On November 09, 2015 ArQule, Inc. (Nasdaq:ARQL) reported the results of preclinical and clinical studies focusing on tivantinib, ARQ 087, ARQ 092, and ARQ 751 (Press release, ArQule, NOV 9, 2015, View Source [SID:1234508101]). The data were presented at the AACR (Free AACR Whitepaper)-NCI-EORTC meeting on November 7th, 2015. The poster presentations can be accessed in the "Investor and Media" section of our website, www.arqule.com, under "Recent Data Presentations."

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For the first time, data from an exploratory sub-analysis of the MARQUEE trial with tivantinib in non-small cell lung cancer in patients with advanced disease and epidermal growth factor receptor (EGFR) mutations were presented. The data showed tivantinib, when added to erlotinib, increased progression-free survival to 13 months compared to 7.5 months in the erlotinib plus placebo arm. The sub-analysis included 109 patients of which 56 were in the combination tivantinib plus erlotinib arm of the trial. The data were highlighted in an AACR (Free AACR Whitepaper) press release and press conference.

"The data from the sub-analysis of the MARQUEE trial supports our focus on precision medicine," said Brian Schwartz, M.D., Head of Research and Development and Chief Medical Officer at ArQule. "Although the study did not meet its primary endpoint, this analysis is encouraging and offers evidence that tivantinib when dosed in a specific patient population can provide substantial benefit."

Additionally, the company presented pre-clinical and clinical data on its early stage proprietary pipeline that support ArQule’s efforts to address the needs of patients in therapeutic areas of high unmet need through precision medicine. Data presented on FGFR inhibitor, ARQ 087, demonstrate that FGFR2 dysregulation correlates with efficacy and supports the on-going phase 2 trial in intrahepatic cholangiocarcinoma. Similarly, data presented on AKT inhibitors, ARQ 092 and ARQ 751, demonstrate that both drugs inhibit AKT and provide strong rationale for further studies in patients harboring AKT1 and PI3K mutations.

"Data presented at this year’s AACR (Free AACR Whitepaper)-NCI-EORTC conference are part of ArQule’s translational effort to connect preclinical and clinical research and guide a true precision medicine endeavor," said Giovanni Abbadessa, Vice President of Clinical Development, Translational Medicine and Medical Affairs at ArQule. "Both ARQ 092 and ARQ 087 have shown single-agent activity in vitro, in vivo and in patients in cancers driven by genetic alterations of their respective targets, AKT and FGFR. In addition, these pre-clinical data find confirmation in the clinical results achieved by ARQ 087 and ARQ 092 in their respective phase 1 clinical trials in genetically-altered endometrial and breast cancer and in FGFR2-driven cholangiocarcinoma, respectively. Combinability data reported for both experimental drugs with standard therapies may allow even more development options for the future."

Precision Medicine

Tivantinib is enrolling in two biomarker-driven phase 3 trials, METIV-HCC and JET-HCC. ARQ 087 is enrolling in a biomarker-driven phase 2 trial in intrahepatic cholangiocarcinoma (iCCA) with FGFR translocations. ARQ 092 is enrolling in a phase 1b biomarker-driven trial in patients with AKT and PI3K activating mutations including patients with breast, endometrial and ovarian cancers.

About MET and tivantinib (ARQ 197)

Tivantinib is an orally administered, selective inhibitor of MET, a receptor tyrosine kinase, which is currently in Phase 3 clinical trials. In healthy adult cells, MET can be present in normal levels to support natural cellular function, but in cancer cells, MET can be inappropriately and continuously activated. When abnormally activated, MET plays multiple roles in aspects of human cancer, including cancer cell growth, survival, angiogenesis, invasion and metastasis. The activation of certain cell signaling pathways, including MET, has also been associated with the development of resistance to anti-EGFR (epidermal growth factor receptor) antibodies such as cetuximab and panitumumab.

Pre-clinical data have demonstrated that tivantinib inhibits MET activation in a range of human tumor cell lines and shows anti-tumor activity against several human tumor xenografts. In clinical trials to date, treatment with tivantinib has been generally well tolerated and has shown clinical activity in a number of tumors. Tivantinib has not yet been approved for any indication in any country.

In December 2008, ArQule and Daiichi Sankyo signed a license, co-development and co-commercialization agreement for tivantinib in the U.S., Europe, South America and the rest of the world, excluding Japan, China (including Hong Kong), South Korea and Taiwan.

About the AKT Pathway, ARQ 092 and ARQ 751

ARQ 092 and ARQ 751 are orally available, selective small molecule inhibitors of the AKT kinase. The AKT pathway when abnormally activated is implicated in multiple oncogenic processes such as cell proliferation and apoptosis. This pathway has emerged as a target of potential therapeutic relevance for compounds that inhibit its activity, which has been linked to a variety of cancers as well as to select non-oncology indications.

ARQ 092, the lead compound in ArQule’s AKT program, has completed Phase 1a clinical testing and has advanced into Phase 1b expansion testing in cohorts of patients with endometrial cancer, lymphoma and tumors harboring either AKT or PI3K mutations. A number of next-generation compounds in the Company’s AKT program are in early to late stages of pre-clinical development. The company plans to file an Investigational New Drug (IND) application by the end of 2015 for ARQ 751, a next generation AKT inhibitor.

About FGFR and ARQ 087

ARQ 087 is a multi-kinase inhibitor designed to preferentially inhibit the fibroblast growth factor receptor ("FGFR") family with demonstrated efficacy in FGFR2 amplified tumors. The FGFR pathway is disrupted in several ways in human cancer, thus providing numerous therapeutic targets for an inhibitor of this pathway. ARQ 087 has demonstrated inhibition of tumor growth and downstream signaling in vivo in tumors whose growth is driven by these targets.

Signals of single agent activity with this compound were observed in Phase 1a testing. Phase 1b expansion cohorts with ARQ 087 include patients with cholangiocarcinoma and adrenocortical tumors, as well as those with FGFR translocations, amplification and mutations. Clinical development of ARQ 087 has advanced into Phase 2 for intrahepatic cholangiocarcinoma ("iCCA") following the observation of two confirmed partial responses in this patient population in the Phase 1 portion of the program.

On November 8, 2015 Ignyta, Inc. (Nasdaq: RXDX) ("Ignyta"), a precision oncology biotechnology company, reported the exclusive license of worldwide rights relating to Eli Lilly and Company’s taladegib oncology development program in exchange for an upfront payment of $2.0 million in cash and the issuance to Lilly of approximately 1.2 million shares of Ignyta’s common stock (Press release, Ignyta, NOV 8, 2015, View Source [SID:1234509530]). Taladegib is a potent, orally bioavailable small molecule hedgehog/smoothened antagonist that has achieved clinical proof-of-concept and a recommended Phase 2 dose based on results from prior clinical studies. Ignyta also licensed exclusive worldwide rights to the topical formulation of taladegib, which is a late preclinical program being developed for the potential treatment of patients with superficial and nodular basal cell carcinoma.

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Concurrently with the license, Ignyta entered into a stock purchase agreement with Lilly under which Lilly will purchase a further 1.5 million shares of Ignyta common stock at a price of $20 per share in a private placement. Lilly has agreed not to sell or otherwise transfer any of the shares acquired from Ignyta until May 10, 2016, and Ignyta is required to register the resale of the shares issued to Lilly with the Securities and Exchange Commission (SEC) prior to such date.

Under the license agreement, Ignyta is obligated to pay to Lilly development and sales milestones related to taladegib products totaling up to approximately $38 million (a portion of which may be paid in Ignyta equity), along with royalties on net sales of taladegib products. Ignyta also granted back to Lilly exclusive rights to develop and commercialize taladegib-containing products in combination with certain Lilly compounds. Lilly is obligated to pay to Ignyta a royalty on net sales of such combination products it commercializes. Further financial terms were not disclosed.

"We are pleased to be working with Ignyta to further the development of taladegib and explore its potential to help patients across multiple tumor types," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "Lilly continues to raise the bar on innovation by leveraging external relationships and expertise. Moreover, we are looking forward to working with Ignyta on potential combination therapies with other Lilly compounds."

"The exclusive license from Lilly of this clinical program with demonstrated compelling Phase 1 activity is well aligned with our strategic vision of developing first-in-class and/or best-in-class therapeutics that can potentially eradicate residual disease in precisely defined patient populations," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "This new targeted oncology program is a hedgehog/smoothened antagonist that complements our pipeline well and provides us with exciting potential monotherapy and combination therapy approaches across multiple solid tumor indications. We are grateful to Lilly for sharing Ignyta’s precision oncology vision and recognizing the strong strategic fit of taladegib with our pipeline and capabilities, which led to its $30 million investment in the company."

On November 08, 2015 Calithera Biosciences, Inc. (Nasdaq:CALA), a clinical stage biotechnology company focused on the development of novel cancer therapeutics, reported that it will announce new clinical data from the solid tumor expansion cohorts of its lead anti-cancer therapeutic candidate, CB-839, at the 2015 AACR (Free AACR Whitepaper)-NCI-EORTC International Conference on Molecular Targets in Boston, Massachusetts (Press release, Calithera Biosciences, NOV 8, 2015, View Source;p=RssLanding&cat=news&id=2110182 [SID:1234508340]). CB-839 is a potent, selective, orally bioavailable glutaminase inhibitor in phase I clinical trials. The data support earlier findings of the clinical activity, tolerability and unique mechanism of action of CB-839 in patients with solid tumors, as well as show one partial response according to RECIST criteria.

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The new data to be presented by Funda Meric-Bernstam, MD, from MD Anderson Cancer Center (Abstract #C49), demonstrate stable disease across a variety of tumor types, as well as a single agent partial response (PR, on study >5 months) in a renal cell carcinoma (RCC) patient. This patient showed a 32% reduction in target lesions by RECIST with generalized shrinkage of lymph node metastases. Among the fifteen evaluable patients with RCC, nine (60%) had stable disease lasting at least three cycles (63 days) or a partial response, with four patients remaining on study. Among efficacy-evaluable patients across a range of tumor types treated on the current dosing schedule of twice-daily with food, 22 of 50 patients (44%) experienced stable disease or better. Five stable disease patients currently on study have been treated with CB-839 for over 8 months without progression (2 triple negative breast cancer, 1 RCC, 1 mesothelioma and 1 IDH1 mutant chondrosarcoma).

"We are very encouraged by these findings in that they reinforce the published safety and efficacy profile of CB-839. We believe that this first partial response in solid tumors points to the potential of our novel agent’s efficacy in renal cell carcinoma, and we look forward to sharing data as our single agent and combination studies mature," said Susan Molineaux, PhD, President and Chief Executive Officer of Calithera. "We are currently expanding enrollment of CB-839 as a monotherapy in renal cell carcinoma patients, as well as dosing CB-839 in combination with everolimus."

The Phase 1 multi-center open label dose escalation study was designed to evaluate the safety and tolerability of CB-839 in locally advanced, metastatic and/or refractory solid tumors. Oral CB-839 was administered in doses of 100 mg to 1000 mg, in 21 day cycles using one of two regimens: TID or BID with food. As of October 1, 2015, 98 patients were enrolled in the solid tumor study (32 TID, 66 BID with food) and evaluable for safety; 77 were evaluable for efficacy. All future patients enrolled to the study will be dosed on the BID with food regimen.

Safety Data

Among 98 patients evaluable for safety, a maximum tolerated dose has not been established. CB-839 was generally well tolerated with the majority of treatment-emergent adverse events being mild to moderate, Grade 1/2 and reversible. Among patients in the BID with food regimen, 4.5% (3/66) experienced a Grade 3/4 adverse event suspected to be related to CB-839 and 3% discontinued due to drug-related adverse events (2/66). The rate of Grade 3 alanine aminotransferase (ALT) elevations of 1.5% (1/66) in the BID with food cohort was substantially reduced relative to that observed in the TID cohort 16% (5/32).

In addition, a preclinical poster was presented by Calithera’s collaborators. Details for the presentation are as follows:

Targeting glutamine metabolism in colorectal cancers with PIK3CA mutations

Abstract #C115
Zhenghe John Wang, Ph.D., Case Western Reserve University
Poster Session C

On November 08, 2015 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers, reported new results from its Phase 1 open-label, dose-escalation trial of LOXO-101, a selective inhibitor of tropomyosin receptor kinase (TRK) signaling molecules, and the first preclinical data for its RET and FGFR programs (Press release, Loxo Oncology, NOV 8, 2015, View Source [SID:1234508117]). The data are being presented at the 2015 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) in Boston.

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Providing a LOXO-101 Phase 1 update, study investigators reported that, as of the October 20, 2015 data cutoff date, 30 patients with solid tumors refractory to standard therapy had been enrolled and treated, including six patients with cancers harboring TRK fusions. Three of the six patients with TRK fusion cancers had been on study sufficiently long for their first efficacy assessment, and all three had achieved an objective response at the first response assessment, as defined by standard RECIST criteria. All three of these patients remain in response and on study. The other three patients with TRK fusion cancers were recently enrolled and thus had not yet been evaluated for response as of the data cutoff date, though they all remain on study. In addition, LOXO-101 has been well tolerated, including the 100 mg twice-daily dose, which has been selected for Phase 2 study and has shown efficacy in TRK fusion patients. The majority of adverse events reported by investigators have been mild to moderate. A maximum tolerated dose (MTD) has not been defined, though near-term Phase 1 enrollment will focus on further characterizing the pharmacokinetics and safety of the 100 mg twice-daily dose dosing.

"The efficacy we are seeing for LOXO-101, at a well-tolerated dose, is as compelling as any I have seen in Phase 1," said David Hong, M.D., deputy chair and associate professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston and presenter of the LOXO-101 oral presentation. "As a community, we need to test for TRK fusions and make sure these patients find their way to a LOXO-101 study. I look forward to participating in the recently initiated Phase 2 trial."

"We are very encouraged by the rapid and dramatic responses we are seeing in TRK fusion patients, which demonstrate LOXO-101’s ability to effectively target these genetically defined tumors," said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. "As we look into 2016, we are focused on continuing to execute on our clinical development strategy for LOXO-101 and plan to release additional data from our Phase 1 study at a medical meeting next year. In addition, our preclinical posters show the progress we have made, with our partners at Array BioPharma, in developing other selective, purpose-built molecules with differentiated and best-in-class potential against highly actionable targets in oncology."

LOXO-101 Phase 1 Results
LOXO-101 is currently being evaluated in an ongoing dose-escalation Phase 1 trial in patients with solid tumors refractory to standard therapy. As of October 20, 2015, 30 patients with advanced cancer had been treated at five dose levels: 50 mg QD, 100 mg QD, 100 mg BID, 150 mg BID, and 200 mg QD. The median age of these patients is 55 (ranging from 28-76) and the median number of prior treatments was three (ranging from 0-11).

Safety Analysis
LOXO-101 has been well tolerated in the 30 patients treated as of October 20, 2015. Adverse events are reported regardless of attribution to study drug. Adverse events are generally consistent with those described after the last data cutoff of March 26, 2015, consisting of Grade 1 and 2 fatigue (33 percent), dizziness (30 percent), anemia (20 percent) and nausea (20 percent). Grade 3 adverse events reported included fatigue, anemia, abdominal pain, increased liver enzymes, delirium and syncope. No Grade 4 adverse events have been reported. The frequency of toxicities did not correlate with dose level. MTD has not yet been defined.

Efficacy Analysis
To date, six patients with cancers harboring TRK fusions have been enrolled, representing a broad range of tumor types: mammary analogue secretory cancer of the salivary glands (MASC) (n=2), soft tissue sarcoma, gastrointestinal stromal tumor, thyroid carcinoma, and non-small cell lung cancer. As of the October 20, 2015 data cutoff date, three patients had been evaluated for response, and all had achieved an objective response at first response assessment. A patient with soft tissue sarcoma harboring an LMNA-NTRK1 fusion remains on study for greater than eight months at a dose of 100 mg BID. This patient was the subject of a peer-reviewed research brief published in Cancer Discovery in July 2015. A patient with a gastrointestinal stromal tumor (GIST) harboring an ETV6-NTRK3 fusion remains on study for greater than four months at a dose of 150 mg BID. A patient with a MASC tumor harboring an ETV6-NTRK3 fusion remains on study for greater than three months at 100 mg BID. All three of these responding patients remain in response and on study as of October 20, 2015. The other three patients (thyroid carcinoma, non-small cell lung cancer, MASC) were recently enrolled and not yet evaluable for efficacy as of the data cutoff date.

On Monday, November 9, 2015, Loxo Oncology will file a Form-8-K with the U.S. Securities and Exchange Commission (SEC) containing the LOXO-101 materials presented at the AACR (Free AACR Whitepaper)-NCI-EORTC meeting. These materials will also be posted to the Loxo Oncology website.

Pipeline Program Updates
Loxo Oncology presented data from the company’s novel Rearranged during Transfection (RET) and Fibroblast Growth Factor Receptor (FGFR) programs showing potential best-in-class selectivity and target coverage. Loxo Oncology expects to advance a RET inhibitor as its next Investigational New Drug (IND) application.

Upcoming Milestones for Loxo Oncology
Loxo Oncology continues to make significant progress across its pipeline. Milestones in 2016 are expected to include:

Continued enrollment of the LOXO-101 Phase 2 global, multi-center, single-arm, open-label basket trial in adult patients with solid tumors that harbor a TRK fusion.
Presentation of additional data from the ongoing Phase 1 study of LOXO-101 at a medical meeting in 2016.
Initiate Phase 1 study of LOXO-101 in pediatric cancer patients, including an oral liquid formulation, in the first half of 2016.
Initiate Phase 1 study of a selective RET inhibitor in late 2016 or early 2017.

About LOXO-101
LOXO-101 is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRKs). Growing research suggests that the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body. In an ongoing Phase 1 clinical trial, LOXO-101 has demonstrated encouraging preliminary efficacy. LOXO-101 is also being evaluated in a global Phase 2 multi-center basket trial in patients with solid tumors that harbor TRK gene fusions. For additional information about both the LOXO-101 clinical trials, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123.