The survival rate depends very much on the stage at diagnosis and the type of cancer.
ROS1 fusions occur in just 1–2% of all NSCLC patients, but those that are ROS1 positive are often younger than the average lung cancer patient, more likely to be female and, frequently, have never smoked.
Therefore, drugs targeted at ROS1 are preferred in patients whose tumours have this genetic alteration.
A new ROS1 agent, repotrectinib, is being developed for such tumours by Bristol-Myers Squibb (BMS); it was originally discovered by Turning Point Therapeutics, which was acquired by BMS in 2022.1
The tyrosine kinase inhibitor is being developed to treat ROS1 or NTRK positive solid tumours that are locally advanced or metastatic, including NSCLC.
After promising preclinical results, a pivotal Phase I/II trial was done.2 Patients with ROS1+ NSCLC were assigned to four cohorts, according to their treatment history: TKI naïve, one line of ROS1 TKI, both with and without platinum-based chemotherapy, and two lines of ROS1 TKI without chemo.
Efficacy for patients with a minimum follow-up of 14 months has been reported for two primary cohorts at the dose recommended for Phase II.
Subjects were given 160 mg of the drug daily for 14 days, then 160 mg twice a day. The Phase II primary endpoint was the confirmed objective response rate (cORR).
At data cut-off, the median follow-up was 24 months in the TKI naïve cohort of 71 patients and 21.5 months in the 56 patients in the one TKI plus chemo cohort.
For the naïve patients, the cORR was 79% with a 34.1-month duration of response and 35.7 months of progression-free survival. In the TKI plus chemo patients, these were 14.8 and 9.0 months, respectively.
Treatment-emergent adverse events occurred in almost all patients, with dizziness being the most common (in 62% of patients). In all, 51% had at least grade 3 treatment-emergent adverse events and were considered to be treatment-related in 29%.
Both treated and untreated asymptomatic CNS metastases were permitted in the trial, with brain scans done on all Phase II patients at screening and at specified intervals until progression.
This enabled the impact on the metastases to be assessed.3 For the eight TKI naïve patients with brain metastases, the intracranial objective response rate (icORR) was 88% — and 42% for the 12 patients in the one TKI without chemo cohort.
At data cut-off, none of the seven responders in the former cohort and two in the latter had intracranial progression or death. The most common neurologic treatment-emergent adverse events were dizziness, dysgeusia, paraesthesia, headache, ataxia and memory impairment.
The safety profile was similar to that of patients with no brain metastases.
References
- A. Drilon, et al., Cancer Discov. 8, 1227 (2018).
- B.C. Cho, et al., IASLC 2023 World Conference on Lung Cancer (9–12 September 2023, Singapore): Abstr. OA03.06.
- J. Jiyeong Lin, et al., J. Clin. Oncol. 41(Suppl. 16), Abstr. 9017 (2021).