Dalloul, Z. | bioRxiv Science

bioRxiv2026

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

BackgroundOsimertinib 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. MethodsUsing 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 (Cochrans 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. ResultsThirty-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). ConclusionsThe 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. HIGHLIGHTSO_LIL858R+T790M compound mutation may represent a distinct pharmacological TKI context. C_LIO_LIErlotinib showed a point-estimate PFS advantage over osimertinib (HR 1.29, p=0.46). C_LIO_LIOsimertinib was significantly superior in L858R-only disease (HR 0.70, p=0.003). C_LIO_LICross-cohort HR reversal in T790M-containing cohorts; interaction p=0.007. C_LIO_LIProspective validation with larger cohorts and allelic phasing data is warranted. C_LI 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

bioinformatics↗

bioRxiv2018

Locus Suicide Recombination actively occurs on the functionally rearranged IgH allele in B-cells from inflamed human lymphoid tissues

B-cell activation yields abundant cell death in parallel to clonal amplification and remodeling of immunoglobulin (Ig) genes by activation-induced deaminase (AID). AID promotes affinity maturation of Ig variable regions and class switch recombination (CSR) in mature B lymphocytes. In the IgH locus, these processes are under control by the 3 regulatory region (3RR) super-enhancer, a region demonstrated in the mouse to be both transcribed and itself targeted by AID-mediated recombination. Alternatively to CSR, IgH deletions joining S to \"like-switch\" DNA repeats that flank the 3 super-enhancer can thus accomplish so-called \"locus suicide recombination\" (LSR) in mouse B-cells. We now show that AID-mediated LSR also actively occurs in humans, and provides an activation-induced cell death pathway in multiple conditions of B-cell activation. LSR deletions either focus on the functional IgH allele or are bi-allelic, since they can only be detected when they are ongoing and their signature vanishes from fully differentiated plasma cells or from \"resting\" blood memory B-cells, but readily reappears when such memory B-cells are re-stimulated in vitro. Highly diversified breakpoints are distributed either within the upstream (3RR1) or downstream (3RR2) copies of the IgH 3 super-enhancer and all conditions activating CSR in vitro also seem to trigger LSR.\n\nAuthor SummaryClass switch recombination, initiated by the activation-induced deaminase enzyme rearranges immunoglobulin (Ig) genes in order to replace expression of IgM by IgG, IgA or IgE. A variant form of this event, locus suicide recombination (LSR), was previously reported in mouse B-lymphocytes and simply deletes all functional Ig constant genes, thus terminating B-cell function. This study first demonstrates that the structure of the human Ig heavy chain locus provides an ideal target for LSR, and is thus actively (but transiently) affected by this deletional process at the activated B-cell stage. LSR then yields recombined genes that do not support B-cell survival and which thus become undetectable among long-lived memory B-cells or plasma cells.

genetics↗