Real-world progression-free survival with erlotinib versus osimertinib in EGFR L858R + T790M compound mutation non-small cell lung Cancer: An exploratory analysis of the MSK-CHORD dataset.

Authors

Zeinab Dalloul, Ahmad Abboud, Iman Dalloul, Mahmoud Abdelsalam

Published in

Lung cancer (Amsterdam, Netherlands). Volume 221. Pages 109637. Sep 27, 2026. Epub Sep 27, 2026.

Abstract

Osimertinib is the standard first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC) harboring common activating mutations, including exon 19 deletions and L858R. It is also active against tumors with acquired T790M resistance. However, the EGFR L858R + T790M compound mutation - where both variants co-occur within the same tumor - may confer distinct drug-sensitivity profiles not predicted by either mutation alone. Limited data exist on comparative treatment outcomes in this rare genotype.
Using the MSK-CHORD clinicogenomic dataset (n = 24,950), we identified patients with concurrent EGFR L858R and T790M mutations receiving erlotinib (Erlo) or osimertinib (Osi) monotherapy. Real-world progression-free survival (rwPFS) per treatment line was calculated using a strict definition requiring confirmed radiological progression events (rwPFS-strict), excluding lines with null endpoint data. Kaplan-Meier analysis, log-rank testing, Cox proportional hazards regression, and cross-cohort heterogeneity testing (Cochran's Q statistic) were performed. Two control cohorts - L858R-only (n = 372) and T790M-only (n = 76) - were analyzed in parallel to assess mutation-context specificity of treatment response.
Thirty-one patients with EGFR L858R + T790M were identified; 21 contributed evaluable monotherapy lines, yielding 23 Erlo and 15 Osi treatment lines (14 unique patients per treatment group, 7 contributing to both). Median rwPFS numerically favored Erlo over Osi (7.10 vs 5.32 months; HR 1.29, 95% CI 0.66-2.52; log-rank p = 0.46). This directional trend was reversed in the L858R-only control cohort, where Osi demonstrated significant superiority (9.03 vs 5.75 months; HR 0.70, 95% CI 0.55-0.89; p = 0.003). The T790M-only cohort showed no significant difference (HR 1.32, p = 0.12). An exploratory post-hoc heterogeneity test confirmed a significant cross-cohort interaction (Q = 9.94, df = 2, p = 0.007).
The expected osimertinib advantage was absent in L858R + T790M compound-mutant NSCLC. The opposing hazard ratio directions across mutation contexts (HR 1.29 vs 0.70), with a significant exploratory cross-cohort interaction (p = 0.007), suggest that the EGFR L858R + T790M compound mutation may represent a pharmacologically distinct entity with differential TKI sensitivity. These hypothesis-generating findings warrant prospective validation.
#EGFR L858R + T790M compound mutation: erlotinib trend over osimertinib (HR 1.29 vs 0.70 in L858R-only), interaction p = 0.007. #LungCancer.

PMID:
42804885
Bibliographic data and abstract were imported from PubMed on 29 Sep 2026.

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