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

ABSTRACT Background 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. Methods 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. Results 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). Conclusions 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. HIGHLIGHTS L858R+T790M compound mutation may represent a distinct pharmacological TKI context. Erlotinib showed a point-estimate PFS advantage over osimertinib (HR 1.29, p=0.46). Osimertinib was significantly superior in L858R-only disease (HR 0.70, p=0.003). Cross-cohort HR reversal in T790M-containing cohorts; interaction p=0.007. Prospective validation with larger cohorts and allelic phasing data is warranted. TWEETABLE ABSTRACT #EGFR L858R+T790M compound mutation: erlotinib trend over osimertinib (HR 1.29 vs 0.70 in L858R-only), interaction p=0.007. #LungCancer