Abstract
Next-generation tyrosine kinase inhibitor candidates are continuing to emerge for patients with tumor types harboring ROS1 fusions. Phase I findings from two trials, TRIDENT-1 and ARROS-1, indicate high response rates with repotrectinib and NVL-520, respectively. The latter may be a potential best-in-class agent, with potent ROS1 selectivity that avoids off-target toxicity.
For patients with tumors harboring ROS1 fusions, the pool of next-generation tyrosine kinase inhibitors (TKI) continues to expand. Researchers presented promising phase I findings on two candidates, repotrectinib (Bristol Myers Squibb) and NVL-520 (Nuvalent), during the 2022 EORTC-NCI-AACR (ENA) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, October 26–28.
Byoung Chul Cho, MD, PhD, of Yonsei University in Seoul, South Korea, reported that in the TRIDENT-1 trial, among 71 evaluable patients not previously treated with a TKI, the objective response rate (ORR) with repotrectinib was 78.9%, including four complete responses. For another 100 patients who had received one or more prior TKIs with or without chemotherapy, the ORR was 37%.
In a subgroup of 17 patients with non–small cell lung cancer (NSCLC) and acquired TKI resistance driven by the ROS1G2032R mutation, 58.8% still responded to repotrectinib. Discussant Irene Brana, MD, PhD, of Barcelona's Vall d'Hebron Institute of Oncology, hailed this robust ORR. “An interesting property of repotrectinib is its small, compact structure,” she said. “It still fits within ROS1's [binding] pocket despite solvent-front motif mutations like G2032R.”
Repotrectinib's main side effect was low-grade dizziness; some patients also experienced dysgeusia. Overall, the drug's manageable toxicity profile “signals potential compatibility with long-term use,” Cho said.
That said, treatment-related dizziness is “a neurologic consequence of off-target TRK inhibition,” noted Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York, NY. Repotrectinib and earlier TKIs such as entrectinib (Rozlytrek; Genentech) “are conversely better at suppressing TRK than ROS1”—a limitation that NVL-520, “potentially a best-in-class inhibitor,” aims to mitigate by potently and selectively targeting ROS1.
At the ENA Symposium, Drilon reported preliminary activity with NVL-520 in the ARROS-1 study's dose-escalation phase. Among 21 patients with NSCLC, all of whom had received prior TKI therapy—often two or more agents including repotrectinib and lorlatinib (Lorbrena; Pfizer), a third-generation ALK/ROS1 inhibitor—the ORR was 48%.
In a subanalysis of acquired resistance, one patient with a ROS1D2033N mutation “achieved a partial response that's pending confirmation,” Drilon said. Meanwhile, of nine patients with G2032R, 78% responded to NVL-520. One had developed the mutation after 9 months of entrectinib; it was still present after further treatment with repotrectinib and chemotherapy. However, “within 4 weeks, he had a brisk partial response to NVL-520, which is ongoing at 5.3 months, with near-complete resolution of his brain lesions.”
NVL-520's “brain penetrance is in fact comparable with lorlatinib,” which was specifically designed to address central nervous system (CNS) metastases, Drilon added. “Our confidence in NVL-520's CNS activity is such that we've allowed not only patients with progressing brain metastases, but also those with asymptomatic leptomeningeal disease, to enroll.”
As anticipated, given NVL-520's ROS1-selective, TRK-sparing profile, no dizziness occurred; the main side effect was mild fatigue. ARROS-1's registrational phase II portion is underway, Drilon said, “and it includes a TKI-naïve cohort, so [Nuvalent's] going for a possible front-line indication.”
Discussant Udai Banerji, MD, PhD, of The Royal Marsden in London, UK, was encouraged that deep responses were seen even at the lowest dose of NVL-520. He observed, though, that the drug having activity across all five dose levels evaluated “may make an optimal selection challenging.”
To Banerji, NVL-520 “is another win for precision oncology,” and beyond NSCLC, “I hope pediatric tumors with ROS1 fusions, which have a terrible prognosis, aren't left behind” in further trials. “Generally, too, we aren't doing enough to find patients with these rare cancers,” he added. “Testing needs to be widespread, because we do get excellent efficacy” with next-generation TKIs. –Alissa Poh
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