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An interview with: Byoung Chul Cho MD PhD, Thoracic Medical Oncologist, from the Yonsei Cancer Center at Yonsei University College of Medicine in Seoul, South Korea.
BARCELONA, Spain—A “next generation” ROS1 tyrosine kinase inhibitor (TKI), repotrectinib—studied in the phase one/two Trident-1 study among patients whose advanced non-small cell lung cancers (NSCLC) had tested positive for the ROS1 fusion protein receptor tyrosine kinase (encoded by the ROS1 oncogene)—resulted in high response rates with low toxicities, according to results reported at the 2022 European Organisation for Research and Treatment of Cancer-National Cancer Institute-American Association for Cancer Research (EORTC-NCI-AACR) Symposium on Molecular Targets and Cancer Therapeutics.
Byoung Chul Cho discusses the trial and its clinical implications for patients with ROS1 positive NSCLC (one or two per cent of all lung cancer cases).
Among the study patients treated at 150 hospitals around the world, some had never been treated with a ROS1 TKI, some had already been treated with one ROS1 TKI, some had been treated with a ROS1 TKI and platinum-based chemotherapy, and some had been treated with two different ROS TKIs. As of June 20, 2022, the primary efficacy population had included 71 TKI-naive patients and 56 TKI-pretreated patients with no prior chemotherapy.
 “In TKI-naïve patients repotrectinib showed a 78 per cent objective response rate (tumor reduction of at least 30 per cent) and the 12 months duration of response was 86 per cent,” said Cho after his late breaking session at the Symposium. In the patients who had no prior chemotherapy who had been treated with a previous-generation ROS1 TKI he said they also found a good response rate. “Repotrectinib showed a 37 per cent objective response rate with a six months duration of response [of] 79 per cent,” he said.
A significant issue with ROS1 TKI treatment had been that patients usually developed the so-called G2032R resistance mutation that rendered further TKI therapy ineffective. “The G2032R resistance mutation is the most common resistance mechanism,” said Cho. “Repotrectinib showed objective response rate of 58 per cent in this population.”
Anti mTrk activity
Another putative advantage for the investigational agent in Trident-1 had been that it also inhibited mutated tropomyosin receptor kinase receptor (Trk: usually pronounced “track”) a molecular feature often found in association with ROS1. “So, in the Trident-1 trial we also evaluated the activity and safety of repotrectinib in m-Trk fusion-positive solid tumors in both TKI naïve and TKI pretreated populations,” Cho said. A phase one study by Besse and colleagues from Villejuif, France—working on Trident-1 in collaboration with Cho and others—had already found that repotrectinib demonstrated efficacy in TKI-naïve and TKI-pretreated patients and was generally well tolerated.
https://aacrjournals.org/mct/article/20/12_Supplement/P02-01/675917/Abstract-P02-01-Repotrectinib-in-patients-with
Brain metastases
When Cho was asked about the impact of the new TKI on cranial metastases he said the drug had been effective. “CNS metastasis is one of the commonest sites of metastasis after progression on a ROS1 TKI. In this study we [observed] a very high intracranial activity of repotrectinib in both TKI naïve and TKI pre-treated populations.” Nearly 90 per cent of the small number of patients with measurable tumors in the brain not previously treated with a ROS1 TKI had intracranial objective responses (iORR). Just less than half of those already treated with one prior ROS1—and half of those treated with one prior ROS1 TKI and chemotherapy—had iORR. But none of the patients pre-treated with both chemotherapy and a TKI had responded.
Cho said that repotrectinib had been generally well tolerated. “The most com