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In second-line NSCLC, every ADC survival win has been biomarker-selected
Every antibody-drug conjugate (ADC) that has beaten docetaxel on survival in second-line non-small cell lung cancer (NSCLC) did it in a biomarker-selected group, and the all-comer bets keep failing. Pfizer’s sigvotatug vedotin became the third all-comer miss in Sleuth’s analysis in June 2026, after datopotamab deruxtecan and sacituzumab govitecan.
That makes the miss a setting problem more than a Pfizer problem, and not a sign of the Seagen platform breaking. The one ADC to beat docetaxel on survival, sacituzumab tirumotecan, did it in EGFR-mutant disease, in China.
Three all-comer trials against docetaxel missed overall survival
All three all-comer ADC trials against docetaxel in Sleuth’s analysis missed overall survival: sigvotatug vedotin (integrin beta-6) in SigVie-002, datopotamab deruxtecan (TROP2) in TROPION-Lung01, where overall survival was a co-primary endpoint, and sacituzumab govitecan (TROP2) in EVOKE-01, with a p-value of 0.0534. The three use different payloads, and two of them are TROP2-directed.
SigVie-002 enrolled 703 patients with non-squamous disease. Pfizer said second-line patients, about two-thirds of the trial, showed a stronger trend toward better overall and progression-free survival, and exploratory analyses found no clear link between integrin beta-6 expression and response.
Changing the target and the payload has not changed the result, which leaves the unselected population as the common factor.
Biomarker-selected results are mixed, but they hold every win
Sacituzumab tirumotecan beat docetaxel on overall survival, a secondary endpoint, in EGFR-mutant NSCLC in the OptiTROP-Lung03 trial and is approved in China. The same drug also improved overall survival over platinum chemotherapy in EGFR-mutant disease after TKI therapy in the Phase 3 OptiTROP-Lung04 trial, published in October 2025.
Selection alone is not enough. Patritumab deruxtecan (HER3) missed overall survival against platinum chemotherapy in EGFR-mutant disease in HERTHENA-Lung02, and its US application was withdrawn in May 2025. Tusamitamab ravtansine (CEACAM5) was discontinued after a progression-free survival miss in CEACAM5-high patients in CARMEN-LC03.
Three ADCs hold US accelerated approvals in pretreated NSCLC based on response rate, not survival: Enhertu (trastuzumab deruxtecan) in HER2-mutant disease, Emrelis (telisotuzumab vedotin) in c-Met-high disease and Datroway (datopotamab deruxtecan) in EGFR-mutant disease.
So far every second-line ADC win has needed a biomarker, but a biomarker has not been enough, and most biomarker-selected approvals still rest on response rate rather than survival. Sleuth’s ADC Intelligence Report, Q3 2026 puts this pattern in the context of how ADCs move from later lines toward first-line use.
Trial outcomes are as of June 2026, from Sleuth’s analysis of pivotal and registrational ADC readouts in previously treated NSCLC. The SigVie-002 details come from Pfizer’s June 2026 topline report, and the OptiTROP-Lung04 result from its October 2025 publication.
Frequently asked questions about ADCs in second-line NSCLC
Has any ADC improved overall survival in second-line NSCLC?
As of June 2026, only in EGFR-mutant disease. Sacituzumab tirumotecan beat docetaxel on overall survival in China’s OptiTROP-Lung03 trial and beat platinum chemotherapy in OptiTROP-Lung04. No ADC had beaten docetaxel on overall survival in an unselected second-line population.
Which ADCs missed overall survival in all-comer second-line NSCLC?
Sigvotatug vedotin (SigVie-002, June 2026), datopotamab deruxtecan (TROPION-Lung01) and sacituzumab govitecan (EVOKE-01) all missed overall survival against docetaxel in previously treated NSCLC.
Which ADCs are approved in previously treated NSCLC?
In the US, Enhertu (HER2-mutant), Emrelis (c-Met-high) and Datroway (EGFR-mutant) hold accelerated approvals based on response rate, not survival, as of June 2026. Sacituzumab tirumotecan is approved in China in EGFR-mutant disease.
What did the sigvotatug vedotin Phase 3 trial show?
In June 2026, Pfizer reported that sigvotatug vedotin did not significantly improve overall survival over docetaxel in 703 patients with previously treated non-squamous NSCLC in SigVie-002. Second-line patients showed a stronger trend, and integrin beta-6 expression did not clearly predict response.
