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Introduction: Pralsetinib is a RET inhibitor found to have antitumor activity in advanced, metastatic, RET fusion-positive NSCLC. Objective: To assess real-world efficacy of pralsetinib and treatment sequences in patients with RET fusion-positive NSCLC. Design: Retrospective study of consecutive patients enrolled in the French expanded-access program for pralsetinib from December 1, 2019, to December 31, 2021. Participants: A total of 41 patients with advanced, refractory, RET fusion-positive NSCLC were included. Pralsetinib was administered at a daily dose of 400 mg based on safety and pharmacokinetic outcomes from previous phase 1/2 study. Results: Pralsetinib was administered as second line in 23 patients (56%) and as third line and beyond in 15 patients (37%). After a median follow-up of 26.3 months, pralsetinib was ongoing in 13 patients. Median real-world progression-free survival was 11.8 (95% confidence interval [CI]: 9.3–15.5) months. Objective response rate was 68% (95% CI: 50%–82%), and disease control rate was 89% (95% CI: 75%–97%). Subsequent line of systemic therapy was initiated in 11 patients. Median overall survival from pralsetinib initiation was 23.8 (95% CI: 16.5–not reached) months. Conclusion: In this extensive real-world cohort of patients with advanced or metastatic NSCLC harboring RET fusions, we highlight the antitumor efficacy of pralsetinib, particularly when administered in later treatment lines. We also observe the aggressive nature of disease progression, frequent utilization of chemotherapy and antiangiogenic agents as initial subsequent therapies, and limited insight into resistance mechanisms due to infrequent rebiopsy and genomic profiling at progression.

Introduction: RET rearrangements occur in 1% to 2% NSCLCs. Since no clinically validated RET antibody is currently available, fluorescence in situ hybridization (FISH) is often used as a screening tool to identify patients likely to benefit from RET-targeted therapy. In this study, we performed a comprehensive review of publications in which RET-rearrangement testing was performed by FISH and compared the methods and results with our data. Methods: The findings of an electronic search for publications using RET-FISH in lung cancer were compared with the results obtained at the Grenoble University Hospital where 784 EGFR-, KRAS-, ALK-, and ROS1-negative NSCLCs were tested by RET break-apart FISH and confirmed by RNA-sequencing (RNA-seq). Results: Out of the 85 publications using RET-FISH analysis, 52 pertained to patients with lung cancer. The most often used positivity threshold was 15%. Six publications compared RET-FISH with at least one other molecular technique on at least eight samples, and the concordance was variable, from 5.9% to 66.7% for FISH-positive cases. Regarding our data, out of the 784 analyzed samples, 32 (4%) were positive by RET-FISH. The concordance between RET-FISH and RNA-seq in RET-FISH positive samples was 69%. Conclusions: Overall, both existing literature and our data suggest that RET-FISH testing can be used for rapid screening of RET rearrangements in NSCLC. Nevertheless, using an orthogonal technique such as RNA-seq to confirm RET-FISH-positive cases is essential for ensuring that only patients likely to benefit from RET-target therapy receive the treatment.