Fusions involving the RET gene have been identified as oncogenic drivers in multiple tumor types, including 1% to 2% of patients with non–small-cell lung cancer (NSCLC). Pralsetinib is an investigational, highly selective RET inhibitor that targets oncogenic RET alterations, including those that confer resistance to multikinase inhibitors. Following the results of the phase 1/2 ARROW study, which demonstrated the clinical activity of pralsetinib in patients with RET fusion–positive NSCLC, the phase 3 AcceleRET Lung trial will evaluate pralsetinib compared with standard of care for first-line treatment of advanced/metastatic RET fusion–positive NSCLC.
In the registration-enabling phase 1/2 ARROW study, 80 patients with RET fusion–positive NSCLC were treated with pralsetinib 400 mg once daily. Patients with prior platinum-based chemotherapy achieved an overall response rate of 61% (95% confidence interval, 50%-72%), with 2 responses pending confirmation. An overall response rate of 73% was attained in patients who had received no prior systemic treatment. Pralsetinib was found to be well-tolerated in the ARROW study. Among 354 patients in the entire safety population treated with pralsetinib 400 mg once daily, most treatment-related adverse events were grade 1 or 2.
AcceleRET Lung is an international, open-label, randomized phase 3 study designed to evaluate the efficacy and safety of pralsetinib compared with standard of care for first-line treatment of advanced/metastatic RET fusion–positive NSCLC. Investigators intend to enroll approximately 250 patients with metastatic RET fusion–positive NSCLC. Patients will be randomized 1:1 to receive oral pralsetinib 400 mg once daily or standard of care. The standard-of-care treatment for nonsquamous histology includes platinum/pemetrexed with or without pembrolizumab, followed by maintenance pemetrexed with or without pembrolizumab. For squamous histology, standard-of-care treatment is platinum/gemcitabine.
Stratification factors for the AcceleRET Lung study include use of pembrolizumab, history of brain metastases, and changes in Eastern Cooperative Oncology Group performance status. Eligibility criteria for enrollment include the presence of a RET fusion–positive tumor by local or central assessment and measurable disease based on Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), as determined by local assessment. Eligible patients must not have prior systemic treatment for metastatic disease, additional actionable oncogenic drivers, or prior selective RET inhibitor treatment. Patients who are randomized to standard of care will be permitted to cross over to receive pralsetinib upon disease progression.
The primary end point of the AcceleRET Lung study is progression-free survival, according to RECIST v1.1 criteria. Secondary end points for the study include overall response rate, overall survival, duration of response, disease control rate, clinical benefit rate, time to intracranial progression, intracranial overall response rate, safety/tolerability, and quality-of-life evaluations. The AcceleRET Lung clinical trial is currently recruiting patients, with study locations in North America, Europe, and Asia.
Source: 2020 ASCO Annual Meeting. Poster TPS9633.