Repotrectinib Approved for Use in NTRK-Positive Solid Tumors

On June 13, the FDA announced the accelerated approval of repotrectinib (Augtyro) for use in patients 12 years and older who have solid tumors with neurotrophic tyrosine receptor kinase (NTRK) gene fusion, are metastatic or locally advanced or would cause severe morbidity if resection is attempted, and with no alternative methods of treatment.

NTRK gene fusions are an alteration of the piece of chromosome that contains the NTRK gene when it breaks off and joins genes of other chromosomes. These fusions could cause cancer cells to grow due to the development of abnormal proteins. Patients with solid tumors rarely have NTRK gene fusions but TRK inhibitor therapy can be chosen as a method of treatment through testing.

FDA Approved

Repotrecetinib, developed by Bristol Myers Squibb, received the approval for the treatment of NTRK gene fusion solid tumors due to the results of phase 1 and 2 trials that are still ongoing due to duration and rate of response. The TRIDENT-1 trial is a global, multicenter, single-arm, open-label phase 1 and 2 clinical trial to assess the efficacy and safety of repotrectinib. The study includes patients who have never received tyrosine kinase inhibitors (TKIs) and those who have been treated with TKIs in the past. Patients who had symptomatic brain metastases were among those excluded from the trial. The 88 patients included had a total of 15 different types of cancers between them, all NTRK-positive locally advanced/metastatic solid tumors.

The confirmed objective response rate (cORR) in patients who were naïve to TKIs was 58% (95% CI, 41%-73%) with 43% having a partial response (PR) and 15% having a complete response (CR) during a median follow-up of 17.8 months. A total of 83% of the patients who had a response to the treatment continued to have a response at a 1-year follow-up. Patients who had previously been treated with TKIs had a cORR of 50% (95% CI, 35%-65%), with all patients having a PR after a median follow-up of 20.1 months. A total of 42% of the patients who had a response still had a response after a 1-year follow-up. The median duration of response was 9.9 months in this group (95% CI, 7.4-13.0).

The TRIDENT-1 trial also found that progression-free survival (PFS) was 64% (95% CI, 43%-86%) in patients who had never used TKIs before. Patients who had used TKIs prior had a PFS of 23% (95% CI, 0%-49%).¹

“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,” Alexander Drilon, MD, chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, said in a press release.²

There were adverse effects reported by patients who took repotrectinib. A total of 35% of patients had serious adverse reactions, which included pneumonia, dyspnea, pleural effusion, and hypoxia. Fatal adverse effects occurred in 3.5% of the patients who received the medication. The most common adverse effects were dizziness (65%), dysgeusia (54%), peripheral neuropathy (49%), constipation (38%), dyspnea (30%), fatigue (30%), ataxia (28%), cognitive impairment (25%), muscular weakness (20%), and nausea (20%), with 2.8% of patients experiencing grade 3 dizziness.

“Cancer can be frightening regardless of the type, but having a rare gene fusion driving it can be especially stressful and isolating,” Susan Spinosa, president and patient cofounder of NTRKers, a patient advocacy group, said in a press release.² “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.”

Reference

1. Solomon BJ, Drillon A, Lin JJ, et al. 1372P Repotrectinib in patients (pts) with NTRK fusion-positive (NTRK+) advanced solid tumors, including NSCLC: update from the phase I/II TRIDENT-1 trial. Ann Oncolog. 2023;34(Suppl 2):S787-S788. doi:10.1016/j.annonc.2023.09.2405

2. 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. News release. Bristol Myers Squibb; June 13, 2024. Accessed June 14, 2024. https://www.businesswire.com/news/home/20240604316506/en/U.S.-Food-and-Drug-Administration-Approves-Augtyro%E2%84%A2-repotrectinib-a-Next-Generation-Tyrosine-Kinase-Inhibitor-TKI-for-the-Treatment-of-Patients-with-NTRK-Positive-Locally-Advanced-or-Metastatic-Solid-Tumors