Selpercatinib was approved on May 8, 2020 as the first therapy specifically indicated for the treatment of adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), and the treatment of adult and pediatric patients aged 12 years and older with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy, or advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).
The efficacy this agent was evaluated in an open-label phase I/II LIBRETTO-001 trial. This agent was approved under the FDA's Accelerated Approval regulations based on the LIBRETTO-001 Phase l/ll trial's endpoints of overall response rate and duration of response. The manufacturer indicates that continued approval for these indications may be dependent upon confirmation and description of clinical benefit in confirmatory trials. The NEJM published separate articles focusing on efficacy and safety data in the RET fusion-positive NSCLC and RET-altered thyroid patient cohorts independently, with data demonstrating durable objective responses across both patient populations.
In the recently published study in The New England Journal of Medicine, Drilon et al enrolled patients with advanced RET fusion–positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase l/ll trial of selpercatinib. The primary endpoint was an objective response (a complete or partial response) as established by an independent review committee. Secondary endpoints included the duration of response, progression-free survival, and safety.
In the study, results indicated that in the first 105 consecutively enrolled patients with RET fusion–positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54-73). The average duration of response was 17.5 months (95% CI, 12.0-[could not be assessed]), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70-94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59-100).
The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event.
The authors concluded that selpercatinib has considerable antitumor activity in patients with RET fusion–positive NSCLC. Antitumor activity was noticed regardless of previous exposure to anti–PD-1 or anti–PD-L1 therapy or multikinase inhibitors. The authors emphasized that implementation of molecular-screening strategies that include detection of RET fusions will be crucial for detecting patients with NSCLC who may benefit from the treatment with selpercatinib. In the press release, the manufacturer indicated that the randomized phase lll trial LIBRETTO-431, which will explore the use of selpercatinib in patients with advanced or metastatic RET fusion positive NSCLC is currently enrolling patients.
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