FDA Grants Priority Review to Rociletinib for T790M-Positive NSCLC

Lecia V. Sequist, MD, MPH

The FDA has granted a priority review designation to rociletinib (CO-1686) for patients with EGFR T790M-mutant metastatic non—small cell lung cancer (NSCLC) following prior administration of an EGFR TKI, according to a statement from the drug's developer, Clovis Oncology.

The application for rociletinib was based on data from the ongoing phase I/II TIGER-X trial, which was updated at the 2015 ASCO Annual Meeting. In patients with T790M-mutant NSCLC who received rociletinib at the 500 mg dose (n = 48), the objective response rate (ORR) was 60% and the disease control rate (DCR) was 90%.

The FDA received data from the TIGER-X trial under a rolling submission, which was allowed as part of a breakthrough therapy designation received in May 2014. Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the application by March 30, 2016.

In addition to TIGER-X, data for rociletinib were submitted from the single-arm phase II TIGER-2 trial, according to Clovis. In this ongoing study, rociletinib is being explored as a second-line therapy in patients with EGFR T790M-mutated NSCLC. Data from this study have not yet been announced, with the first patient enrolled in June 2014.

Qiagen’s therascreen EGFR RGQ PCR Kit is anticipated to be a companion diagnostic (CDx) for rociletinib, according to a statement. The therascreen EGFR test was initially approved in 2013 as a CDx for afatinib (Gilotrif) and received a new indication as a CDx for gefitinib (Iressa) in July 2015. Additionally, plasma-genotyping of T790M is under exploration using Sysmex's BEAMing system, which uses emulsion PCR and hybridization followed by flow cytometry.

"We found that plasma BEAMing is a successful technique for detecting T790M and imagine that in the future this will be quite useful clinically, either as an initial screen or as a replacement for tissue biopsy," Lecia V. Sequist, MD, MPH, explained when she presented the results at the ASCO Meeting.

In the TIGER-X study, about 8% of patients who underwent a tumor biopsy for T790M had inadequate tissue to conduct the analyses, Sequist noted. In the end, both plasma and tissue detected approximately the same number of patients with T790M-positive NSCLC. Overall, there was an 81% rate of agreement between the two testing procedures.

"It may not be appropriate to consider the tissue results as the gold standard comparator," Sequist suggested. "We know that a single needle biopsy could potentially misrepresent the entire heterogeneity of T790M that is present throughout the cancer in the patient’s body. In fact, plasma may be a better assessment of the sum of disease."

In the ongoing TIGER-X trial, 456 patients received rociletinib across 4 doses (range, 500-1000 mg). All patients enrolled were EGFR-positive. Overall, 119 patients received rociletinib at 500 mg twice daily, which was the dose selected for future study. 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 ORR across all dose levels was 53%. The DCR was 85%. 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 evaluable patients with T790M-positive tumors by plasma testing (n = 147), the ORR was 53% and the DCR was 82%. In those who received the 500 mg dose of rociletinib who were identified by plasma testing (n = 30), the ORR was 57% and the DCR was 80%.

In patients with T790M-negative tumors, the ORR was 35% with plasma and 32% with tissue testing. For those who tested T790M-negative by both modalities (n = 11), the ORR was 27%. In those who tested positive by both testing methods (n = 130), the ORR was 55%.

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," said Sequist. "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."

Along with the FDA submission, data from the TIGER-X and TIGER-2 trials were also submitted to the European Medicines Agency for patients with pretreated EGFR T790M-mutant NSCLC. This application was granted an accelerated assessment by the Committee for Medicinal Products for Human Use. Under this program, the European Medicines Agency will review the application within 150 days.

“We are actively preparing for what we hope to be our first US commercial launch, and the opportunity to address the needs of patients with T790M-positive EGFR-mutant non-small cell lung cancer," Patrick J. Mahaffy, president and CEO of Clovis Oncology, said in a statement when the data were submitted. "We are also actively building our commercial organization in Europe to prepare for a potential launch next year.”

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).