Clovis Oncology (NASDAQ:CLVS) announced today updated findings from the Phase I portion of its ongoing Phase I/II clinical study of CO-1686, the Company’s novel, oral, targeted covalent (irreversible) inhibitor of mutant forms of the epidermal growth factor receptor (EGFR) for the treatment of non-small cell lung cancer (NSCLC) in patients with initial activating EGFR mutations as well as the dominant resistance mutation T790M. Interim results from the Phase I dose-escalation portion of this Phase I/II study are being presented today in an oral presentation by Professor Jean-Charles Soria at the IASLC 15 th World Conference on Lung Cancer in Sydney. Six RECIST partial responses have been observed to date in nine evaluable T790M positive patients dosed at 900mg BID of the free base formulation, for a 67 percent objective response rate. Eight of the nine evaluable patients, or 89 percent, experienced tumor shrinkage greater than 10 percent. Fifty-six patients have been treated with CO-1686 to date across all dosing cohorts, with no evidence of systemic wild-type EGFR-driven toxicities such as rash. Dose escalation is ongoing with the improved HBr formulation, currently dosing at 750mg BID, as the maximum tolerated dose (MTD) has not yet been reached. “These results are exciting, and confirm and extend the initial data reported at ASCO 2013 for this new agent,” said Professor Jean-Charles Soria, Professor of Medicine and Medical Oncology at Paris University XI and cancer specialist at Gustave Roussy Institute. “The T790M acquired resistance mutation is a critical problem in mutant-EGFR lung cancer patients, and CO-1686 appears to be meaningfully benefiting these patients, without triggering the skin and GI toxicities typically seen with older EGFR inhibitors that are not mutant-selective.” “CO-1686 continues to demonstrate impressive activity and is very well tolerated in these heavily pre-treated patients,” said Patrick J. Mahaffy, president and CEO of Clovis Oncology. “Additionally, the initial pharmacokinetic and safety data from patients in the ongoing Phase I dose-finding study with the hydrobromide formulation are very promising. We are very optimistic about this new formulation since we are already seeing such encouraging results with an inferior formulation at a suboptimal dose. We look forward to identifying the recommended Phase II dose for CO-1686 and quickly proceeding into our first registration study.”
The Phase I dose escalation portion of the study is being conducted in the United States, France and Australia in patients with metastatic or unresectable recurrent NSCLC and a documented EGFR mutation. Patients were not required to be T790M positive for the Phase I portion of the study but had to have progressed on prior EGFR-directed tyrosine kinase inhibitor (TKI) therapy (prior chemotherapy was also allowed).Evidence of Activity As of October 2013, nineteen patients have been treated in the 900mg BID cohort. Of those nineteen patients, five were T790M negative and fourteen were T790M positive (five non-evaluable). In the nine evaluable T790M positive patients, a 67 percent overall response rate was demonstrated. Six patients achieved RECIST partial responses and two patients achieved tumor shrinkage of 10-20 percent. Patients were heavily pretreated prior to receiving CO-1686; eight of the nine patients had immediately progressed on a TKI prior to treatment. Six of the nine patients received two or more previous TKI lines. As expected, no objective responses were seen in T790M negative patients. Previously, the Company reported data at ASCO for a total of four evaluable T790M positive patients treated in the 900mg BID cohort; one patient with stable disease and three patients with PRs. Additionally, the Company reported one patient with a PR from the 300mg BID cohort. Of the four patients with PRs, three of the four remain on drug. Two patients have maintained their responses and one patient remains on drug despite having formally progressed. The median progression free survival time for these four responding patients has not yet been reached but is greater than 181 days. Safety and Tolerability CO-1686 appears to be well-tolerated with no evidence of rash or dose-related diarrhea. There are limited and low-grade adverse events in patients to date. The most common adverse events attributed to CO-1686 therapy include nausea (21%), diarrhea (20%), fatigue (20%), vomiting (13%) and decreased appetite (11%). These did not lead to study drug discontinuation.
The incidence of adverse events did not increase with dose escalation and does not appear to be dose dependent. These data offer no evidence of dose-related adverse events related to wild-type EGFR inhibition by CO-1686.Hydrobromide Formulation In August, the Company transitioned development of CO-1686 from an initial free base capsule presentation to a tablet HBr formulation. Preliminary pharmacokinetic data from the first cohort of three patients treated at 500mg BID are being presented today. The HBr formulation at the 500mg BID dose was expected to demonstrate approximately equivalent exposures with reduced variability compared with the free base formulation at the 900mg BID dose. Data from the first cohort of the HBr formulation has demonstrated far greater exposures than expected, with no adverse events. There has been no evidence of cutaneous or gastrointestinal toxicity of any grade in the 500mg BID cohort, and no dose limiting toxicity, and enrollment of the 750mg BID cohort has commenced. Presentation Details The presentation, titled “First-in-human evaluation of CO-1686, an Irreversible, Selective, and Potent Tyrosine Kinase Inhibitor of EGFR T790M (Activating and T790M),” is being presented on Monday, October 28, between 10:30am-12 noon in the Bayside B Auditorium at the Sydney Convention and Exhibition Centre. The presentation will also be available at www.clovisoncology.com. About CO-1686 CO-1686 is a novel, oral, targeted covalent (irreversible) inhibitor of the cancer-causing mutant forms of epidermal growth factor receptor (EGFR) currently being studied for the treatment of non-small cell lung cancer (NSCLC). CO-1686 was designed to selectively target both the initial activating EGFR mutations as well as the T790M resistance mutation, while sparing wild-type, or “normal” EGFR at anticipated therapeutic doses. Accordingly, it has the potential to treat NSCLC patients with EGFR mutations both as a first-line or second-line treatment with a reduced toxicity profile compared to current EGFR inhibitor therapies. The Phase I/II study is currently in the dose escalation phase, being conducted in the U.S., France and Australia. Following the establishment of an appropriate dose, the Company intends to study CO-1686 in Phase II expansion cohorts of NSCLC patients with activating EGFR mutations who have failed initial EGFR-directed therapy and have developed the T790M resistance mutation as well as NSCLC treatment-naïve patients with activating EGFR mutations.
About Clovis OncologyClovis Oncology, Inc. is a biopharmaceutical company focused on acquiring, developing and commercializing innovative anti-cancer agents in the U.S., Europe and additional international markets. Clovis Oncology targets development programs at specific subsets of cancer populations, and simultaneously develops diagnostic tools that direct a compound in development to the population that is most likely to benefit from its use. Clovis Oncology is headquartered in Boulder, Colorado, and has additional offices in San Francisco, California and Cambridge, UK. To the extent that statements contained in this press release are not descriptions of historical facts regarding Clovis Oncology, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in our clinical development program for CO-1686, including the uncertainties inherent in the initiation of future clinical trials, availability of data from ongoing clinical trials, expectations for regulatory approvals, and other matters that could affect the availability or commercial potential of the drug product candidate. Clovis Oncology does not undertake to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of the company in general, see Clovis Oncology’s Annual Report on Form 10-K for the year ended December 31, 2012 and its other reports filed with the Securities and Exchange Commission.