Pfizer’s Phase 3 SigVie-002 trial of sigvotatug vedotin in previously treated advanced NSCLC missed its primary overall survival endpoint, but second-line patients showed encouraging survival trends
Written By: Kirti Kumbhar, M. Pharm (QA)
Reviewed By: Pharmacally Editorial Team
Pfizer has reported topline results from the Phase 3 SigVie-002 trial (NCT06012435) evaluating sigvotatug vedotin in patients with previously treated locally advanced, unresectable, or metastatic non-squamous non-small cell lung cancer (NSCLC). While the study did not meet its primary endpoint of overall survival (OS) in the overall population, findings from key subgroups suggest the investigational ADC may still hold potential in earlier treatment settings.
The global trial enrolled 703 adults whose disease had progressed after one or more prior systemic therapies. Sigvotatug vedotin was compared directly with docetaxel, a long-established chemotherapy standard for previously treated advanced NSCLC.
Integrin Beta-6: A Novel ADC Target in Lung Cancer
Sigvotatug vedotin is an investigational antibody-drug conjugate that targets integrin beta-6 (IB6), a cell surface protein expressed in approximately 90% of NSCLC tumors. Elevated IB6 expression has been associated with poor clinical outcomes.
The ADC combines an antibody that selectively binds IB6 with a cytotoxic payload, allowing targeted delivery of chemotherapy to tumor cells. Pfizer believes the molecule’s high selectivity and rapid internalization may reduce off-target toxicity compared with less selective approaches.
Phase 3 Trial Misses Primary Endpoint
Despite the biological rationale, SigVie-002 failed to demonstrate a statistically significant improvement in overall survival compared with docetaxel across the full study population.
The open-label, randomized Phase 3 study evaluated sigvotatug vedotin administered intravenously on Days 1 and 15 of a 28-day cycle versus docetaxel administered every 21 days.
Overall survival served as the primary endpoint. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) assessed by blinded independent central review.
Pfizer reported that the safety profile remained manageable and consistent with earlier studies, with no new safety concerns identified.
Encouraging Signal in Second-Line Patients
Although the overall trial outcome was negative, a potentially important signal emerged among patients who had received only one prior line of systemic therapy. This subgroup accounted for roughly two-thirds of enrolled participants.
In these second-line patients, sigvotatug vedotin demonstrated stronger trends toward improved overall survival and progression-free survival compared with docetaxel. Investigators described the findings as clinically encouraging, although detailed efficacy data have not yet been released.
An exploratory biomarker analysis also failed to identify a clear relationship between IB6 expression levels and treatment response, suggesting that IB6 expression alone may not reliably predict benefit.
Development Continues in Earlier-Line Disease
Pfizer views the subgroup findings as support for continued development of sigvotatug vedotin, particularly in combination with immunotherapy.
According to Chief Oncology Officer Jeff Legos, the second-line efficacy trends and manageable safety profile reinforce confidence in the broader program. Independent experts also noted that docetaxel remains an active comparator in heavily pretreated NSCLC, making any observed survival advantage noteworthy.
The company is currently conducting a Phase 3 trial evaluating sigvotatug vedotin plus pembrolizumab as first-line treatment for advanced NSCLC in patients with PD-L1 tumor proportion scores of at least 50%.
Additional studies are exploring combinations with Pfizer’s investigational PD-1×VEGF bispecific antibody PF-08634404 and evaluating the ADC across other IB6-expressing solid tumors.
Detailed results from SigVie-002 are expected to be presented at a future medical meeting. While the study fell short of its primary objective, the emerging efficacy signal in second-line disease may define a more focused development path for the IB6-targeted ADC program.
Reference
About the Writer
Kirti Kumbhar (LinkedIn) is an M.Pharm graduate with experience in Quality Assurance at Lupin Limited and a strong interest in clinical research, regulatory affairs, and Trial Master File (TMF) management. She has developed knowledge of regulatory documentation, quality systems, compliance, and healthcare research through her professional experience. Passionate about clinical development and continuous learning, Kirti is committed to supporting high-quality healthcare documentation, regulatory excellence, and research-driven healthcare advancements.