Clovis Oncology Inc.'s breakthrough-designated lung cancer drug Xegafri (rociletinib) is expected to face a challenging FDA Oncologic Drugs Advisory Committee review April 12 on three fronts: efficacy, safety and appropriate dose.

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 and duration of response data from two non-randomized trials.

However, FDA briefing documents released April 8 suggest the agency may first want to see data from an ongoing Phase III, open-label randomized trial before allowing the tyrosine kinase inhibitor to reach the market.

FDA disagrees with Clovis' decision during the course of the NDA review to move away from pursuing approval of a 500 mg dose in favor of a 625 mg dose.

In the briefing document, the agency questions whether the overall response rate and duration of response for rociletinib-treated patients are better than currently available therapy – a threshold requirement for granting accelerated approval – and likely to predict a clinical benefit (see box).

FDA's safety review highlights the risk of QTc prolongation, leading to Torsade de pointes and other serious ventricular arrhythmias. This risk warrants a boxed label warning and, potentially, a Risk Evaluation and Mitigation Strategy, the agency said.

The agency also disagrees with Clovis' decision during the course of the NDA review to move away from pursuing approval of a 500 mg twice-daily dose in favor of a 625 mg twice-daily dose, suggesting this decision is unsupported by the efficacy or clinical pharmacology data.

Approved Therapies For Second-Line NSCLC

Sanofi's Taxotere (docetaxel)
Lilly's Alimta (pemetrexed)
Lilly's Cyramza (ramucirumab)
Bristol-Myers Squibb's Opdivo (nivolumab)

Even if FDA allows rociletinib to come to market via the accelerated approval process, the drug appears headed for less favorable efficacy and safety labeling than that of its expected closest competitor, AstraZeneca PLC's recently approved Tagrisso (osimertinib).

Should Approval Await Confirmatory Trial?

In draft questions, FDA seeks advisory panel discussion on whether rociletinib's benefit-risk profile is favorable in the proposed population.

The agency poses one voting question: whether the results of TIGER-3, an ongoing, randomized, confirmatory trial, should be submitted before FDA makes a regulatory decision on rociletinib.

TIGER-3 will randomize 900 patients in 1:1:1 fashion to either rociletinib 500 mg BID, 625 mg BID or investigator's choice standard-of-care chemotherapy. As of late February, 114 patients had been randomized, and the trial is projected to complete in 2018, Clovis' briefing document states.

The study will compare the two rociletinib arms individually to the chemotherapy group, but it is not powered for a formal comparison between the two rociletinib groups.

Review Slowed By Information Request, AdComm

FDA granted rociletinib breakthrough therapy designation in May 2014 on the basis of an investigator-assessed overall response rate of 54.5%, according to FDA's briefing documents.

Clovis had been neck-and-neck with AstraZeneca in the race to bring their T790M mutation-targeting drugs to market for NSCLC.

However, Clovis fell behind in November when FDA granted an early accelerated approval to osimertinib based on an objective response rate (ORR) of 59% in a pooled analysis of 411 patients in two single-arm trials ([A#14151116005]). Osimertinib also received breakthrough designation for this indication.

Since osimertinib remains under accelerated approval, it is not considered "available therapy" pursuant to the agency's final guidance on expedited regulatory programs.

Just days after the AstraZeneca drug's approval, Clovis disclosed that FDA requested more data for rociletinib's efficacy analysis, representing a major amendment to the NDA. The drug's user fee goal date is June 28.

FDA requested the additional information because the number of confirmed responses in patients treated with rociletinib in the two trials that served as the basis for the NDA were dramatically lower in the updated datasets submitted to the agency at the end of October, Clovis said ([A#14151116005]).

In February, Clovis announced plans for an FDA advisory committee review of rociletinib ([A#14160212006]).

Some breakthrough-designated drugs have gone to an advisory committee, the most recent being Acadia Pharmaceuticals Inc.'s Nuplazid (pimavanserin) for Parkinson's disease psychosis ([A#14160329006]). However, taking a breakthrough drug to a panel review is not common practice, particularly for an oncology review division that has generally been quick to approve drugs holding the designation.

QT Effects Warrant Boxed Warning, Maybe REMS

The most common adverse events were diarrhea (55%), nausea (52%), hyperglycemia (58%) and fatigue (44%).

Dose modifications due to adverse events were frequent, with interruptions occurring in 57% of patients, while reductions and discontinuations occurred in in 51% and 21% of patients, respectively. The most common adverse events leading to dose interruption were hyperglycemia (22%), QT interval prolongation and nausea (10% each).

FDA's analysis found that 55% of patients had one or more dose reductions. Study investigators "did not apply a consistent and uniform approach to dose modification," FDA said.

The agency concludes that the toxicity profile across the dose range studied (500-1,000 mg) was similar.

"The proportion of patients requiring three or four dose reductions was higher for patients given 625 mg BID or higher," FDA said. "The number of dose reductions per patient was higher with increasing doses of rociletinib, likely because a dose reduction to 500 mg BID does not lead to decreased exposure to rociletinib or its major metabolites."

QT prolongation was reported in 33% of patients. There was one case of Torsade de pointes and some cases of life-threatening arrhythmias, FDA said.

Among patients with normal fasting glucose at baseline, 89% had one or more events of hyperglycemia during rociletinib treatment.

A total of nine deaths were reported as being due to an adverse reaction: five attributed to pneumonia, one sepsis, one acute respiratory distress syndrome, and two sudden deaths.

"FDA recommends the inclusion of a Boxed Warning for the risk of QTc prolongation leading to Torsades de pointes," the agency's briefing document states. "FDA also recommends that labeling describe ECG monitoring of QTc interval at baseline and periodically while receiving treatment with rociletinib."

The agency said it has considered whether a REMS "should be required to mitigate the risk of QTc leading to Torsades de pointes and to ensure that the benefits of rociletinib outweigh its risks, or whether prescribers can be sufficiently informed of the risk in product labeling alone and are capable of monitoring patients for QTc prolongation."

"If a REMS is required, this may consist of a communication plan to educate healthcare professionals on the safe use of rociletinib or could include other measures, such as mandatory prescriber certification," the agency said, adding that it has requested Clovis submit a risk mitigation proposal.

Clovis' briefing document describes a five-point strategy for addressing QT prolongation:

Patient selection criteria to avoid prescribing in individuals at risk for QT prolongation
ECG monitoring during therapy
Patient education on the effects of electrolyte depletion and risk for QT prolongation
Avoiding co-administration of drugs that cause QT prolongation
Labeling guidance on when to interrupt rociletinib for prolonged QT interval and how to restart the drug.

Agency Prefers Lower Dose

Clovis' original NDA submission proposed a recommended 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, FDA's briefing document states.

The NDA's efficacy population comprises 325 patients across three doses (500 mg, 625 mg, 750 mg), while the safety population totals 400 patients, including study participants dosed with 1,000 mg.

Across the two trials, the primary outcome measure of objective response rate as assessed by central radiologic review was 22.8% for the 500 mg dose, with a median duration of response of 9.1 months. ORR and duration of response in the 625 mg group were 32.4% and 8.8 months.

FDA said that although the ORR and median duration of response are numerically different for the 500 and 625 mg doses, "based on the pharmacokinetic data, any differences in point estimates may be due to chance and differences in patient factors in these sequentially enrolled cohorts. Overall, the exposure to rociletinib is similar at doses of 500 mg BID and above."

In a pooled analysis across the 500, 625 and 750 mg doses, the ORR is 30.2% with median duration of response of 8.9 months.

FDA's discussion of dosing makes clear the agency disagrees with Clovis' mid-review decision to request approval of the higher, 625 mg dose.

"Based on the pharmacokinetic data and the exposure-response analyses for safety and efficacy, FDA proposes 500 mg orally BID with a meal as the recommended dose," the briefing document states.

"The dose of 500 mg BID is recommended because of the similar systemic exposures of rociletinib across the dose range of 500 mg to 1,000 mg BID," FDA said.

"Furthermore, the exposure-response and exposure-toxicity analyses of the 500 and 625 mg doses indicate a similar ORR with overlapping confidence intervals for efficacy, and no major differences in safety."

Targeted Drug, Broad Questions: Clovis' Rociletinib Faces Scrutiny On Efficacy, Safety, Dosing

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