Clovis Begins FDA Submission Process for Rociletinib in NSCLC

Clovis Oncology has initiated the rolling submission process for rociletinib in EGFR T790M-positive advanced non–small cell lung cancer following prior treatment with a TKI.

Patrick J. Mahaffy

Clovis Oncology has initiated the rolling submission process for rociletinib (CO-1686) inEGFR T790M-positive advanced non—small cell lung cancer (NSCLC) following prior treatment with a TKI. The company hopes to finish the submission process by the end of July 2015.

“The initiation of this rolling submission represents a very important first step toward our biggest milestone of 2015—the submission of our first NDA for rociletinib as treatment for patients with T790M-positive EGFR-mutant non–small cell lung cancer,” Patrick J. Mahaffy, president and CEO of Clovis Oncology, said in a statement. “We look forward to completing the NDA by the end of July, and are actively preparing for our first commercial launch.”

Rociletinib received a breakthrough therapy designation from the FDA in May 2014, allowing for the rolling submission of data from the ongoing phase I/II TIGER-X trial. Findings from this study were presented at the 2015 ASCO Annual Meeting.

In the ongoing TIGER-X trial, 456 patients received rociletinib across 4 doses (range, 500-1000 mg). All patients enrolled were EGFR-positive. Patients with stable central nervous system (CNS) metastases were allowed to enroll in the trial. Overall, 119 patients received rociletinib at 500 mg twice daily, which was the dose selected for future study.

The majority of patients were enrolled in the United States (84%). The median age of patients was 63 years, 10% had a prior history of diabetes and 41% had CNS metastases. The median prior number of therapies was 2 and nearly half of patients had received more than one TKI (44%).

In patients with T790M mutations by tissue (n = 243), the objective response rate (ORR) across all dose levels was 53%. The disease control rate (DCR) was 85%. In those with T790M mutations who received rociletinib at 500 mg (n = 48), the ORR was 60% and the DCR was 90%.

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.

In the updated 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 hyperglycemia that we see with rociletinib is due to the M502 metabolite of the drug, which inhibits IGF1-R/IR, leading to insulin resistance. This adverse event was not anticipated based on the preclinical animal studies," lead investigator Lecia V. Sequist, MD, MPH, from the Massachusetts General Hospital, said when she presented the results. "Once appreciated in the patients, investigators began to screen for early signs of this side effect, and overtime the incidence of severe side effects has dramatically decreased."

In addition to numerous monotherapy trials in the TIGER program, multiple studies are planned to assess rociletinib in combination with other therapies. Studies looking at rociletinib with inhibitors of PD-L1, PD-1, and MEK are anticipated to begin enrolling patients in the second half of 2015.

Sequist LV, Goldman JW, Wakelee HA, et al. Efficacy of rociletinib (CO-1686) in plasma-genotyped T790M-positive non-small cell lung cancer (NSCLC) patients (pts).J Clin Oncol. 2015;33 (suppl; abstr 8001).