FDA Panel Denies Accelerated Approval of Lung Cancer Drug

Nick Mulcahy

April 12, 2016

The oral agent rociletinib (Xegafi, Clovis Oncology), an experimental treatment for a subset of lung cancer patients, has not been recommended for accelerated approval from the US Food and Drug Administration (FDA).

Instead, the FDA's Oncologic Drugs Advisory Committee (ODAC) voted 12 to 1 in favor of waiting for the results of an ongoing phase 3 randomized clinical trial to be submitted before a regulatory decision is made.

Rociletinib is a third-generation tyrosine kinase inhibitor (TKI), intended for use in patients with non–small-cell lung cancer (NSCLC) who have the epidermal growth factor receptor (EGFR) mutation T790M.

The panel reviewed early-phase study data on rociletinib as a treatment for patients with metastatic mutant EGFR-positive NSCLC who had been treated with an EGFR-targeted therapy.

That data consisted of two single-arm trials, which collectively showed that rociletinib had an overall response rate (ORR) of 30% and a median duration of response of 8.9 months.

These results compare unfavorably with rival drug osimertinib (Tagrisso, AstraZeneca), suggested a number of the ODAC members.

Osimertinib received accelerated approval from the FDA for this same patient population in November 2015, as reported by Medscape Medical News.

Osimertinib had an ORR of 59% and a median duration of response of 12 months, and is the first drug approved for this subset of patients.

Osimertinib was the "elephant in the room" at the rociletinib hearing, said ODAC's Grzegorz S. Nowakowski, MD, from the Mayo Clinic in Rochester, Minnesota. Osimertinib appears less toxic and more effective than rociletinib, he said.

ODAC's Arun Rajan, MD, from the National Cancer Institute in Bethesda, Maryland, said that "had there been no other [treatment] options" he "would have voted differently."

There was also concern as to whether rociletinib was superior to other therapies available to EGFR+ NSCLC patients with metastatic disease who progress on first-line TKIs. Those therapies include nivolumab, pemetrexed, and docetaxel as single agents or in combination with ramucirumab, which have all been shown to improve overall survival. However, the efficacy of these drugs in the subgroup of patients with EGFR T790M mutation-positive NSCLC has not been studied.

An agent must be shown to be superior to available therapy to qualify for accelerated approval, noted Lola Fashoyin-Aje, MD, MPH, a medical officer at the FDA.But the vote to wait for more data on rociletinib was also the result of the committee's concern about the drug's toxicities and efficacy and the quality of the currently submitted data.

Rociletinib's ORR data had included patients with unconfirmed responses, said Dr Fashoyin-Aje, and she pointed out that ORR data must be based on confirmed responses only.

There were also questions as to whether Clovis' proposed recommended dose of 625 mg bid was convincingly supported by the clinical and clinical pharmacology data. Panel members also had concerns about whether risks (particularly with respect to QTc prolongation) were acceptable.

Ultimately, the ODAC members preferred to wait for more data on rociletinib from the TIGER-3 trial, which is an open-label, randomized, multinational study of rociletinib versus single-agent chemotherapy (pemetrexed, docetaxel, or gemcitabine) in patients with EGFR mutation-positive NSCLC with disease progression following both an EGFR-TKI and platinum-doublet chemotherapy.


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