Rociletinib: has the TIGER lost a few of its stripes?

Abstract

In this issue of Annals of Oncology, Yver et al. [1] chronicle the history of the development of osimertinib (AZD9291), an epi-dermal growth factor receptor (EGFR) tyrosine kinase inhibitor designed to target T790, a common mutation associated with re-sistance to first-and second-generation EGFR-targeted small molecule drugs. A commendable time of 32 months from first human dose to first approval was achieved through a combin-ation of thoughtful clinical development strategy, close inter-action with regulatory authorities and timely development of companion diagnostics. A number of other T790 targeted drugs are also in development. The most advanced amongst these is rociletinib, being developed by Clovis Oncology. There are nu-merous lessons to be learnt by comparing and contrasting the development of these two drugs. This brief perspective is an attempt to shed light on the clinical data on rociletinib and the lessons it provides for biotechnology companies, academic investigators (who often play a leadership role in the develop-ment of these drugs), regulators, and investors who choose to bet on the success (or failure) of oncology drugs. rociletinib and the TIGER studies Rociletinib (CO-1686; Clovis Oncology) entered clinical testing about the same time as osimertinib and was also granted Breakthrough Therapy status based on the preliminary data. It is a small-molecule, mutant-selective, covalent inhibitor of both the activating EGFR mutations, such as exon 19 deletions and L858R, as well as the resistance mutation T790M. It lacks activ-ity against exon 20 insertions [2]. Two formulations of the drug with the same active moiety were developed—a free-base form and a hydrogen bromide salt formulation (HBr). Rociletinib first entered the clinic in March 2013 as the free-base formula-tion and the company quickly transitioned to the salt formula-tion (August 2013) after demonstrating improved absorption and pharmacokinetic profile. Dosing schedules in the dose-escalation portion of the study included once daily, twice daily and three times daily oral administrations of the drug. One hundred and thirty patients with mutant EGFR-asso-ciated NSCLC who had received prior anti-EGFR therapy were enrolled in a phase I/II study [2]. The phase II portion of the study required that the patients' tumor also had evidence of the T790M mutation. The highest dose of free-base rociletinib administered was 900 mg twice daily. The starting dose of the HBr form was 500 mg twice daily up to 1000 mg twice daily. No protocol-defined maximum tolerated dose was identified. At the time of original publication, objective responses were consistently observed at a dose of 900 mg twice daily of the free-base form and all doses of the HBr form (defined as active doses [2]). Among 38 patients who received the free-base form at a dose of <900 mg twice daily, 1 partial response and some minor tumor shrinkage and sustained disease control were observed. The response rate, as defined by RECIST 1.1, among 46 patients with centrally confirmed T790M-positive tumors treated with an active dose was 59% [95% confidence interval (CI) 45–73]. The median follow-up was short—10.5 weeks (range, 0.1–53.9 weeks), and no duration of response was reported. The estimated median progression-free survival at the time of the analysis was 13.1 months (95% CI 5.4–13.1), with data on 82% of the patients censored [2]. The predominant grade 3 adverse event was hyperglycemia, occurring in 20 of the 92 patients (22%) who received therapeut-ic doses. Hyperglycemia is attributed to a metabolite of rocileti-nib [2] and was most often managed with dose reduction, an oral hypoglycemic agent (typically metformin), or both, and did not result in rociletinib discontinuation in any patient. Thirty-five of the 92 patients (38%) received glucose-lowering therapy to treat hyperglycemia. Grade 3 prolongation of the QT interval corrected for heart rate caused no symptoms and was managed in all cases by dose reduction; no ventricular arrhythmias were reported. Acneiform rash was not observed, though a single patient had a grade 1 maculopapular rash. Grade 1 or 2 diarrhea was noted in 20% of the patients, with no reports of diarrhea of grade 3 or higher. Dose reduction occurred in 44 of the 92 patients (48%) who received therapeutic doses. The preliminary activity of both rociletinib and osimertinib looked promising for patients with mutant EGFR NSCLC, and the sponsoring companies appeared to be neck-to-neck in com-petition for first approval. Both agents were associated with compelling response rates and relatively acceptable safety profiles. Clovis Oncology had secured Breakthrough Therapy status for rociletinib, and the Food and Drug Administration (FDA) agreed to a rolling submission and priority review of the New Drug Application (NDA).