Pfizer (NYSE: PFE) reported that sigvotatug vedotin, an integrin beta-6 (IB6)-directed antibody-drug conjugate (ADC), failed to demonstrate a statistically significant improvement in overall survival versus docetaxel in the SigVie-002 Phase III trial in previously treated non-squamous non-small cell lung cancer (NSCLC). The miss on the primary endpoint complicates the molecule's near-term development path in the second-line setting with Pfizer set to prioritize salvaging the program through earlier-line combination strategies.
The open-label, randomized study enrolled 703 participants with locally advanced, unresectable or metastatic non-squamous NSCLC who had received at least one prior line of systemic therapy. Most had been previously exposed to both platinum-based chemotherapy and immunotherapy, a heavily pre-treated population in which docetaxel historically delivers modest but meaningful benefit. The trial did not disclose specific hazard ratios or median survival figures in the topline release; detailed results are to be presented at a future medical congress.
A subgroup signal, but not a primary win
Pfizer highlighted that in patients who had received only one prior line of therapy — approximately two-thirds of the enrolled population — a "stronger trend" favoring sigvotatug vedotin was observed for both overall survival and progression-free survival. The company also reported a manageable safety profile consistent with prior studies. However, no statistically significant benefit was demonstrated in the overall population, and an exploratory analysis found no clear IB6 expression-response relationship, undermining the hypothesis that biomarker selection could enrich for responders. Given that IB6 is expressed on approximately 90% of NSCLC tumors, the absence of a predictive biomarker also limits the ability to identify a more responsive subgroup.
Cross-trial comparisons are inherently limited, but the result stands in contrast to the competitive ADC landscape in lung cancer, where Daiichi Sankyo and AstraZeneca's Enhertu (trastuzumab deruxtecan) has demonstrated substantial survival benefit in HER2-mutant NSCLC, and where Pfizer's own fetrastobart vedotin, a PD-L1-directed ADC, is currently in Phase III development in NSCLC. The second-line unselected NSCLC population remains one of the most difficult settings to improve upon docetaxel, which continues to perform competitively as a comparator — a point acknowledged by the trial's external investigators.