medwireNews: The next-generation ROS1–tyrosine kinase inhibitor (TKI) repotrectinib has demonstrated durable clinical activity in people with ROS1 fusion-positive non-small-cell lung cancer (NSCLC) in the phase 1/2 TRIDENT-1 trial.
Response rates were high regardless of whether participants had previously received a ROS1–TKI or not, and the median duration of response ranged from just over a year to nearly 3 years, highlight Alexander Drilon (Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, USA) and colleagues.
Moreover, “[a]dverse events [AEs] were mainly of low grade and compatible with long-term administration,” they add in The New England Journal of Medicine.
The researchers explain that although early-generation ROS1–TKIs such as crizotinib and entrectinib are approved for the treatment of ROS1 fusion-positive NSCLC, “resistance develops in tumors, and intracranial activity is suboptimal.”
They are therefore evaluating repotrectinib – a next-generation agent designed to address these issues – in the multicohort TRIDENT-1 study including patients with different advanced solid tumors, with the current report focusing on those with ROS1 fusion-positive NSCLC.
The phase 1 part of the study established the recommended phase 2 dose of repotrectinib as 160 mg daily for 14 days, followed by 160 mg twice daily until disease progression or unacceptable toxicity. This dose was given to the majority of patients in the primary efficacy population comprising 71 patients who had not previously received a ROS1–TKI and 56 patients who had received one ROS1–TKI but were chemotherapy-naïve. However, eight patients in the former group and three in the latter were drawn from phase 1 and may have received a different dose.
Among the patients naïve to ROS1–TKIs, 79% achieved a response to repotrectinib at a median follow-up of 24.0 months, with complete responses in 10% and partial responses in 69%. The median durations of response, progression-free survival (PFS), and overall survival (OS) were 34.1 months, 35.7 months, and unreached, respectively.
The objective response rate among those who had received one previous ROS1–TKI was 38%, of which 5% were complete responses and 32% were partial. The median follow-up in this group was 21.5 months, the median duration of response was 14.8 months, and the median PFS and OS times were 9.0 and 25.1 months, respectively.
Drilon et al report that repotrectinib demonstrated intracranial activity, and “[i]n each cohort, the percentage of patients with an intracranial response was generally similar to the percentage with a systemic response.” Specifically, among participants with measurable brain metastases at baseline, intracranial responses occurred in 89% of nine patients naïve to ROS1–TKIs and 38% of 13 who had received one ROS1–TKI.
Furthermore, the 12-month rates of intracranial PFS were high among participants without baseline brain metastases, at 91% and 82%, respectively, suggesting that “repotrectinib may delay or prevent the development of brain lesions,” say the study authors.
The safety analysis included all patients who received the recommended phase 2 dose (n=426) and showed that the most common any-grade AEs related to treatment were dizziness (58%) and dysgeusia (50%), but the events were primarily of grade 1 or 2.
Treatment-related AEs of grade 3 or worse occurred in 29% of patients, with the most frequent being anemia and increased blood creatine kinase levels, each in 4%, and dizziness, in 3%.
Thirty-eight percent of patients required a dose reduction due to AEs, while 50% needed a dose interruption and 7% discontinued permanently. None of the fatal AEs (4%) were considered related to study treatment.
The team concludes: “Comparative trials may be needed to define the role of repotrectinib in the treatment sequence.”
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