Mixed Phase 3 Results for IB6-Targeting ADC Raise Questions on Optimal Use in NSCLC

Topline findings from a phase 3 trial showed mixed results for an investigational antibody-drug conjugate (ADC) targeting integrin beta-6 (IB6) in previously treated nonsquamous non–small cell lung cancer (NSCLC), Pfizer announced yesterday.¹

Specifically, the SigVie-002 trial (NCT06012435) showed sigvotatug vedotin did not produce a statistically significant improvement in overall survival (OS) compared with docetaxel in the overall study population of 703 adults with locally advanced, unresectable, or metastatic nonsquamous NSCLC who had received at least 1 prior line of systemic therapy.² However, a subgroup of second-line patients showed a strong survival signal.¹

IB6-Targeting ADC Shows Mixed Phase 3 Results

IB6 is a novel target in this space, according to Pfizer. It is expressed in about 90% of NSCLC tumors and has been associated with poor prognosis. Sigvotatug vedotin was designed as a highly selective IB6-directed ADC with rapid internalization, intended to limit binding to other integrins in normal tissue and reduce off-target toxicity.

In the SigVie-002 trial, eligible patients were randomized to receive sigvotatug vedotin administered intravenously on days 1 and 15 of each 28-day cycle or docetaxel administered intravenously on day 1 of each 21-day cycle. The primary end point was OS, with secondary end points including progression-free survival (PFS), confirmed objective response rate, and duration of response.

Across the full study population, sigvotatug vedotin demonstrated a manageable safety profile consistent with earlier studies of the agent. Still, the trial did not demonstrate an OS advantage over docetaxel. In an exploratory analysis, no clear relationship emerged between IB6 expression levels and treatment response.

A more encouraging signal emerged in patients who had received only 1 prior line of systemic therapy, representing roughly two-thirds of the study population. In this second-line subgroup, sigvotatug vedotin showed a stronger trend toward improvement in both OS and PFS compared with docetaxel.

“Although the overall study results did not demonstrate superiority over docetaxel, it is encouraging that second-line patients treated with sigvotatug vedotin achieved strong efficacy outcomes compared to an established standard of care, alongside a manageable safety profile,” Jeff Legos, chief oncology officer at Pfizer, said in a news release. “This observed clinical benefit, along with our phase 1 combination data in the first-line setting, reinforces our confidence in the potential of the sigvotatug vedotin program, including an ongoing phase 3 trial in combination with pembrolizumab in first-line advanced NSCLC.”

Detailed findings are expected to be submitted for presentation at a future medical congress.

Next Steps in the Sigvotatug Vedotin Program

The overall negative result, paired with a positive second-line subgroup trend, raises questions about the optimal positioning of sigovotatug vedotin, meaning whether its future role lies in combination regimens and earlier treatment lines rather than as a docetaxel replacement in heavily pretreated patients.

As Legos noted, Pfizer is continuing to evaluate sigvotatug vedotin in several settings, including a phase 3 trial combining it with pembrolizumab in first-line NSCLC with high PD-L1 expression. Other efforts include early exploration of combinations with PF-08634404, Pfizer's investigational PD-1xVEGF bispecific antibody.

“The ability of sigvotatug vedotin to induce immunogenic cell death provides a strong rationale for combination approaches with immunotherapy, particularly in earlier treatment settings where immune competence is better preserved,” Solange Peters, MD, PhD, chair of medical oncology and thoracic cancers clinic at Lausanne University Hospital in Switzerland, said in the news release. “In this context, the promising phase 1 efficacy signals observed in treatment-naïve patients with high PD-L1 expression warrant further evaluation and may represent a more effective clinical application of this strategy.”

References

1. Pfizer announces topline phase 3 results for sigvotatug vedotin in previously treated metastatic non-squamous non-small cell lung cancer. News release. Pfizer Inc. June 22, 2026. Accessed June 23, 2026. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-topline-phase-3-results-sigvotatug-vedotin
2. A study of SGN-B6A versus docetaxel in previously treated non-small cell lung cancer. ClinicalTrials.gov. Last updated May 27, 2026. Accessed June 23, 2026. https://clinicaltrials.gov/study/NCT06012435