Second- and third-line outcomes after selective RET inhibitor failure in RET fusion-positive metastatic lung cancer: A real-world analysis from the RET-MAP registry

PURPOSE: Selective RET inhibitors (SRIs) are the first-line standard for RET fusion-positive NSCLC, but no treatment is established after progression. Real-world outcomes are needed to inform trial design and contextualize single-arm studies in this rare population. EXPERIMENTAL DESIGN: Using the international RET-MAP registry (52 centers), we evaluated second-line platinum-pemetrexed with or without immunotherapy after first-line SRI progression and characterized third-line treatments after exposure to both regimens in any order. RESULTS: Among 207 patients treated with first-line SRI, 81 (39%) discontinued because of progression; 65 (80%) received subsequent therapy, most commonly platinum-pemetrexed with or without immunotherapy (n=35, 54%). At 53 months' median follow-up, real-world objective response rate was 41% (12/29), median real-world progression-free survival (rwPFS) 6.1 months (95% CI 4.8-11.4), and median overall survival (OS) 13.7 months (95% CI 8.7-26.5). Outcomes were similar with chemotherapy alone (n=12) versus chemo-immunotherapy (n=23) for rwPFS (5.9 vs 6.8 months; HR 1.05, p=0.903) and OS (18.5 vs 13.7 months; HR 0.83, p=0.674). Three patients had rwPFS beyond 24 months with chemo-immunotherapy, all after short first-line SRI exposure. Among 32 patients receiving third-line therapy, taxane with or without antiangiogenic therapy was most common (n=11), with no responses and median rwPFS of 1.5 months (95% CI 0.8-NR). CONCLUSIONS: Second-line platinum-pemetrexed with or without immunotherapy achieved a median rwPFS of 6.1 months. Third-line outcomes were poor, highlighting the need for new treatment strategies.

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Journal
Clinical Cancer Research
Published
2026-10-14
DOI
https://doi.org/10.1158/1078-0432.ccr-26-2942
Primary Topic
Lung Cancer Treatments and Mutations
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article
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article

Second- and third-line outcomes after selective RET inhibitor failure in RET fusion-positive metastatic lung cancer: A real-world analysis from the RET-MAP registry

Clarisse Audigier-Valette, Mariana Brandão, Julia K. Rotow, Vladmir Cláudio Cordeiro de Lima et al.
Clinical Cancer Research
Lung Cancer Treatments and Mutations
article

Second- and third-line outcomes after selective RET inhibitor failure in RET fusion-positive metastatic lung cancer: A real-world analysis from the RET-MAP registry

Clarisse Audigier-Valette, Mariana Brandão, Julia K. Rotow, Vladmir Cláudio Cordeiro de Lima, Philippe Rochigneux, Noémie Simon‐Tillaux, Petros Christopoulos, Fabrizio Citarella, Benjamin Besse, Francesco Cortiula, Vinicius Ernani, David Planchard, Biagio Ricciuti, Massimiliano Cani, Patricia Iranzo, Daniela Miliziano, Frank Aboubakar Nana, Mihaela D. Aldea, Jordi Remón, Jamie Feng, Lea Ruge, Alessio Cortellini, Alexander Edward Dela Cruz Drilon, Lorenza Maria Landi, Florian Guisier, Marco Tagliamento, Barliz Waissengrin, Helena Bote, Andrea De Giglio, Arianna Marinello, Antonio Calles, Francesca Colamartini, Sophie Cousin, Annarita Avanzo, Meghanne Lomibao
article en

Abstract

PURPOSE: Selective RET inhibitors (SRIs) are the first-line standard for RET fusion-positive NSCLC, but no treatment is established after progression. Real-world outcomes are needed to inform trial design and contextualize single-arm studies in this rare population. EXPERIMENTAL DESIGN: Using the international RET-MAP registry (52 centers), we evaluated second-line platinum-pemetrexed with or without immunotherapy after first-line SRI progression and characterized third-line treatments after exposure to both regimens in any order. RESULTS: Among 207 patients treated with first-line SRI, 81 (39%) discontinued because of progression; 65 (80%) received subsequent therapy, most commonly platinum-pemetrexed with or without immunotherapy (n=35, 54%). At 53 months' median follow-up, real-world objective response rate was 41% (12/29), median real-world progression-free survival (rwPFS) 6.1 months (95% CI 4.8-11.4), and median overall survival (OS) 13.7 months (95% CI 8.7-26.5). Outcomes were similar with chemotherapy alone (n=12) versus chemo-immunotherapy (n=23) for rwPFS (5.9 vs 6.8 months; HR 1.05, p=0.903) and OS (18.5 vs 13.7 months; HR 0.83, p=0.674). Three patients had rwPFS beyond 24 months with chemo-immunotherapy, all after short first-line SRI exposure. Among 32 patients receiving third-line therapy, taxane with or without antiangiogenic therapy was most common (n=11), with no responses and median rwPFS of 1.5 months (95% CI 0.8-NR). CONCLUSIONS: Second-line platinum-pemetrexed with or without immunotherapy achieved a median rwPFS of 6.1 months. Third-line outcomes were poor, highlighting the need for new treatment strategies.

Clinical Cancer Research
TH Köln - University of Applied Sciences (DE), Hebron University (PS), Cedars-Sinai Medical Center (US), BC Cancer Agency (CA), University of Udine (IT), Cliniques Universitaires Saint-Luc (BE), Memorial Sloan Kettering Cancer Center (US), Università Campus Bio-Medico (IT), University of Cologne (DE), Heidelberg University (DE), University of Perugia (IT), Institut Jules Bordet (BE), Institut Gustave Roussy (FR), University Hospital Heidelberg (DE), Hospital General Universitario Gregorio Marañón (ES), AC Camargo Hospital (BR), IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IT), Hospital Universitario 12 De Octubre (ES), Normandie Université (FR), Dana-Farber Cancer Institute (US), Vall d'Hebron Hospital Universitari (ES), Mayo Clinic Hospital (US), Institut Bergonié (FR), Tumori Foundation (US), Institut Paoli-Calmettes (FR), Centre Hospitalier Intercommunal Toulon-La Seyne-sur-Mer (FR), University of Turin (IT), Université de Rouen Normandie (FR), University of Naples Federico II (IT), University of Genoa (IT)
Good health and well-being
Openalex Percentile: Top 13%
Lung Cancer Treatments and Mutations
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