NEW YORK – Turning Point Therapeutics on Wednesday shared encouraging interim data from the registrational Phase II TRIDENT-1 study of repotrectinib in patients with ROS1- and NTRK-positive tumors.
The drugmaker has had discussion with the US Food and Drug Administration about its regulatory plan for repotrectinib based on the efficacy and safety seen in interim analysis.
Repotrectinib, the lead product in the San Diego-based precision oncology company's pipeline, is a next-generation tyrosine kinase inhibitor designed to target tumors with rearrangements in ROS1, NTRK, or ALK. The TRIDENT-1 study is enrolling previously treated and treatment-naïve patients with these alterations.
At the data cutoff of July 10, preliminary readouts were available for 39 repotrectinib-treated patients at a median follow up of 3.6 months with a median duration of treatment of 3.7 months.
In the seven ROS1-positive, TKI-naive patients with non-small cell lung cancer, the confirmed objective response rate was 86 percent, with six patients responding. All six patients were still responding at the time of the data cutoff. After July 10, the one remaining patient also achieved an unconfirmed partial response and remains on treatment awaiting a confirmatory scan.
This interim data is in line with repotrectinib's activity in the Phase I portion of TRIDENT-1, in which the overall response rate was 91 percent among 11 ROS1-positive, TKI-naïve NSCLC patients. The median duration of response in these patients was 23.1 months, with a median progression-free survival of 24.6 months.
Turning Point Chief Medical Officer Mohammad Hirmand said in a call with investors on Wednesday that the activity seen with repotrectinib is in line with the activity of other TKIs, such as the ROS1 inhibitor crizotinib (Pfizer's Xalkori), and entrectinib (Genentech's Rozlytrek), recently approved for the treatment of ROS1-positive NSCLC and refractory solid tumors with NTRK rearrangements. The FDA approved entrectinib based on response rates of 78 percent and 57 percent in lung cancer and solid tumor patients, respectively.
In TRIDENT-1, there were also 26 previously treated, ROS1-positive NSCLC patients — six received one prior TKI and no chemotherapy; five received one prior TKI and chemo; 10 received two prior TKIs and chemo; and five received two prior TKIs and no chemo.
In the six who had one TKI but no chemo, the objective response rate was 67 percent; four patients with a confirmed response remained in response at the time of data cutoff. For the five patients who had previously received one TKI and chemo, the objective response rate was 40 percent, with two patients achieving a confirmed response.
None of the 10 patients who received two prior TKIs and chemotherapy had confirmed responses, but five patients had stable disease. Based on the limited activity seen in this group, Turning Point would like to modify this cohort to remove the requirement for prior chemotherapy.
Lastly, in the five patients who received two prior TKIs but no chemo, the objective response rate was 40 percent, with two patients having a confirmed response.
In TRIDENT-1 there were also six NTRK-positive solid tumor patients who had prior TKI therapy. Among this subset, the objective response rate was 50 percent; the three patients with a confirmed response remained in response at data cutoff. There wasn't sufficient follow up to report on the outcomes of the NTRK-positive, TKI-naïve subgroup.
Repotrectinib appeared to be well tolerated, and mostly grade 1 or 2 treatment-related adverse events were reported. The most common adverse events were dizziness, fatigue, constipation, dysgeusia, and dyspnea. No adverse events more serious than grade 3 were seen in the study.
Based on feedback from the FDA, Turning Point believes it may be possible to expedite repotrectinib through the regulatory process by modifying cohorts and pooling data from patients in the Phase I portion of the study who were treated at the recommended Phase II dose.
Turning Point CEO Athena Countouriotis said during the call that the company had discussed with the agency the possibility of using smaller cohort sizes to support repotrectinib's approval. The FDA has been increasingly willing to approve precision oncology drugs based on data from small, multi-cohort trials. For example, the agency approved capmatinib (Novartis' Tabrecta), Countouriotis noted, based on data from fewer than 100 patients in a multi-cohort basket trial.
Approximately 2 percent of NSCLC patients harbor rearrangements in ROS1. However, Countouriotis believes that the market for repotrectinib in this setting is still sizable after factoring in patients who will receive it as a frontline option and those who eventually relapsed on crizotinib.
The company is planning further data analyses in the ROS1-positive, TKI-pretreated cohorts. It is expecting to achieve full site activation in 2021.
NTRK fusions occur in less than 1 percent of solid tumors. In this setting, Countouriotis said that larotrectinib (Bayer's Vitraki) remains a leading option for treatment-naive patients, though larotrectinib-refractory patients have few alternatives, and repotrectinib has shown activity in this setting.
In July, Turning Point entered into an exclusive license agreement with Zai Lab for the development and commercialization of repotrectinib in China, Hong Kong, Macau, and Taiwan. Although NTRK-positive patients are rare, Countouriotis is hoping that this new partnership will allow Turning Point to identify and enroll more eligible patients into the trial.