Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 2025
Clinical Significance of MTAP Deletions and Their Overlap With Concurrent Oncogenic Driver Alterations Including EGFR in NSCLC.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Ross Jessica S, Thummalapalli Rohit, Febres-Aldana Christopher A, Muldoon Daniel, Falcon Christina, Pupo Amanda, Choudhury Noura J, Harada Guillherme, Yang Soo-Ryum, Eckert Scott, Bodd Francis M, Sauter Jennifer L, Bandlamudi Chaitanya, Berger Michael, Jeng Mark Y, Offin Michael, Drilon Alexander, Kris Mark G, Awad Mark M, Yu Helena, Riely Gregory J, Ladanyi Marc, Arbour Kathryn C
Аннотация
INTRODUCTION: Methylthioadenosine phosphorylase (MTAP) deletions (dels) occur with CDKN2A dels in a subset of NSCLCs. These deletions have been associated with inferior survival in several tumor types, and they may be targetable by PRMT5 and MAT2A inhibitors through synthetic lethality. Their co-occurrence with oncogenic drivers including EGFR is underexplored.
METHODS: We analyzed 4926 NSCLC tumors sequenced with MSK-IMPACT, a next-generation sequencing panel, and evaluated the incidence of MTAP dels with a copy number-based approach.
RESULTS: Of 4926 NSCLC tumors, 475 (10%) harbored an MTAP del. Among 258 stage IV MTAP-del NSCLC tumors, 214 (83%) also had a co-occurring oncogenic driver alteration, including 123 (48%) with EGFR mutations. Baseline MTAP del was associated with shorter time to osimertinib monotherapy discontinuation (19.0 versus 24.9 mo, hazard ratio 1.8, confidence interval 1.02-3.15, p = 0.01) but did not statistically significantly affect overall survival (38.4 versus 40.5 mo, hazard ratio 1.7, CI 0.8-3.6, p = 0.1). In patients who developed resistance to osimertinib with paired pre- and post-treatment tissue samples, acquired MTAP del was identified in nine of 69 patients (13%). A heavily pretreated patient with metastatic EGFR-mutant, MTAP-del NSCLC had a confirmed partial response to treatment with PRMT5 inhibitor monotherapy (BMS-986504).
CONCLUSIONS: MTAP dels frequently co-occur with oncogenic driver alterations and can develop at time of osimertinib resistance. A patient with oncogenic driver-positive, MTAP-del NSCLC had a partial response to PRMT5 inhibitor treatment. This work could inform future trials of PRMT5 and MAT2A inhibitors.
METHODS: We analyzed 4926 NSCLC tumors sequenced with MSK-IMPACT, a next-generation sequencing panel, and evaluated the incidence of MTAP dels with a copy number-based approach.
RESULTS: Of 4926 NSCLC tumors, 475 (10%) harbored an MTAP del. Among 258 stage IV MTAP-del NSCLC tumors, 214 (83%) also had a co-occurring oncogenic driver alteration, including 123 (48%) with EGFR mutations. Baseline MTAP del was associated with shorter time to osimertinib monotherapy discontinuation (19.0 versus 24.9 mo, hazard ratio 1.8, confidence interval 1.02-3.15, p = 0.01) but did not statistically significantly affect overall survival (38.4 versus 40.5 mo, hazard ratio 1.7, CI 0.8-3.6, p = 0.1). In patients who developed resistance to osimertinib with paired pre- and post-treatment tissue samples, acquired MTAP del was identified in nine of 69 patients (13%). A heavily pretreated patient with metastatic EGFR-mutant, MTAP-del NSCLC had a confirmed partial response to treatment with PRMT5 inhibitor monotherapy (BMS-986504).
CONCLUSIONS: MTAP dels frequently co-occur with oncogenic driver alterations and can develop at time of osimertinib resistance. A patient with oncogenic driver-positive, MTAP-del NSCLC had a partial response to PRMT5 inhibitor treatment. This work could inform future trials of PRMT5 and MAT2A inhibitors.