FDA should await results from a randomized, confirmatory trial before approving Clovis Oncology Inc.'s lung cancer drug Xegafri (rociletinib), even though it's unclear how informative the ongoing study will be as to the tyrosine kinase inhibitor's appropriate dose, advisory committee members said April 12.

The Oncologic Drugs Advisory Committee voted 12-1 that results from the ongoing TIGER-3 trial should be submitted before FDA makes a regulatory decision on rociletinib. TIGER-3 is a three-arm, 900-patient, Phase III trial expected to complete in late 2018 or early 2019. As of April 8, 137 patients have been enrolled.

Panelists said more efficacy data are needed to better characterize the benefit/risk profile before rociletinib comes to market.

Clovis is seeking accelerated approval for the treatment of patients with EGFR mutation-positive non-small cell lung cancer who have been previously treated with an EGFR-targeted therapy and who have the T790M mutation as detected by an FDA-approved test. The NDA is based on overall response rate and duration of response data from two non-randomized trials.

Advisory committee members said the drug appeared to have activity and its toxicities, such as QT prolongation and hyperglycemia, were potentially manageable. Nevertheless, more efficacy data are needed to better characterize the benefit/risk profile before it comes to market, the panelists said.

"The benefit/risk to me was not as clear as I would like it at this stage," said Eva Szabo, chief of the Lung and Upper Aerodigestive Cancer Research Group at the National Cancer Institute. "There are multiple drugs in this space currently, so how this drug would be used … was not clear to me. And there are some very definite risks associated with it, so I just wanted some more information."

The ongoing TIGER-3 trial "will provide additional efficacy data that will be very useful in assessing the risk/benefit," said Donald Mager, associate professor of pharmaceutical sciences at the State University of New York at Buffalo.

The panel's consumer representative, Michele Orza of the Patient-Center Outcomes Research Institute, was the lone vote against waiting for the confirmatory trial results before rociletinib could come to market. Orza said there could be a population of patients who might benefit from the drug during the three-year wait for TIGER-3 data. However, Orza said her vote was not necessarily a recommendation for accelerated approval now and that many issues needed to be worked out between FDA and the sponsor.

The user fee date for rociletinib, which holds breakthrough therapy designation, is June 28.

Dosing Questions ….

Orza was among numerous panelists who said they were not confident the ongoing confirmatory study, as currently designed, would provide answers the committee was seeking particularly around dosing.

In its July 2015 NDA submission, Clovis proposed a dose of 500 mg twice daily. However, in December the company notified FDA of plans to amend the proposed dose to 625 mg twice daily based on the observation of a better point estimate for tumor response at that dose. In January, the company submitted revised draft labeling reflecting 625 mg as the proposed commercial dose.

FDA informed Clovis in February that the available pharmacokinetic data do not support a proposed commercial dose of 625 twice daily. Nevertheless, the design of the confirmatory trial was also amended to reflect the company's decision to pursue a higher commercial dose.

TIGER-3 had been designed as a 600-patient study comparing the 500 mg rociletinib dose to investigator's choice standard-of-care chemotherapy. In March the company submitted an amendment for the TIGER-3 protocol to evaluate the 625 mg dose in a third study arm and to increase the trial's sample size from 600 to 900 patients with 1:1:1 randomization. While the study will compare the two rociletinib arms individually to the chemotherapy group, it is not powered for a formal comparison between the two rociletinib groups.

FDA continues to disagree with Clovis' mid-review proposal for a higher dose ([A#14160408001]). Rociletinib's dose-exposure relationship is flat from 500 mg to 1,000 mg BID, and the exposure-efficacy relationship also is flat, suggesting that patients with higher rociletinib exposure are unlikely to gain further benefit, pharmacometrics reviewer Chao Liu said.

In contrast, the exposure-safety relationship is steep, and patients with higher metabolite exposure are at an increased risk of QT prolongation and hyperglycemia, Liu said.

… May Go Unanswered Due To Design Shortcomings

Advisory committee members said the most appropriate dose remained a question that is unlikely to be answered by the confirmatory trial because of the lack of a direct comparison between the 500 mg and 625 mg arms in that study.

"I don't think the confirmatory trial will necessarily give us any further information about the dose," Mager said.

Some committee members urged the company to redesign the trial to either eliminate one of the doses, or to increase the size of the study so that a formal comparison between rociletinib arms was possible.

"Maybe the company ought to go back to the FDA and say, 'You know what, you were right. 500 is the same'" as the 625 mg dose in terms of efficacy, Columbia University oncologist Tito Fojo said. "Why don't we just get rid of the third arm and do a 600-patient trial?"

If the company were to limit the trial to two 300-patient arms – one with the 500 mg dose, and one with chemotherapy – "you'll get done sooner and go forward with 500," Fojo said. "Worry about 625 later."

"I would either pick one dose – and you can pick 625 or 500, just pick one dose and adequately test it – or power the study for each of the doses, power to compare," Cleveland Clinic oncologist Brian Rini said.

"This is not just from a regulatory standpoint," Rini continued. "You want people to use your drug at the end of the day if it ultimately gets approved, so you want data to say that the benefit/risk is more favorable with one or the other. Otherwise, you're going to end up just with some underpowered data that won't really be informative, and I think that's a shame to waste those resources."

Accelerated Approval Standard Not Met

In voting to recommend delaying approval until the TIGER-3 data come through, some advisory committee members said they did not believe rociletinib met one of the threshold requirements for accelerated approval – superiority to other currently available therapies for second-line metastatic NSCLC.

FDA's efficacy analysis of pooled data across the two studies reported an objective response rate of 30.2%, with a median duration of response of 8.9 months.

Sanofi's Taxotere (docetaxel), in combination with Eli Lilly & Co.Cyramza (ramucirumab), has demonstrated an overall response rate of 23% and a survival advantage. Bristol-Myers Squibb Co.'s Opdivo (nivolumab) has demonstrated an overall response rate of 19%, a 12-month median duration of response and a survival benefit, FDA said.

Notably, AstraZeneca PLC's Tagrisso (osimertinib) is not considered available therapy because it was approved under accelerated approval. The drug, which is indicated for the same population for which Clovis seeks approval, demonstrated an overall response rate of 59%.

Clovis and its experts asserted that that rociletinib is associated with less cutaneous and other toxicities than other drugs used in the second-line setting. Hyperglycemia seen in the rociletinib studies was commonly managed without serious consequences, and QT prolongation was rarely clinically significant, said Ross Camidge, a University of Colorado oncologist and expert for Clovis.

Clovis has proposed a Risk Evaluation and Mitigation Strategy with a communication plan to address the QT prolongation risk.

Clovis' Rociletinib Facing Three-Year Delay If FDA Follows Panel's Lead

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