Clovis Completes Rociletinib NDA for EGFR T790M-positive NSCLC

Patrick J. Mahaffy

A new drug application (NDA) has been submitted for rociletinib (CO-1686) as a treatment for patients with EGFR T790M-positive 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 NDA 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 recommended 500 mg dose (n = 48), the objective response rate (ORR) was 60% and the disease control rate (DCR) was 90%.

A marketing authorization application (MAA) has also been submitted to the European Medicines Agency for the same population, based on data from the TIGER-X trial. Both applications will be evaluated by the regulatory agencies before officially being accepted. These regulatory filings were preceded by a breakthrough therapy designation for the potent mutant-selective EGFR inhibitor in May 2014.

“The submissions of our first NDA and MAA for rociletinib represent a major step forward for our company,” Patrick J. Mahaffy, president and CEO of Clovis Oncology, said in a statement. “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. We are also actively building our commercial organization in Europe to prepare for a potential launch next year.”

In addition to the NDA, an application for premarket approval (PMA) is anticipated for Qiagen’s therascreen EGFR RGQ PCR Kit as a companion diagnostic (CDx) for rociletinib, according to the statement from Clovis. The therascreen EGFR test was initially approved in 2013 as a CDx for afatinib (Gilotrif) and recently received a new indication as a CDx for gefitinib (Iressa).

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%).

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 patients with T790M-mutant NSCLC by tissue testing (n = 243), the ORR across all rociletinib dose levels was 53% and the DCR was 85%.

“Rociletinib demonstrates compelling activity and is well-tolerated at the recommended dose of 500 mg BID in a predominantly US cohort of EGFR-mutant patients with acquired resistance to prior TKIs,” lead investigator Lecia V. Sequist, MD, MPH, medical oncologist, associate professor, Massachusetts General Hospital, Harvard Medical School, said when updated results were presented at ASCO. “The response rate at the 500-mg dose level was 60% and the toxicity profile is improved at this dose level compared with higher dose levels.”

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."

A number of clinical trials continue to assess rociletinib for patients with NSCLC. The phase II/III TIGER 1 trial is comparing rociletinib with erlotinib as first-line therapy in treatment-naïve patients with EGFR mutations who have not been screened for T790M status. TIGER 2, a single-arm phase II trial, is evaluating rociletinib as second-line therapy in patients with EGFR-mutated NSCLC who are T790M-positive. The randomized phase III TIGER 3 trial is evaluating rociletinib versus chemotherapy in patients who have progressed on a first-line EGFR TKI and are also T790M-positive.

In addition to monotherapy trials, multiple trials 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).