The breakthrough therapy designation marks the agents seventh regulatory designation.
The FDA has granted a breakthrough therapy designation to repotrectinib (TPX-0005) for the treatment of patients with NRTK-positive, (Tyrosine kinase inhibitor) TKI-pretreated advanced solid tumors, according to a press release by ZaiLab.1
The breakthrough therapy designation marks the agent’s seventh regulatory designation. It also holds a breakthrough therapy designation in non-small cell lung cancer (NSCLC).
The designation is based on results of the phase 1/2 TRIDENT-1 study (NCT03093116). The open-label, interventional, single-group assignment study has an estimated enrollment of 450 participants and an estimated study completion date of December 2022. Primary end points of phase 1 include dose limiting toxicities and recommend phase 2 dose. The primary end point of phase 2 is overall response rate (ORR). Secondary end points of phase 1 include maximum plasma concentration of repotrectinib, area under the plasma concentration time curve, and preliminary ORR. Secondary phase 2 end points include duration of response (DOR), clinical benefit rate, progression-free survival, overall survival, and ORR.2
Phase 1 of the study has 3 distinct parts. Phase 1a is a dose-escalation study, phase 1b is a food-effect sub-study, and phase 1c is a dose escalation with food, and midazolam drug-drug interaction sub-study.
Phase 2 is made up of 6 distinct expansion cohorts. Expansion 1 is ROS1 TKI-naïve ROS1-positive NSCLC. Expansion 2 is 1 prior ROS1 TKI and 1 platinum-based chemotherapy ROS1-positive NSCLC. Expansion 3 is2 prior ROS1 TKIs ROS1-positive NSCLC, without chemotherapy or immunotherapy. Expansion 4 is 1 prior ROS1 TKI ROS1-positive NSCLC, without chemotherapy or immunotherapy. Expansion 5 is TKI-naïve NTRK-positive solid tumors. Expansion 6 is TKI-pretreated NTRK-positive solid tumors.
Interim results on 39 patients presented in 2020 found that at a starting dose of 160mg daily, 90% of patients were able to escalate after 14 days to 160 mg twice daily. In the cohort of patients with ROS1-positive TKI-naïve NSCLC (n = 7), the ORR was 86% (95% CI, 42%-100%). The DOR ranged from 0.9+ to 2.0+ months.
In the ROS1-positive NSCLC with 1 prior TKI and platinum-based chemotherapy cohort (n = 5), the ORR was 40% (95% CI, 5%-85%) with a DOR ranging from 4.5+ to 5.6+ months. In the ROS1-positive NSCLC cohort pretreated with 1 prior TKI but did not receive chemotherapy (n = 6), the ORR was 6.7% (95% CI, 22%-96%).
In the cohort of patients who had ROS1-positive disease pretreated with 2 prior TKIs and had not received chemotherapy (n = 10), stable disease was seen in 5 patients, but no objective response was seen in this cohort at the time of data cutoff.
In the cohort of patients with NTRK-positive NSCLC who were pretreated with a TKI (n = 6), the ORR was 50% (95% CI, 12%-88%). The DOR in this group ranged from 1.7+ months to 3.6+ months. Three patients were still responding at the time of data cutoff.
The agent was found to be well tolerated, with most adverse events (AEs) being grade 1 or 2. Common AEs included dizziness (62%), fatigue (39%), constipation (33%), dysgeusia (33%), and dyspnea (28%). Grade 3 dizziness was not observed, and dizziness did not lead to treatment discontinuation.
In order to participate in TRIDENT-1, patients must have an ECOG status of 0 or 1, the ability to swallow capsules intact, at least 1 measurable lesion, and a life expectancy of 3 months of greater. Both cytotoxic chemotherapy and prior immunotherapy is allowed. Patients with asymptomatic central nervous system metastasis are eligible to participate if safety profile is met. Patients with symptomatic brain metastases, a history of previous cancer, major surgery within 4 weeks of therapy start, clinically significant cardiovascular disease, known active infections, peripheral neuropathy, or gastrointestinal disease are not eligible to participate.