FDA Approves Repotrectinib for NTRK-Positive Locally Advanced, Metastatic Solid Tumors

The FDA has approved repotrectinib (Augtyro; Bristol Myers Squibb), a next-generation tyrosine kinase inhibitor (TKI), for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, are locally advanced or metastatic, or in cases where surgical resection is likely to result in severe morbidity, as well as patients who have progressed following treatment or have no satisfactory alternative therapy. The indication is approved under accelerated approval.¹

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NTRK are a family of receptors involved in neural development, and an NTRK gene fusion occurs when a piece of the chromosome containing the NTRK gene breaks off and joins with a gene on another chromosome. Such fusions can result in abnormal proteins, which can cause the growth of cancer cells. Although NTRK gene fusions are rare in patients with solid tumors, testing for these fusions helps identify patients who may benefit from TRK inhibitor therapy.²

“NTRK fusion-positive tumors can present challenges in the clinical setting, which is why it is important that we have additional treatment options for these patients,” said Alexander Drilon, MD, global trial lead of TRIDENT-1 and Chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, in a news release. “The FDA approval of repotrectinib adds an important tool to our toolbox, offering oncologists a next-generation TKI that can be used across a broad range of NTRK fusion-positive solid tumors for both TKI-naïve and TKI-pretreated patients.”¹

The approval is based on results from the phase 1/2 TRIDENT-1 study, which included both TKI-naïve (n=40) and TKI-pretreated (n=48) patients with NTRK-positive locally advanced or metastatic solid tumors across 15 different cancer types.¹

TKI-naïve patients had a median follow up of 17.8 months, and 58% (95% CI: 41 to 73) had a cORR. Of those, 43% experienced partial responses (PR) and 15% had complete response (CR).1 Among the TKI-naïve responding patients, 83% were still in response at 1 year and the median DOR was not yet reached.¹

TKI-pretreated patients had a median follow up of 20.1 months and a cORR of 50% (95% CI: 35 to 65). Of those, 50% experienced PR and no patients achieved CR. Furthermore, 42% of TKI-pretreated responding patients were still in response at 1 year and the mDOR was 9.9 months (95% CI: 7.4 to 13). Among patients who had measurable central nervous system (CNS) metastases at baseline, intracranial response was observed in 2 out of 2 TKI-naïve patients and in 3 out of 3 TKI-pretreated patients.¹

Repotrectinib has several warnings and precautions, including central CNS effects, interstitial lung disease and pneumonitis, hepatotoxicity, myalgia with creatine phosphokinase elevation, hyperuricemia, skeletal fractures, and embryo-fetal toxicity.¹

“Today’s FDA approval of Augtyro for patients with NTRK-positive tumors adds to its indication in ROS1-positive [non–small cell lung cancer], showing its clinical value for more people across multiple genetic markers,” said Nick Botwood, senior vice president of Medical Oncology at Bristol Myers Squibb, in a news release. “Previously, there was not an FDA approved treatment option for NTRK-positive cancers that was studied in both TKI-naïve and TKI-pretreated patients across solid tumors. This milestone helps address this area of unmet need.”¹

Repotrectinib has also shown significant efficacy in ROS1 fusion-positive non­–small cell lung cancer (NSCLC), which was also studied in the TRIDENT-1 trial. In this population, response occurred in 56 of the 71 patients (79%; 95% CI: 68 to 88) with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI. The median DOR was 34.1 months (95% CI, 25.6 to could not be estimated), and median PFS was 35.7 months (95% CI, 27.4 to could not be estimated).³

Furthermore, response occurred in 21 of the 56 patients (38%; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who had previously received 1 ROS1 TKI and had never received chemotherapy. In this population, the median DOR was 14.8 months (95% CI, 7.6 to could not be estimated), and median PFS was 9 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (59%; 95% CI, 33 to 83) with the ROS1 G2032R mutation had a response.³

“Cancer can be frightening regardless of the type, but having a rare gene fusion driving it can be especially stressful and isolating,” said Susan Spinosa, president and patient co-founder of NTRKers, a patient advocacy group, in the news release. “It’s exciting to know that there’s a new targeted therapy option for patients with NTRK-positive gene fusions, as this may offer hope to patients and their loved ones navigating this difficult journey.”¹

References

1. US Food and Drug Administration Approves Augtyro (repotrectinib), a Next-Generation Tyrosine Kinase Inhibitor (TKI), for the Treatment of Patients With NTRK-Positive Locally Advanced or Metastatic Solid Tumors. News release. Bristol Myers Squibb. June 13, 2024. Accessed June 14, 2024. https://news.bms.com/news/details/2024/U.S.-Food-and-Drug-Administration-Approves-Augtyro-repotrectinib-a-Next-Generation-Tyrosine-Kinase-Inhibitor-TKI-for-the-Treatment-of-Patients-with-NTRK-Positive-Locally-Advanced-or-Metastatic-Solid-Tumors/default.aspx

2. Manea CA, Badiu DC, Ploscaru IC, et al. A review of NTRK fusions in cancer. Ann Med Surg (Lond). 2022;79(103893). doi:10.1016/j.amsu.2022.103893

3. Drilon A, Camidge R, Lin JJ, et al. Repotrectinib in ROS1 fusion-positive non–small cell lung cancer. New Eng J Med. 2024;390:118-131. doi:10.1056/NEJMoa2302299