Clovis has stopped clinical development of rociletinib, its once promising EGFR inhibitor for the treatment of patients with EGFR T790Mâ€“mutated nonâ€“small cell lung cancer.
Patrick J. Mahaffy
Clovis has stopped clinical development of rociletinib, its once promising EGFR inhibitor for the treatment of patients with EGFR T790M—mutated non–small cell lung cancer (NSCLC).
In a statement, the company reported that it had been notified by the FDA that it would receive a complete response letter on or before the scheduled PDUFA date of June 28, 2016. Receiving such correspondence means that the FDA is not approving a new drug application based on the available data.
Clovis has terminated enrollment in all ongoing rociletinib studies, including the phase III TIGER-3 trial, and has withdrawn its application for regulatory approval in the European Union. Rociletinib will continue to be provided to patients whose clinicians recommend continuing therapy, according to Clovis.
This final chapter in the rociletinib saga follows a series of negative developments for the drug, including updated data revealing lower response rates than initially reported, a negative vote from the FDA’s Oncologic Drugs Advisory Committee (ODAC), and FDA approval of rociletinib’s main competitor in the setting, osimertinib (Tagrisso).
“We are very disappointed in the outcome for rociletinib, as there is a need for additional options for this difficult to treat disease,” Patrick J. Mahaffy, president and CEO of Clovis Oncology, in a statement.
In April 2016, ODAC voted 12-1 against the accelerated approval of rociletinib for patients with metastatic EGFR T790M—mutated NSCLC who 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 drug.
With its negative vote, the panel recommended that the results of the now-terminated phase III CO-1686-020 trial (TIGER-3) should be submitted before the FDA made a decision on the application. The open-label, multinational TIGER-3 trial was 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.
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 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 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 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 single-arm phase II TIGER-2 trial was examining rociletinib as a second-line therapy in patients with EGFR T790M—mutated NSCLC.
Clovis now plans to prioritize development of the PARP inhibitor rucaparib which demonstrated robust clinical activity and a tolerable safety profile for women with biomarker-defined relapsed ovarian cancer in the phase II ARIEL2 trial. The company has begun a rolling submission with the FDA for approval of rucaparib for use in heavily pretreated patients with BRCA-positive advanced ovarian cancer. Clovis intends to complete the submission by mid-2016 and plans to file for regulatory approval in the EU by the end of the year.