TRIDENT-1

Treatment with repotrectinib in patients with ROS1-positive non–small cell lung cancer (NSCLC), specifically those who were tyrosine kinase inhibitor (TKI)-naïve or -pretreated, continued to demonstrate durable clinical activity, as well as durable intracranial responses, according to updated results from the phase 1/2 TRIDENT-1 trial (NCT03093116) presented at the 2023 World Conference on Lung Cancer.1,2

“These results from TRIDENT-1 demonstrate repotrectinib as a potential new standard-of-care option for TKI-naïve and TKI-pretreated patients with ROS1-positive metastatic NSCLC” Byoung Chul Cho, MD, PhD, medical oncologist and professor in the Division of Medical Oncology at Yonsei Cancer Center, Yonsei University College of Medicine, and chief of the Lung Cancer Center at Yonsei Cancer Center, said during a presentation at the meeting.

In his presentation, Cho reported on efficacy, with a minimum follow-up of 14 months, in 2 primary efficacy cohorts–patients who were TKI-naïve (n = 71) or previously treated with 1 TKI and no chemotherapy (n = 56)–as well as safety in all patients treated at the recommended phase 2 dose (RP2D). The data cutoff was December 19, 2022.

After a median follow-up of 24.0 months (range, 14.2-66.6) in the TKI-naïve cohort, the confirmed objective response rate (cORR) was 79% (95% CI, 68%-88%). Further, the median duration of response (DOR) was 34.1 months (95% CI, 25.6–not estimable [NE]), median progression-free survival (PFS) was 35.7 months (95% CI, 27.4–NE), and median overall survival (OS) was NE (95% CI, 44.4-NE). The 12- and 18-month PFS rates were 77% and 70%, respectively, while 12- and 18-month OS rates were 91% and 88%).

When evaluating time to response (TTR), 83% of patients in the TKI-naïve cohort experienced a response at 12 months, and 79% at 18 months.

Of those treated at the RP2D in the TKI-naïve cohort (n = 63), cORR was 78% (95% CI, 66%-87%), median DOR was NE (95% CI, 25.6-NE), median PFS was NE (95% CI, 27.4-NE), and median OS was NE.

After a median follow-up of 21.5 months (range, 14.2-58.6) in the cohort of patients who previously received 1 TKI and no chemotherapy, cORR was 38% (95% CI, 25%-52%). In addition, median DOR was 14.8 months (95% CI, 7.6–NE), median PFS was 9.0 months (95% CI, 6.8-19.7), and median OS was 25.1 months (95% CI, 17.8–NE). The 12-month PFS and OS rates were 41% and 69%, respectively.

In terms of TTR, 56% of patients experienced a response at 12 months.

Of those treated at the RP2D in this cohort (n = 53), cORR was 38% (95% CI, 25%-52%), median DOR was 14.8 months (7.5–NE), median PFS was 9.0 months (95% CI, 6.8-19.6), and median OS was 20.5 months (95% CI, 17.8–NE).

Lastly, in patients who were TKI-pretreated with a baseline G2032R resistance mutation (n = 17), cORR was 59% (95% CI, 33%-82%), median DOR was 7.6 months (95% CI, 4.4-17.8), and median PFS was 9.2 months (95% CI, 1.9-12.8).

In the TKI-naïve and TKI-pretreated cohorts, the intracranial cORRs were 89% (95% CI, 52%-100%) and 38% (95% CI, 14%-68%), respectively. Complete response occurred in 1 patient (11%) in the TKI-naïve group vs no patients in the TKI-pretreated group, and partial responses were seen in 7 (78%) and 5 (38%), respectively. Cho noted that in an analysis of time to first intracranial progression only, none had occurred within 18 months of therapy in both cohorts.

“Repotrectinib led to durable intracranial responses and may have delayed or prevented the development of brain lesions in patients without baseline brain metastases,” Cho added.

In total, 34 patients (48%) in the TKI-naïve group and 40 patients (71%) in the TKI-pretreated group discontinued treatment with repotrectinib. The majority of those patients (24% vs 30%, respectively), went on to receive chemotherapy with or without immunotherapy after repotrectinib discontinuation.

Among patients with ROS1-positive NSCLC in the trial treated at the RP2D (n = 320), treatment-emergent (TEAEs) and -related adverse events (TRAEs) occurred in 99% and 96% of patients, respectively, with 49% and 27% being grade 3 or higher. The most common TEAE was dizziness (62%; grade 3 or higher, 3%); however, no patients discontinued treatment as a result, Cho noted. Thirteen TEAEs (4%) were reported as fatal.

“Repotrectinib safety in patients treated at the RP2D was manageable and consistent with previous reports in all treated patients,” Cho said.

In the open-label, global, multicenter, first-in-human, phase 1/2 TRIDENT-1 trial, investigators aim to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity of repotrectinib as treatment for patients with advanced solid tumors.

The goal of phase 1 of the trial is to assess primary and secondary safety end points and pharmacokinetics. ORR as assessed by Blinded Independent Central Review using RECIST v1.1 serves as the primary end point of phase 2 of the trial, with secondary end points including DOR, TTR, PFS, OS, and clinical benefit rate in 6 expansion cohorts.2

To be eligible for the phase 1/2 trial, patients had to have locally advanced or metastatic solid tumors harboring ROS1 or NTRK1-3 gene fusions; asymptomatic central nervous system metastases were allowed.

The RP2D dose of repotrectinib was 160 mg once daily for 14 days, followed by 160 mg twice daily.

Cohorts were comprised of patients who were TKI-naïve (n = 110), previously received 1 TKI and no chemotherapy (n = 60), previously received 1 TKI and 1 platinum-based chemotherapy (n = 40), or previously received 2 TKIs and no chemotherapy (n = 60).

In the TKI-naïve and 1 prior TKI with no chemotherapy cohorts, patients were a median age of 57 (range, 28-80 vs 33-78, respectively), while 43 (61%) and 38 (68%) were female. Further, in the TKI-naïve cohort, 34% and 66%, respectively, had an ECOG performance score of 0 or 1, compared with 32% and 68% in those who received 1 prior TKI and no chemotherapy. Seventeen patients (24%) had brain metastases in the TKI-naïve cohort, vs 26 (46%) in the second cohort.

In the TKI-naïve cohort, 72% previously received no prior chemotherapy with or without immunotherapy, 24% received 1 line of prior chemotherapy with or without immunotherapy, 72% previously received no prior systemic anticancer therapy, and 22% received 1 prior systemic anticancer therapy. In the second cohort, 46 patients (82%) previously received crizotinib (Xalkori) and 9 (16%) were given entrectinib (Rozlytrek).

Based on results from this pivotal, registrational trial, the FDA has accepted the new drug application for repotrectinib to treat patients with ROS1-positive, locally advanced or metastatic NSCLC and granted it priority review, with a Prescription Drug User Fee Act date of November 27, 2023.2

“These updated results reflect the potential of repotrectinib as a best-in-class ROS1 inhibitor. Furthermore, the data offer hope for the patients with ROS1-positive NSCLC who still face high remaining unmet needs,” Joseph Fiore, executive director, global program lead, repotrectinib, Bristol Myers Squibb, said in a press release ahead of the meeting. “Building on our heritage of transformational science with immunotherapy in the treatment of NSCLC, we are excited to advance this next-generation precision medicine, which has shown an unprecedented level of durability of responses and robust intracranial responses in patients with ROS1-positive NSCLC, so that it can hopefully help patients in their fight against cancer.”