Association of Biomarker‐Matched Therapy With Survival in Non‐Small Cell Lung Cancer by Surgical Status and Sequencing Specimen Source: A Cohort Study From MSK ‐ CHORD

Real-world analyses of biomarker-matched therapy (BMT) are complicated when sequencing, surgery, and treatment occur at different times. We evaluated associations between BMT and overall survival (OS) by surgical status at sequencing and specimen source and examined treatment timing. Among 6624 patients with non-small cell lung cancer in MSK-CHORD, 5467 with an operational opportunity for BMT formed the propensity-weighted cohort. OS was measured from first sequencing; surgical status reflected surgery completed by that date. Fixed-exposure analyses used stabilized inverse probability of treatment weights. The overall HR was 1.10 (95% CI 1.01-1.20). HRs were 1.40 (1.23-1.59) with surgery completed by sequencing and 0.83 (0.74-0.93) without surgery, and 1.30 (1.15-1.47) for primary-tumor specimens and 0.80 (0.71-0.91) for metastatic-site specimens; interaction tests were significant (all p < 0.001). Time-dependent HRs were 2.06 (1.76-2.42) and 1.12 (0.99-1.26) by surgical status, and 1.76 (1.52-2.03) and 1.14 (1.01-1.30) by specimen source. Landmark analyses did not retain the lower fixed-exposure estimates in the no-surgery and metastatic-specimen strata. In a 685-patient non-MSK metastatic cohort, HRs were 0.88 (0.63-1.25) for primary-tumor sequencing and 0.64 (0.48-0.84) for metastatic-site sequencing. BMT-OS associations were sensitive to clinical context and treatment timing, underscoring temporal alignment of sequencing, surgery, treatment initiation, and follow-up.