The U.S. Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) met April 12 to consider a New Drug Application by Clovis Oncology for rociletinib, an investigational therapy for epidermal growth factor receptor (EGFR)-mutated non–small cell lung cancer (NSCLC) in patients with the T790M mutation who were previously treated with an EGFR- targeted therapy.
The committee voted 12–1 to recommend that the agency wait for results from a phase III randomized trial, TIGER-3, before deciding on approval for rociletinib. The trial is expected to complete patient enrollment at the end of 2018 or early 2019. Clovis Oncology sought accelerated approval of rociletinib based on two nonrandomized clinical trials: TIGER-X and TIGER-2.
We have well-documented issues about toxicity, dosing, and metabolism that have not been completely addressed.— Deborah Armstrong, MD
“We have well-documented issues about toxicity, dosing, and metabolism that have not been completely addressed,” said ODAC Chairperson Deborah Armstrong, MD, Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore. “Primarily, I don’t think the requirement for accelerated approval to have superiority over current treatment has been shown by the data we have at this time.”
Clovis Oncology was entering a crowded field with rociletinib. Several other therapies have been approved by the FDA for NSCLC in the second-line setting, including docetaxel as a single agent or in combination with ramucirumab (Cyramza); pemetrexed (Alimta); nivolumab (Opdivo); and osimertinib (Tagrisso; accelerated approval). The FDA granted Clovis Oncology the Breakthrough Therapy designation for rociletinib in May 2014.
Debate Over Proposed Dose
Complicating matters, the company changed its proposed recommended dose relatively late in the review process. In the new drug application (NDA) submission, Clovis Oncology’s proposed recommended dose was 500 mg twice daily. On December 15, 2015, Clovis Oncology notified the FDA that it planned to amend the proposed recommended dose to 625 mg twice daily. The company submitted draft labeling with this change on January 8, 2016.
At the ODAC meeting, Lindsey Rolfe, MBCHB, MRCP, Chief Medical Officer of Clovis Oncology, argued that the higher dose provided a better response rate. In the 79 patients who received 500 mg, the objective response rate was 23% (95% confidence interval [CI]: 14%–34%), with a median duration of response of 9.1 months. In the 170 patients who received 625 mg, the objective response rate was 32% (95% CI: 25%–40%), with a median duration of response of 8.8 months.
The FDA review disagreed with Clovis Oncology’s position. Clinical pharmacologic and trial data did not support the higher dose, according to the FDA review. Systemic exposure of the therapy was similar across the doses used in the two trials, from 500 mg to 1,000 mg. Both the 500-mg and 625-mg doses resulted in a similar objective response rate with overlapping confidence intervals. As the dose increased, the number of patients requiring dose reductions also increased, the agency said.
According to the FDA, the most common adverse reactions in the pooled safety analysis of 400 patients receiving rociletinib at doses from 500 to 1,000 mg twice daily were diarrhea, hyperglycemia, fatigue, nausea, decreased appetite, QT prolongation, and vomiting. The most common grade 3/4 adverse reactions were hyperglycemia and QTc prolongation.
Dose reductions occurred in 51% of patients. The most common adverse reactions leading to dose reductions were hyperglycemia (22%) and QTc prolongation (11%). In addition, the FDA noted that the criteria for dose reduction “were not clearly specified in the protocol” and “were inconsistently applied by investigators.” Discontinuation of treatment due to an adverse reaction occurred in 11% of patients, most commonly due to QTc prolongation (2%) and pneumonia/pneumonitis (2%).
Serious adverse reactions occurred in 47% of patients, most commonly due to malignant neoplasm progression (16%), hyperglycemia (8%), and pneumonia (4%). A total of 17% of patients had post-baseline QTc intervals of greater than 500 msec on at least one occasion. There were two sudden deaths (on days 4 and 13), and one patient experienced torsades de pointes.
The FDA asked ODAC to discuss whether the benefit-risk profile of rociletinib is favorable in the proposed population. The agency asked the committee to vote on whether the results of the randomized clinical trial TIGER-3 be submitted before the FDA makes a regulatory decision on the application.
Richard Pazdur, MD
Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said his office was concerned about the incidence of QT prolongation and how to interpret its risk in a nonrandomized trial, without a comparator. “We don’t know what’s going on with this drug in QT,” he said.
During the public hearing portion of the meeting, several patients who were taking rociletinib or their family members spoke in favor of approval. Some indicated that Clovis Oncology had paid for their travel to the meeting.
Questions Still Remain
Following the vote, Dr. Armstrong asked all committee members to discuss the rationale for their vote. Members who voted to wait for the phase III trial results said that the risk-benefit was not clear at this point and not clearly superior to available therapies.
Michele Orza, ScD
Michele Orza, ScD, of the Patient-Centered Outcomes Research Institute, was the only committee member to vote against waiting for results from the phase III trial to approve the drug. “I think 2018–2019 is a long time to wait, which is not to say that I would vote for accelerated approval today,” she said. “There are a lot of questions that we have to work out. I’m not confident that the [phase III] study, even when it’s done, will give us a lot of the answers we’re looking for. I’m concerned that there is a population that could be benefiting from this, and we need to do some more work to identify that group and consider accelerated approval for them.”
“We are disappointed with today’s outcome, as we believe in the strength of the data we presented for rociletinib,” Patrick J. Mahaffy, President and CEO of Clovis Oncology, said in a statement after the meeting. “We will work with the FDA to evaluate the best path forward as it continues to review our application.”
ODAC provides the FDA with independent expert advice and recommendations, but the agency makes the final decision regarding drug approvals. ■
Disclosure: Drs. Armstrong, Rolfe, Pazdur, and Orza reported no potential conflicts of interest. Mr. Mahaffy is President and CEO of Clovis Oncology.