractory glioblastoma, an area of significant unmet medical need."

In an oral presentation titled, "The Novel c-MET inhibitor altiratinib (DCC-2701) inhibits tumor growth and invasion in a bevacizumab resistant glioblastoma mouse model," John F. de Groot, MD and colleagues from the Brain Tumor Center at MD Anderson Cancer Center described data that demonstrated altiratinib, either alone or in combination with anti-VEGF therapy (bevacizumab), inhibited tumor growth, epithelial-mesenchymal transition (EMT) progression and invasion both in vitro and in vivo, compared with anti-VEGF therapy alone:

• Altiratinib, alone or in combination with bevacizumab treatment, dramatically suppressed EMT and tumor invasion in vivo. This anti-invasive effect correlated with decreased N-cadherin and vimentin levels.

• In vivo, microvascular density associated with evasive revascularization induced by bevacizumab, was significantly inhibited in the groups treated with altiratinib and altiratinib plus bevacizumab, compared with control or the group treated with bevacizumab alone.

• Similarly, F4/80+ bone marrow derived macrophage cell infiltration was significantly suppressed in the groups treated with altiratinib and altiratinib plus bevacizumab, compared to control or the group treated with bevacizumab alone.

Inovio Pharmaceuticals to Independently Develop Prostate Cancer Immunotherapy; Will Maintain Collaboration and License Agreement with Roche for Inovio’s Hepatitis B Immunotherapy

On November 17, 2014 Inovio Pharmaceuticals reported that the company and Roche have terminated their 2013 collaboration, option, and license agreement to co-develop INO-5150, Inovio’s DNA immunotherapy targeting prostate cancer, as well as their research collaboration in prostate cancer (Press release Inovio, NOV 17, 2014, View Source [SID:1234500973]). All of Roche’s rights to INO-5150, including the right to license the product to other parties, will be returned to Inovio. Inovio plans to independently advance INO-5150 into a phase I clinical trial in the first half of 2015.

Inovio and Roche will continue to collaborate and co-develop Inovio’s DNA immunotherapy (INO-1800) against hepatitis B virus under their existing license agreement. The partnership is on track to move INO-1800 collaboratively into a phase I study in 2015.

Dr. J. Joseph Kim, Inovio’s president & CEO, said, “The Inovio/Roche partnership will continue to thrive focusing on the development of INO-1800 for the treatment of hepatitis B. In addition to recently demonstrating clinical efficacy and the ability to induce potent antigen specific CD8+ T cell responses in our VGX-3100 phase II study, Inovio will be moving a broad portfolio of immuno-oncology products through development, including INO-3112 (head/neck and cervical cancers), INO-1400 (breast, lung and pancreatic cancers) and INO-5150 (prostate cancer). We believe that these products along with pre-phase III VGX-3100 will further our growth and represent opportunities for additional value-adding partnerships.”

Merck KGaA, Darmstadt, Germany, Announces Global Strategic Alliance with Pfizer on Anti-PD-L1 to Accelerate Presence in Immuno-Oncology

On November 17, 2014 Merck KGaA reported that it has entered into a global agreement with Pfizer to co-develop and co-commercialize MSB0010718C, an investigational anti-PD-L1 antibody currently in development by Merck KGaA as a potential treatment for multiple tumor types to accelerate the two companies’ presence in immuno-oncology (Press release Merck KGaA, NOV 17, 2014, View Source [SID:1234500969]).

The asset will be developed as a single agent as well as in various combinations with Pfizer’s and Merck KGaA, Darmstadt, Germany,’s broad portfolio of approved and investigational pipeline candidates. The two companies will also combine resources and expertise to advance Pfizer’s anti-PD-1 antibody into Phase 1 trials. As part of the agreement, Merck KGaA, Darmstadt, Germany, will co-promote Pfizer’s XALKORI, a medicine to treat non-small cell lung cancer, in the United States and several other key markets.

Karl-Ludwig Kley, Chairman of the Executive Board of Merck KGaA, Darmstadt, Germany, stated: “We live up to our promise to strengthen all three pillars of our business: Healthcare, Performance Materials and Life Science. After this year’s acquisition of AZ Electronic Materials and the proposal to acquire Sigma-Aldrich, we have now turned the focus on healthcare. The agreement with Pfizer is a very important milestone in taking our pharma pipeline forward.”

“Collaborating globally with Pfizer will allow us to benefit from the strengths and capabilities of both companies in immuno-oncology, further accelerating this promising asset in the race to address the needs of cancer patients across multiple tumor types. Up to 20 high priority immuno-oncology clinical development programs are expected to commence in 2015, including pivotal registration studies,” continued Belén Garijo, President and Chief Executive Officer of the biopharmaceutical division of Merck KGaA, Darmstadt, Germany, and Executive Board Member Elect. “On top of that, the global alliance will enable Merck to gain an early entry into the US oncology market as well as to strengthen our existing oncology business in several other important global markets.”

There are currently two clinical development programs underway evaluating the anti-PD-L1 antibody of Merck KGaA, Darmstadt, Germany. In a Phase 1 trial, more than 550 patients have been treated with MSB0010718C across multiple types of cancers. As part of the Analyst and Investor Day hosted by Merck KGaA, Darmstadt, Germany, on September 18, 2014, interim data were presented from the ongoing Phase 1 study demonstrating a complete response and partial responses in patients with non-small cell lung cancer and ovarian cancer. Additional data are expected to be presented at medical congresses in 2015. There is also an ongoing Phase 2 trial evaluating this antibody in patients with m-Merkel cell carcinoma, a rare form of skin cancer.

Under the terms of the agreement, Merck KGaA, Darmstadt, Germany, will receive an upfront payment of $ 850 million (around € 680 million) and is eligible to receive regulatory and commercial milestone payments up to $ 2.0 billion. Both companies will jointly fund all development and commercialization costs and all revenues obtained from selling any anti-PD-L1 or anti-PD-1 products generated from this collaboration will be shared.

“Our strategic focus in the immuno-oncology space will be significantly enhanced through this global alliance, giving us the financial firepower to fully leverage the potential of our anti-PD-L1-compound” said Stefan Oschmann, Chief Executive Officer Pharma and Vice Chairman Elect of the Executive Board of Merck KGaA, Darmstadt, Germany. “The success of the anti-PD-L1 program and the value recognised by Pfizer is a clear reflection of the progress we have made on our R&D pipeline in recent years.”

“This global alliance enables Pfizer and Merck KGaA, Darmstadt, Germany, to join forces and combine complementary strengths with the goal of meeting the needs of patients with multiple types of cancer,” said Albert Bourla, Group President Vaccines, Oncology and Consumer Healthcare Businesses, Pfizer. “Immuno-oncology is a top priority for Pfizer. Combining this promising anti-PD-L1 antibody with Pfizer’s extensive portfolio of small molecules and antibodies provides an opportunity to potentially broaden the use of immunotherapy for patients with cancer and rapidly expand our oncology business. In addition, this alliance enables us to significantly accelerate the timeframe of our development programs and move into the first wave of potential immuno-oncology based treatment regimens.”

FDA approves Roche’s Avastin plus chemotherapy to treat women with platinum-resistant recurrent ovarian cancer

On November 17, 2014 Roche reproted that the U.S. Food and Drug Administration (FDA) approved Avastin (bevacizumab) in combination with chemotherapy for the treatment of women with platinum-resistant, recurrent ovarian cancer (Press release Hoffmann-La Roche, NOV 17, 2014, View Source [SID:1234500968]). The approval was based on results from the Phase III AURELIA study that showed Avastin plus chemotherapy reduced the risk of disease worsening or death (progression-free survival or PFS) by 62 percent compared to women who received chemotherapy alone (median PFS: 6.8 vs. 3.4 months, Hazard Ratio (HR)=0.38; p<0.0001). Adverse events were consistent with those seen in previous trials of Avastin across tumour types for approved indications, but also included high blood pressure and pain, redness or swelling of the hands or feet from the Phase III study. "Avastin plus chemotherapy is the first new treatment option for women with this difficult-to-treat type of ovarian cancer in more than 15 years," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "Risk of the disease worsening was reduced by 62 percent for women who received Avastin plus chemotherapy in the study, and a notable treatment effect was observed with paclitaxel, which may be important when choosing treatment." The new indication of Avastin is in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan chemotherapy for the treatment of women with platinum-resistant, recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received no more than two prior chemotherapy regimens. With this approval, Avastin is approved in the United States to treat six distinct tumour types. Avastin was also approved to treat women with platinum-resistant, recurrent ovarian cancer in the European Union earlier this year.