Clinical Development of Rociletinib in Lung Cancer Ends

Excerpt:

“Clovis has stopped clinical development of rociletinib, its once promising EGFR inhibitor for the treatment of patients with EGFR T790M–mutated non–small cell lung cancer (NSCLC).

“In a statement, the company reported that it had been notified by the FDA that it would receive a complete response letter on or before the scheduled PDUFA date of June 28, 2016. Receiving such correspondence means that the FDA is not approving a new drug application based on the available data.

“Clovis has terminated enrollment in all ongoing rociletinib studies, including the phase III TIGER-3 trial, and has withdrawn its application for regulatory approval in the European Union. Rociletinib will continue to be provided to patients whose clinicians recommend continuing therapy, according to Clovis.”

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NSCLC Drug Hits Speed Bump on Road to FDA Approval

Excerpt:

“The FDA should wait for results of an ongoing phase III clinical trial before deciding whether to approve the EGFR inhibitor rociletinib for non-small cell lung cancer (NSCLC), advisers recommended today.

“The Oncologic Drugs Advisory Committee (ODAC) voted 12-1 in favor of the delay, although several committee members acknowledged that the drug demonstrated activity in two phase II trials submitted in support of the application for accelerated approval. Others, however, expressed a desire to see more compelling efficacy data from the larger, phase III trial, and some expressed uncertainty about about how to interpret the drug’s safety, specifically a 33% incidence of QT-prolongation in the single-arm phase II trials.

“Additionally, FDA staff review of the trial data ‘revealed high variability of systemic exposure to rociletinib and its major metabolites. Rociletinib demonstrated nonlinear pharmacokinetics, as systemic exposures did not increase when the dose increased from 500 mg to 1000 mg.’ ”

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Clovis Oncology Announces Rociletinib New Drug Application Scheduled for Presentation at Upcoming FDA Oncologic Drugs Advisory Committee Meeting

“Clovis Oncology, Inc. (NASDAQ: CLVS) announced today that the U.S. Food and Drug Administration (FDA) has scheduled the New Drug Application (NDA) for rociletinib for discussion by the Oncologic Drugs Advisory Committee (ODAC) on April 12, 2016. Rociletinib is an investigational therapy for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) who have been previously treated with an EGFR-targeted therapy and have the EGFR T790M mutation.

“The ODAC reviews and evaluates data concerning the safety and effectiveness of marketed and investigational human drug products for use in the treatment of cancer and makes recommendations to the FDA.

“ ‘We are actively preparing for this advisory committee meeting and look forward to the discussion about rociletinib,’ said Patrick J. Mahaffy, President and CEO of Clovis Oncology. ‘New treatments are needed for this hard-to-treat patient population, and we believe that rociletinib represents an important new option for patients with mutant EGFR T790M-positive lung cancer.’ “


FDA Grants Priority Review to Rociletinib for Advanced NSCLC

“The FDA granted priority review to a new drug application for rociletinib.

“Rociletinib (Clovis Oncology) — a novel, oral, targeted covalent mutant-selective epidermal growth factor receptor inhibitor — is intended for patients with advanced EGFR-mutant, T790M-positive non–small cell lung cancer who already received EGFR-targeted therapy.

“The FDA is expected to make a decision about the agent’s status by March 30, 2016.”


Clovis Completes Rociletinib NDA for EGFR T790M-positive NSCLC

“A new drug application (NDA) has been submitted for rociletinib (CO-1686) as a treatment for patients with EGFR T790M-positive metastatic non–small cell lung cancer (NSCLC) following prior administration of an EGFR TKI, according to a statement from the drug’s developer, Clovis Oncology.

“The NDA was preceded by a breakthrough therapy designation for the potent mutant-selective EGFR inhibitor in May 2014. The application was based on findings from the ongoing phase I/II TIGER-X trial, which were published in The New England Journal of Medicine and updated at the 2015 ASCO Annual Meeting. In patients with T790M-mutant NSCLC by tissue testing (n = 243), the objective response rate (ORR) across all dose levels was 53% and the disease control rate (DCR) was 85%.

“An application for premarket approval (PMA) is anticipated for Qiagen’s therascreen EGFR RGQ PCR Kit as a companion diagnostic (CDx) for rociletinib, according to the statement. The therascreen EGFR test was initially approved in 2013 as a CDx for afatinib (Gilotrif) and recently received a new indication as a CDx for gefitinib (Iressa).”


Clovis Oncology's Rociletinib (CO-1686) Phase 2 Study Results Demonstrate Consistent and Promising Clinical Activity and Disease Control in Very Advanced Patients with EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC)

“Clovis Oncology (NASDAQ:CLVS) announced today updated findings from its Phase 2 clinical study of rociletinib (CO-1686), the Company’s novel, oral, targeted covalent (irreversible) mutant-selective inhibitor 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. These data from the TIGER-X trial are being presented today in an oral presentation (Abstract #8001) at the 2015 American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

“ ‘The maturing data for rociletinib confirm in a large patient population what we have seen in our early clinical experience,’ said Jonathan Goldman, MD, TIGER-X investigator and Assistant Professor, UCLA Hematology & Oncology, Associate Director of Drug Development and Director of Clinical Trials in Thoracic Oncology. ‘Rociletinib has shown very encouraging and durable activity in the most advanced mutant EGFR lung cancer patients, including in a large population of patients with CNS metastases. Importantly, the data continue to show activity in both T790M-positive and T790M-negative patients, which gives us a potential treatment option for all patients who have progressed on their initial EGFR targeted therapy.’ “


EGFR Inhibitor Rociletinib Active in EGFR T790M Mutation–Positive NSCLC Previously Treated With EGFR Inhibitors

“In a phase I/II study reported in The New England Journal of Medicine, Sequist et al found that rociletinib—an EGFR inhibitor active in the presence and absence of the EGFR T790M mutation known to mediate resistance to available EGFR inhibitors—produced a high response rate in patients with T790M-positive non–small cell lung cancer (NSCLC) who had progressed on prior EGFR inhibitor therapy. Responses were also observed in patients with T790M-negative disease.

“The study included 92 evaluable patients with EGFR-mutant NSCLC that had progressed on treatment with an EGFR inhibitor who were treated with a free-base form of rociletinib (first group of enrolled patients) at a dose of 900 mg twice daily (10 with centrally confirmed presence or absence of T790M mutation) or a hydrogen bromide salt form at doses of 500 mg twice daily to 1,000 mg twice daily (all remaining patients; 53 with centrally confirmed presence or absence of T790M mutation).

“A total of 83 patients were evaluable for response. Among 46 patients with centrally confirmed T790M-positive tumors, 59% (95% confidence interval [CI] = 45%–73%) had a partial response, and 35% had stable disease (disease control rate = 93%). Response rates were similar in patients with deletion 19 or L858R EGFR mutations. Estimated median progression-free survival at the time of analysis was 13.1 months (95% CI = 5.4–13.1 months), with data censored for 82% of patients. Among 17 patients with T790M-negative tumors on central testing, the response rate was 29% (95% CI = 8%–51%), and 29% had stable disease (disease control rate = 59%). Estimated median progression-free survival in these patients was 5.6 months (95% CI = 1.3 months to not reached). Among 20 patients whose tumors were not assessable for T790M mutation, the response rate was 15%.”


Two New Drugs for EGFR+ Lung Cancer That Has Progressed

“Two new drugs for a specific lung cancer scenario are approaching the market –― AZD9291 (AstraZeneca Pharmaceuticals LP) and rociletinib (Clovis Oncology), and both companies are preparing to file for approval.

“Both drugs are third-generation EGFR inhibitors destined for use in patients who have non–small cell lung cancer (NSCLC) that is EGFR-mutation-positive and has responded to treatment with first-line EGFR inhibitors, but is now progressing.

“In about 60% of these cases, the disease is progressing because the tumor has developed a new mutation, known as EGFR T790M. This mutation confers resistance to treatment with first- generation EGFR inhibitors, such as erlotinib (Tarceva, Osi Pharmaceuticals, Inc) and gefitinib (Iressa, AstraZeneca Pharmaceuticals LP) or the second-generation EGFR inhibitor afatinib (Gilotrif, Boehringer Ingelheim Pharmaceuticals, Inc).”


A Blood-Based Test for EGFR Mutations in NSCLC Is Being Developed

“Clovis Oncology is evaluating a blood-based assay to detect EGFR mutations in circulating tumor DNA in non-small cell lung cancer patients as a way to better identify candidates for treatment with rociletinib (CO-1686), its investigational EGFR inhibitor, a Clovis scientist said this week.

“During a talk at the Cambridge Healthtech Institute Molecular Medicine Tri-Conference held here, Chris Karlovich, principal scientist for molecular diagnostics at Clovis, said that his company is comparing the performance of Sysmex Inostics’ BEAMing assay service to that of Qiagen’s TheraScreen EGFR PCR test in a subset of patients from the company’s “third-generation inhibitor of mutant EGFR lung cancer” (TIGER) clinical trial for rociletinib.

“The goal, Karlovich said, is to overcome some of the limitations of tissue-based PCR testing in identifying EGFR mutations, particularly the T790M resistance mutation, which can be used to identify patients who have become resistant to EGFR-directed therapy and thus are candidates for second- or later-line treatment with rociletinib. In addition, Karlovich said, blood-based assays like BEAMing could potentially be used to more easily monitor response to the drug.

“Rociletinib was designed to selectively target initial activating EGFR mutations and the T790M resistance mutation, while sparing wild-type EGFR at anticipated therapeutic doses, with an improved toxicity profile, according to Clovis’ website.”