Repotrectinib shows encouraging safety, efficacy for patients with ROS1+ NSCLC

Medical writer: Emily Kuhl, PhD

Early results from the first-in-human phase I/II clinical trial of the tyrosine kinase inhibitor (TKI) repotrectinib, presented May 31 (Abstract 9011), suggest that the novel drug is both well tolerated and efficacious for patients with advanced ROS1 fusion–positive non–small cell lung cancer (NSCLC). These findings are important because TKIs, like all targeted therapies, are limited by drug resistance; however, repotrectinib was developed to overcome treatment-resistant mutations. Study investigator Byoung Chul Cho, MD, PhD, of Yonsei Cancer Centre, Yonsei University College of Medicine, South Korea, presented the preliminary analyses.

Repotrectinib is a next-generation, macrocyclic TKI designed for potent selectivity against tumours with ROS1, tropomyosin receptor kinase (TRK), and ALK rearrangements. Preclinical studies thus far appear to support the robust activity of repotrectinib against ROS1 fusion–positive resistance mutations—including G2032R, the most common ROS1 solvent-front mutation. However, until now, it has been unclear whether or not preclinical findings are generalizable to humans with ROS1 fusion–positive NSCLC.

In an effort to tackle this issue, Dr. Cho and colleagues are currently conducting a phase I/II dose-escalation trial (TRIDENT-1; NCT03093116) of repotrectinib for patients with advanced ROS1/NTRK1-3/ALK–positive solid tumours that are TKI naive or TKI refractory. The primary endpoints include determining the maximum tolerated dose, the recommended phase II dose, and overall response rate (ORR).

Dr. Cho shared results from the phase I safety analysis, conducted for all 83 patients with solid tumours, and the efficacy analysis, which included the 33 patients with ROS1-positive NSCLC. All patients received repotrectinib at dose levels from 40 mg daily to 200 mg twice daily.

The overall confirmed ORR of the 11 evaluable patients with ROS1-positive NSCLC whose disease was TKI-naive was 82%, and the ORR for 160 mg daily or higher doses was 83%.

“Intracranial response rate was 100%, and the clinical benefit rate was 100%,” Dr. Cho said. “This is exciting because this is the most promising data presented so far on a ROS1 TKI in a TKI naive population.”

Patients with TKI-refractory disease experienced similarly positive outcomes. Three of four patients treated with more than one prior TKI experienced tumour regression from baseline. Among 18 patients pre-treated with only one prior TKI, the confirmed ORR was 39%, and the ORR for doses of 160 mg daily or higher was 55%. The intracranial response rate was 75%, and the clinical benefit response rate was 78%. Interestingly, five patients who underwent prior crizotinib also had the G2032R mutation—and all five experienced tumour regression with repotrectinib.

Most adverse events were manageable and minor (grade 1-2). Four dose-limiting toxicities (grade 3 dyspnea/hypoxia and grade 2 or 3 dizziness) occurred, and 12 treatment-related adverse events were observed that required dose modifications. The maximum tolerated dose is still unknown.

“Time to response was rapid, usually within 2 months following treatment,” Dr. Cho said. “Dose escalation was preceded in 11 patients. And, interestingly, dose escalation was well tolerated and allowed for treatment continuation for several months.”

Further data are still needed, such as progression-free survival. To meet this goal, discussant Benjamin Besse, MD, PhD, of Paris-Sud University, Orsay, and Gustave Roussy, France, emphasized the importance of recruiting patients with ROS1-positive NSCLC for trials going forward.

“One of my concerns is, since we have such a potent drug, are we sure it is being tested adequately? Are we sure we are testing [for] ROS1?” Dr. Besse said. “Roughly a third of patients with NSCLC are not tested for ROS1. So, there might be a little bit of a concern here if we don’t adequately test these patients.”

Building on these optimistic outcomes, the phase II portion of TRIDENT-1 is projected to begin the second half of 2019.



Posted on 15 July 201925 March 2021