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.
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 common side effects were low grade: grade one or two. The most common was low-grade dizziness. It occurred in about 60 per cent of patients,” he said. But despite this relatively high incidence of dizziness the incidence of treatment discontinuation had been low, he said—less than ten per cent.
“With around 16 months median follow up, the median duration of response to repotrectinib treatment in TKI naïve patients has not yet been met. This is very meaningful, and a clear measure to utilize repotrectinib in the TKI naïve setting,” said Cho. “The number two message is: We also demonstrated a high response rate in TKI-pre-treated ROS1 positive lung cancer. And we also demonstrated the activity of repotrectinib in G2032R mutant ROS1 positive lung cancer,” he said.
He regarded the data as the strongest yet seen with a TKI in this setting. “In our study we demonstrated the potential role and value of repotrectinib in both TKI naïve and TKI pretreated ROS1 positive advanced stage NSCLC,” he said.
For many patients with the ROS1 marker, Cho predicted an important role for repotrectinib in picking up the baton to take over from previous generation TKI therapy. “Because the current standard of care at the time of diagnosis of advanced stage ROS1 positive lung cancer is a ROS1 TKI such as crizotinib, or entractinib, so: After 15 or 20 month of progression-free survival the majority of patients experience disease progression due to acquired resistance. So, in the second line setting we [currently] only have cytotoxic chemotherapy. So, these data support the use of repotrectinib in the setting of resistance to prior ROS1 TKI in the first-line setting,” Cho said.
“Our data suggest that repotrectinib could represent a potential new treatment option for patients with ROS1 positive NSCLC in both TKI naïve and TKI pre-treated populations,” he concluded.
Abstract P02-01: Repotrectinib in patients with NTRKfusion-positive advanced solid tumors: update from the registrational phase 2 TRIDENT-1 trial
Benjamin Besse; Christina Baik; Christoph Springfeld; Alice Hervieu; Victor Moreno; Lyudmila Bazhenova; Jessica J. Lin; D. Ross Camidge; Benjamin Solomon; Vamsidhar Velcheti; Anthonie J. van der Wekken; Enriqueta Felip; Dipesh Uprety; Denise Trone; Shanna Stopatschinskaja; Byoung Chul Cho; Alexander Drilon
NTRK fusions drive a broad range of solid tumors. Two FDA approved TRK tyrosine kinase inhibitors (TKIs) have demonstrated efficacy in patients (pts) with NTRK fusion+ advanced solid tumors; however, emergent TRK solvent front (SF) and gatekeeper resistance mutations occur. Repotrectinib is a next-generation ROS1/TRK TKI with potency against wildtype and mutant forms of ROS1 and TRK. In preclinical studies, repotrectinib was more potent than larotrectinib, entrectinib, and selitrectinib against wildtype TRK, SF and gatekeeper mutations. Early interim data from the Phase 1/2 TRIDENT-1 trial led to Fast Track designation by the FDA for repotrectinib in TRK TKI-pretreated pts. This abstract is an updated analysis of this population and the first presentation of repotrectinib activity in TRK TKI-naïve pts.
Pts with NTRKfusion+ advanced solid tumors were enrolled into the ongoing registrational Phase 2 TRIDENT-1 trial (NCT03093116). Pts with no prior TRK TKIs were enrolled into Expansion Cohort 5 (EXP-5) and pts who received up to 2 lines of prior TRK TKIs were enrolled into EXP-6. Prior chemotherapy and/or immunotherapy were allowed in both cohorts. The primary endpoint is cORR by Blinded Independent Central Review using RECIST v1.1. Results: As of efficacy data cutoff date of 28 July 2021, 8 pts in EXP-5 and 19 pts in EXP-6 had at least 2 post-baseline scans and were evaluable for efficacy analysis. Median age was 63 y (range 33–80) in EXP-5 and 50 y (range 23–81) in EXP-6; median number of prior lines of chemo/immunotherapy was 1 (range 0–2) in EXP-5 and 1 (range 0–4) in EXP-6. In EXP-6, 79% (15/19) of pts received 1 prior TRK TKI. Confirmed responses were reported by physician assessment. In EXP-5, cORR was 63% (5 of 8 pts; 95% CI: 24–91%) with DOR from 1.9+ to 7.4+ months (mo). In EXP-6, cORR was 47% (9 of 19 pts; 95% CI: 24–71%) with DOR from 1.9+ to 15.1 mo. In 10 pts enrolled in EXP-6 with a SF mutation, the cORR was 60% (6 of 10 pts; 95% CI: 26–88%). Median duration of treatment was 6.3 mo (range 0.9–13.4+) in EXP-5 and 8.1 mo (range 1.1–20.8) in EXP-6. An updated safety analysis for Phase 1 and Phase 2 (n=243) based on a data cut-off date of 4 May 2021 was conducted. Repotrectinib was generally well tolerated. Treatment-emergent adverse events (TEAEs) observed in ≥20% of patients were dizziness (62%), dysgeusia (43%), constipation (33%), dyspnea (30%), paresthesia (28%), anemia (26%), and fatigue (26%). The majority (77%) of dizziness TEAEs were Grade 1 and 4% were Grade 3; none of the dizziness events led to treatment discontinuation. Dose modifications remained infrequent (24% of pts had a dose reduction and 10% of pts discontinued study drug due to a TEAE).
Repotrectinib is a next-generation ROS1 and TRK inhibitor. In an ongoing registrational Phase 2 trial, repotrectinib demonstrated efficacy in TRK TKI-naïve and TKI-pretreated pts and was generally well tolerated. Enrollment in the multi-cohort Phase 2 trial is ongoing.
Benjamin Besse, Christina Baik, Christoph Springfeld, Alice Hervieu, Victor Moreno, Lyudmila Bazhenova, Jessica J. Lin, D. Ross Camidge, Benjamin Solomon, Vamsidhar Velcheti, Anthonie J. van der Wekken, Enriqueta Felip, Dipesh Uprety, Denise Trone, Shanna Stopatschinskaja, Byoung Chul Cho, Alexander Drilon. Repotrectinib in patients with NTRKfusion-positive advanced solid tumors: update from the registrational phase 2 TRIDENT-1 trial [abstract].
Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P02-01.