ODAC Rejects Rociletinib in Lung Cancer

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 12-1 against the accelerated approval of rociletinib for patients with metastatic EGFR T790M­—mutated non–small cell lung cancer (NSCLC) who have previously received an EGFR-targeted therapy.

The panel was considering whether a pooled efficacy and safety analysis from the early-stage CO-1686-008 (TIGER-X) and CO-1686-019 (TIGER-2) trials was sufficient to recommend accelerated approval of the third-generation EGFR inhibitor. With its negative vote, the panel recommended that the results of the randomized phase III CO-1686-020 trial (TIGER-3) should be submitted before the FDA makes a decision on the application.

The open-label, multinational TIGER-3 trial is comparing rociletinib with 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.

The current action date for a final FDA approval decision on rociletinib is June 28, 2016.

“The requirement for accelerated approval—to have superiority to current treatment—I don’t think has been shown by the data that we have at this point in time,” panel chair Deborah K. Armstrong, MD, a professor of Oncology at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, said when explaining her vote.

“There are too many unanswered questions that need to be addressed. I am also concerned that the ongoing phase III TIGER-3 trial will not answer all the necessary questions,” added William Figg, PharmD, a senior investigator at the NCI.

In the pooled TIGER-X/TIGER-2 analysis, the overall response rate (ORR) with rociletinib (dose range, 500 mg to 750 mg twice daily) among 325 patients with EGFR T790M—positive metastatic NSCLC who progressed on at least 1 EGFR inhibitor was 30.2% (95% CI, 25.2-35.5). The ORR was 32% (95% CI, 25-40) and 23% (95% CI, 14-34) in patients receiving the 625 mg (n = 170) and 500 mg (n = 79) doses, respectively. The median duration of response for the 2 treatment doses was 8.8 and 9.1 months, respectively.

For its safety analysis, ODAC considered pooled data from 400 patients enrolled in either TIGER-X or TIGER-2 who were treated at either 500 mg, 625 mg, 750 mg, or 1000 mg twice daily.

The most common all-grade adverse events (AEs), occurring in >30% of patients, were diarrhea, hyperglycemia, fatigue, nausea, decreased appetite, QT prolongation, and vomiting. The most frequent (>10%) grade 3/4 AEs were hyperglycemia and QTc prolongation.

Dose reductions occurred in 51% of patients, most commonly due to hyperglycemia (22%) and QTc prolongation (11%). Fifty-seven percent of patients had dose interruptions, which were most often due to hyperglycemia (22%), QTc prolongation (10%), and nausea (10%). AEs led to discontinuation for 11% of patients, most frequently due to QTc prolongation (2%), and pneumonia/pneumonitis (2%).

Serious AEs were experienced by 47% of patients, with the most common being malignant neoplasm progression (16%), hyperglycemia (8%) and pneumonia (4%). Post-baseline QTc intervals of greater than 500 msec on at least one occasion occurred in 17% of patients. One patient experienced Torsades de pointes, and there were 2 sudden deaths (on day 4 and day 13), according to the ODAC briefing documents.

A rolling submission was originally completed for rociletinib in July 2015, which was subsequently granted a priority review by the FDA. However, at a preplanned 90-day review meeting, changes in response rates from TIGER-X and TIGER-2 prompted the FDA to request additional data, which set off a chain of events leading to the scheduling of the ODAC hearing.

In the earlier TIGER-X/TIGER-2 data submitted to the FDA, patients with T790M mutations (n = 243) experienced an ORR across all dose levels of 53% and a disease control rate of 85%.

TIGER-X included 456 patients with EGFR-positive NSCLC who received rociletinib across 4 doses (range, 500-1000 mg). The median age of patients was 63 years, 10% had a prior history of diabetes, and 41% had central nervous system (CNS) metastases. The median number of prior therapies was 2 and nearly half of patients had received more than one TKI (44%).

At a data cutoff of April 27, 2015, the median progression-free survival (PFS) in evaluable patients with T790M mutations across the 500- and 625-mg doses (n = 270) was 8.0 months. In those without baseline CNS metastases, the median PFS was 10.3 months. The company did not release new data for PFS.

In the safety analysis, the most frequently occurring all-grade adverse events (AEs) in the 500-mg arm were hyperglycemia (35%), diarrhea (33%), fatigue (29%), decreased appetite (15%), muscle spasms (14%), weight loss (10%), and vomiting (8%).

Grade 3 QTc prolongation was seen in 2.5% of patients. No cases of interstitial lung disease were seen at the 500-mg dose level. AEs leading to treatment discontinuation were seen in 2.5% of patients with the 500 mg dose.

Grade 3/4 hyperglycemia occurred in 17% of patients treated with the 500-mg dose. To adjust for this, a monitoring and treatment algorithm was put in place to detect glucose levels and initiate treatment with oral insulin sensitizing agents, when needed. Prior to initiating these measures in September 2014, the rate of grade 3/4 hyperglycemia was 22%. With proper monitoring and treatment, this rate dropped to 8%.

The ongoing single-arm phase II TIGER-2 trial is exploring rociletinib as a second-line therapy in patients with EGFR T790M—mutated NSCLC.

The availability of osimertinib (Tagrisso) in this space was another factor considered by several panelists who voted against accelerated approval. In November 2015, the FDA granted an accelerated approval to osimertinib for patients with advanced EGFR T790M mutation-positive NSCLC following progression on a prior EGFR TKI, based on data from 411 patients in two single-arm studies.

In the first study, labeled AURA, the ORR with osimertinib was 61% for those with EGFR T790M—mutant NSCLC. In the second trial, known as AURA2, the ORR was 57%.

“There is an elephant in the room, which is osimertinib, which was granted an accelerated approval and appears to be less toxic in this space. For this reason, I think more data are needed,” said panelist Grzegorz S. Nowakowski, MD, assistant professor of Medicine at Mayo Clinic.

“The risk-benefit ratio is informed by other options that are available. Had there been no option for T790M-positive non—small cell lung cancer, maybe I would have voted differently, said Arun Rajan, MD, associate research physician in the Thoracic and GI Oncology Branch of the NCI.

The lone panel member who voted for the FDA to move forward without the TIGER-3 data was Michele Orza, ScD, the acting consumer representative on the ODAC panel.

“I voted very narrowly on the question. I think that 2018/2019 [estimated TIGER-3 completion time frame] is a long time to wait—which is not to say I would vote for accelerated approval. There are a lot of questions that have to be worked out, and I am not confident that [TIGER-3], even when it’s done, will give us a lot of the answers that we’re looking for. But I’m concerned that there is a population that could be benefiting from [rociletinib] in the meantime, and we would need to do some more work to identify that [group] and consider accelerated approval for them,” said Orza, a senior advisor to the executive director of the Patient-Centered Outcomes Research Institute.