Repotrectinib Gets Breakthrough Therapy Designation in China for NTRK+ TKI-Pretreated Solid Tumors

The Center for Drug Evaluation, of the National Medical Products Administration (NMPA) in China, has granted breakthrough therapy designation to repotrectinib for use in patients with advanced solid tumors harboring a NTRK gene fusion who experienced disease progression after TKI treatment.¹

The designation was based on findings from the global and Chinese NTRK-positive, TKI-pretreated populations enrolled on the phase 1/2 TRIDENT-1 study (NCT03093116).

“We are excited to receive our fourth breakthrough therapy designation for repotrectinib in China. Today’s recognition further supports repotrectinib as a potential first-in-class treatment for patients with NTRK-positive, TKI-pretreated solid tumors in China,” Rafael G. Amado, MD, president and head of Global Oncology Research and Development at Zai Lab Limited, stated in a press release.¹ “…We look forward to working with regulatory authorities in China to bring this important medicine to patients in need as soon as possible.”

The global, open-label, multicenter, first-in-human trial consists of 2 phases that will enroll patients to 6 expansion cohorts, including those with TKI-naïve and -pretreated disease who have ROS1-positive locally advanced or metastatic NSCLC and NTRK-positive advanced solid tumors.²

In the first portion of the research, investigators set out to identify the recommended phase 2 dose of repotrectinib, to evaluate dose-limiting toxicities and to examine the pharmacokinetic profile of the agent, specifically maximum plasma concentration and area under the plasma concentration time curve. For the second portion, the key objective is ORR as evaluated by blinded independent central review and RECIST v1.1 criteria. Secondary objectives include DOR, clinical benefit rate, PFS, overall survival, and intracranial ORR.

In June 2023, the NMPA accepted for review a new drug application seeking the approval of repotrectinib in adult patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring ROS1 fusions.³ The application was also supported by TRIDENT-1 findings.

Topline data showed that in patients with ROS1-positive NSCLC who were not previously exposed to a TKI (n = 71), the confirmed objective response rate (cORR) achieved with the agent was 79% (95% CI, 68%-88%). In this group, there was a 6% complete response rate and a 73% partial response rate.

The duration of response (DOR) ranged from 1.4+ months to 35.1+ months. At a median follow-up of 10.2 months, 91% (95% CI, 82%-100%) of responders were estimated to still be in response to treatment at 6 months. The estimated percentage of patients remaining in response to repotrectinib for 9, 12, and 18 months were 88% (95% CI, 78%-98%), 85% (95% CI, 73%-96%), and 76% (95% CI, 61%-91%), respectively. The median progression-free survival (PFS) ranged from 0+ months to 40.4+ months. At 6, 9, 12, and 18 months, respectively, 91% (95% CI, 84%-98%), 85% (95% CI, 75%-94%), 82% (95% CI, 72%-93%), and 72% (95% CI, 58%-86%) of patients were estimated to remain free of disease progression.

In the group of patients who previously received 1 TKI and platinum-based chemotherapy (n = 26), repotrectinib induced an cORR of 42% (95% CI, 23%-62%). In those who previously received 1 TKI (n = 56) or 2 TKIs (n= 18) and no chemotherapy (n = 18), the cORRs were 36% (95% CI, 23%-50%) and 28% (95% CI, 10%-54%), respectively. In a subset of patients who harbored a ROS1 G2032R mutation (n = 17), the cORR with the agent was 59% (95% CI, 33%-82%).

Data from an updated analysis that will be presented at the upcoming 2023 IASLC World Conference on Lung Cancer show that at a median follow-up of 24 months, the cORR was 79% in the TKI-naïve population, with a median DOR of 34.1 months and a median PFS of 35.7 months.⁴ In the subset of patients who had measurable baseline brain metastases (n = 9), the intracranial ORR with repotrectinib was 89%, with prolonged responses observed.

With a median follow-up of 21.5 months, the cORR was 38% in the group of patients who received 1 prior TKI without chemotherapy, with a median DOR of 14.8 months and a median PFS of 9 months. In the subset of patients with baseline brain metastases (n = 13), the intracranial ORR was 38%.

Previously, in October 2021, the FDA granted a breakthrough therapy designation to repotrectinib for use as a potential option in patients with advanced solid tumors harboring NTRK gene fusions who progressed following prior treatment with 1 or 2 TKIs, with or without chemotherapy, who have no satisfactory alternative options.⁵ In May 2023, repotrectinib was also granted priority review from the regulatory agency for patients with ROS1-positive, locally advanced or metastatic NSCLC based on findings from TRIDENT-1.⁶

The study is ongoing to evaluate long-term outcomes and additional end points spanning patient populations with ROS1-positive locally advanced or metastatic NSCLC and NTRK-positive advanced solid tumors.⁴

References

1. Zai Lab announces breakthrough therapy designation granted for repotrectinib for treatment of patients with NTRK-positive TKI-pretreated advanced solid tumors in China. News release. Zai Lab Limited. August 30, 2023. Accessed August 30, 2023. https://ir.zailaboratory.com/news-releases/news-release-details/zai-lab-announces-breakthrough-therapy-designation-granted-1
2. A study of repotrectinib (TPX-0005) in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements (TRIDENT-1). ClinicalTrials.gov. Updated May 18, 2023. Accessed August 30, 2023. https://clinicaltrials.gov/ct2/show/NCT03093116
3. Zai Lab announces NDA acceptance of repotrectinib for patients with ROS1-positive NSCLC by China’s NMPA. News release. Zai Lab Limited. June 28, 2023. Accessed August 30, 2023. https://ir.zailaboratory.com/news-releases/news-release-details/zai-lab-announces-nda-acceptance-repotrectinib-patients-ros1
4. Updated data from TRIDENT-1 trial show durable efficacy benefits with repotrectinib for patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer. News release. Bristol Myers Squibb. August 16, 2023. Accessed August 30, 2023. https://news.bms.com/news/corporate-financial/2023/Updated-Data-from-TRIDENT-1-Trial-Show-Durable-Efficacy-Benefits-with-Repotrectinib-for-Patients-with-Locally-Advanced-or-Metastatic-ROS1-Positive-Non-Small-Cell-Lung-Cancer/default.aspx
5. Zai Lab Partner Turning Point Therapeutics granted breakthrough therapy designation for repotrectinib treatment in patients with NTRK-positive, TKI-pretreated advanced solid tumors. News release. Zai Lab Limited and Turning Point Therapeutics, Inc. October 4, 2021. Accessed August 30, 2023. https://ir.zailaboratory.com/news-releases/news-release-details/zai-lab-partner-turning-point-therapeutics-granted-breakthrough
6. US Food and Drug Administration accepts for priority review Bristol Myers Squibb’s application for repotrectinib for the treatment of patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer. News release. Bristol Myers Squibb. May 30, 2023. Accessed August 30, 2023. https://investors.bms.com/iframes/press-releases/press-release-details/2023