As reported in The Lancet Oncology by Justin F. Gainor, MD, and colleagues, an interim analysis of the phase I/II ARROW trial has shown that the oral RET inhibitor pralsetinib produced high response rates in previously treated and treatment-naive patients with advanced RET fusion–positive non–small cell lung cancer (NSCLC).

The study supported the September 2020 accelerated approval of pralsetinib for the treatment of adult patients with metastatic RET fusion–positive NSCLC as detected by an FDA-approved test on the basis of overall response rate and duration of response.

Justin F. Gainor, MD

Study Details

The study enrolled 233 patients with locally advanced or metastatic disease from sites in 13 countries between March 2017 and May 2020 (data cutoff). Of these, 87 patients who had received previous platinum-based chemotherapy and 29 treatment-naive patients treated with pralsetinib before July 2019 (efficacy enrollment cutoff) had centrally adjudicated baseline measurable disease and constituted the efficacy evaluable population.

Patients received pralsetinib at 400 mg once daily, with treatment continuing until disease progression or intolerance. The primary efficacy endpoint was overall response rate on Response Evaluation Criteria in Solid Tumors version 1.1 according to blinded independent central review.

Responses

Among the 87 previously treated patients, objective response was observed in 53 (61%, 95% confidence interval [CI] = 50%–71%), including complete response in 5 (6%). Responses were observed irrespective of RET fusion partner, previous multikinase inhibitor treatment, and previous PD-1 or PD-L1 inhibitor treatment.

At a median follow-up from first response of 12.9 months, median duration of response was not reached (95% CI = 15.2 months–not estimable), with 83% of responses maintained at 6 months and 74% maintained at 12 months. Median progression-free survival was 17.1 months at a median follow-up of 14.7 months. Median overall survival was not reached at a median follow-up of 17.1 months.  

Among the 27 treatment-naive patients, objective response was observed in 19 (70%, 95% CI = 50%–86%), with complete response in 3 (11%). Responses were observed irrespective of RET fusion partner. Median duration of response was 9.0 months (95% CI = 6.3 months–not estimable) at a median follow-up of 10.2 months. Median progression-free survival was 9.1 months at a median follow-up of 11.6 months. Median overall survival was not reached at a median follow-up of 13.6 months.

Adverse Events

Among all 233 patients with RET fusion–positive NSCLC who received pralsetinib in the study, treatment-related grade ≥ 3 adverse events occurred in 48%, with the most common being neutropenia (18%), hypertension (11%), and anemia (10%). Serious treatment-related adverse events occurred in 24%, with the most common being pneumonia (4%), pneumonitis (4%), anemia (2%), and neutropenia (2%). Treatment-related adverse events led to discontinuation of treatment in 6%. Adverse events led to death in 6% of patients, with none considered related to treatment.

The investigators concluded: “Pralsetinib is a new, well tolerated, promising, once-daily oral treatment option for patients with RET fusion–positive NSCLC.”

Dr. Gainor, of Massachusetts General Hospital, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Blueprint Medicines. For full disclosures of the study authors, visit thelancet.com.