Repotrectinib Sustains ORR, Safety in Locally Advanced or Metastatic ROS1+ NSCLC

August 16, 2023

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Treatment with repotrectinib continued to produce high and durable responses with a manageable safety profile in patients with ROS1-positive locally advanced or metastatic non–small cell lung cancer who were naïve to a TKI or previously treated with 1 TKI and no chemotherapy.

Byoung Chul Cho, MD, PhD

Treatment with repotrectinib (TPX-0005) continued to produce high and durable responses with a manageable safety profile in patients with ROS1-positive locally advanced or metastatic non–small cell lung cancer (NSCLC) who were naïve to a TKI or previously treated with 1 TKI and no chemotherapy, according to updated data from the phase 1/2 TRIDENT-1 trial (NCT03093116).¹

Findings showed that at a median follow-up of 24.0 months, TKI-naïve patients (n = 71) experienced a confirmed objective response rate (cORR) of 79% per blinded independent central review (BICR) assessment. Additionally, this group achieved a median duration of response (DOR) of 34.1 months and a median progression-free survival (PFS) of 35.7 months.

At a median follow-up of 21.5 months for patients who were previously treated with a TKI and no chemotherapy (n = 56), the cORR was 38% per BICR. The median DOR and PFS were 14.8 months and 9.0 months, respectively.

The safety profile of repotrectinib was manageable and consistent with prior data among patients treated at the recommended phase 2 dose.

Full updated data from TRIDENT-1 will be presented at the 2023 IASLC World Conference on Lung Cancer in September.

“The data from the TRIDENT-1 trial hold great significance in the field of NSCLC research, as they add to the growing body of evidence pointing toward durable results with repotrectinib in patients who test positive for ROS1 gene fusions,” Byoung Chul Cho, MD, PhD, of the Yonsei Cancer Center at the Yonsei University College of Medicine and DAAN Cancer Laboratory in Seoul, South Korea, stated in a news release. “With these results, we are seeing durable benefit, including in the brain, in patients with ROS1-positive NSCLC that differentiates repotrectinib from existing agents and is especially impressive in the context of historic data with current ROS1 TKIs. This targeted therapy has true potential to change the treatment landscape and become a new standard of care for patients with ROS1-positive NSCLC.”

In May 2023, the FDA granted priority review to repotrectinib for the treatment of patients with ROS1-positive locally advanced or metastatic NSCLC, based on prior data from TRIDENT-1.² The target action data is November 27, 2023, under the Prescription Drug User Fee Act.

Previously reported topline findings from TRIDENT-1 showed that patients with ROS1-positive, TKI-naïve, advanced NSCLC experienced a cORR of 79% (95% CI, 68%-88%), including a complete response (CR) rate or 6% and a partial response (PR) rate of 73%.³

In those with ROS1-positive advanced NSCLC who were pretreated with 1 prior TKI without prior chemotherapy, the cORR was 36% (95% CI, 23%-50%), including a CR rate of 7% and a PR rate of 30%.

TRIDENT-1 is an open-label, global, multi-center, first-in-human trial evaluating repotrectinib in patients at least 18 years of age with advanced solid tumors, including those with NSCLC. Patients are required to have an ALK, ROS1, or NTRK1/2/3, gene rearrangement per protocol-specified tests, an ECOG performance status of 0 or 1, at least 1 measurable target lesion per RECIST v1.1 criteria, and a life expectancy of at least 3 months.⁴

Prior treatment with chemotherapy or immunotherapy is allowed. Patients with asymptomatic central nervous system metastases and/or asymptomatic leptomeningeal carcinomatosis are permitted.

The goal of phase 1 is to identify dose-limiting toxicities and establish the recommended phase 2 dose. BICR-assessed ORR per RECIST v1.1 criteria is the primary end point of phase 2. Key secondary end points including DOR, time to response, PFS, overall survival and clinical benefit rate (CBR) in 6 distinct expansion cohorts, including patients with TKI-naïve or TKI-pretreated, ROS1-positive locally advanced or metastatic NSCLC and NTRK-positive advanced solid tumors.¹

Additional updated data demonstrated that TKI-naïve patients with measurable brain metastases at baseline (n = 9) experienced an intracranial ORR of 89% per BICR. In patients who had received a prior TKI and had measurable brain metastases at baseline (n = 13), the intracranial ORR was 38% per BICR.

“These updated results reflect the potential of repotrectinib as a best-in-class ROS1 inhibitor. Furthermore, the data offer hope for the patients with ROS1-positive NSCLC who still face high remaining unmet needs,” Joseph Fiore, executive director, global program lead, repotrectinib, at Bristol Myers Squibb, stated in a news release. “Building on our heritage of transformational science with immunotherapy in the treatment of NSCLC, we are excited to advance this next-generation precision medicine, which has shown an unprecedented level of durability of responses and robust intracranial responses in patients with ROS1-positive NSCLC, so that it can hopefully help patients in their fight against cancer.”