Pfizer reports topline Phase 3 findings for sigvotatug vedotin in previously treated metastatic non-squamous non-small cell lung cancer

Pfizer has recently released topline findings from the Phase 3 SigVie-002 study, formerly known as Be6A Lung-01, assessing sigvotatug vedotin, an investigational potential first-in-class integrin beta-6 directed antibody-drug conjugate. The trial recruited adults with locally advanced, unresectable, or metastatic non-squamous non-small cell lung cancer who had already been through one or more prior lines of therapy.

Across the overall study population, sigvotatug vedotin fell short of demonstrating a statistically significant improvement in the primary endpoint of overall survival when placed alongside docetaxel. The safety profile was manageable and in keeping with what earlier studies had shown. A more compelling picture emerged in the subgroup of patients who had received just one prior systemic therapy, representing around two thirds of those enrolled, where a stronger trend toward improved overall survival and progression-free survival was observed with sigvotatug vedotin over docetaxel. An exploratory analysis found no clear relationship between integrin beta-6 expression levels and treatment response. Full results from SigVie-002 will be prepared for submission to a future medical congress.

“Patients with previously treated advanced NSCLC are a historically difficult-to-treat population, and there is clearly more work to be done to improve the outcomes for this population,” said Jeff Legos, Chief Oncology Officer, Pfizer. “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. 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.”

“It is important not to underestimate the activity of docetaxel as a comparator in this setting. Patients enrolled in this trial were heavily pre-treated, with most having previously received both platinum-based chemotherapy and immunotherapy, yet docetaxel continues to provide meaningful clinical benefit. Although the study did not meet its overall survival endpoint, in second-line patients the data suggest a clinically meaningful survival benefit for sigvotatug vedotin over docetaxel, supporting continued scientific evaluation of sigvotatug vedotin in earlier lines in combination with immunotherapy,” said Solange Peters, M.D., PhD, Chair of Medical Oncology and Thoracic Cancers Clinic, Lausanne University Hospital, Switzerland. “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. 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.”

Within non-small cell lung cancer, integrin beta-6 is present on approximately nine in ten tumours and its expression is associated with a poorer prognosis. Sigvotatug vedotin has been engineered as a novel antibody-drug conjugate built around precise targeting of integrin beta-6 and rapid internalisation, a design intended to minimise binding to other integrins more commonly found in healthy tissues, thereby reducing the likelihood of off-target toxicity.

Pfizer continues to assess sigvotatug vedotin through several active studies spanning multiple stages of disease and patient groups in non-small cell lung cancer and other solid tumours. Among these is an ongoing Phase 3 study pairing sigvotatug vedotin with pembrolizumab in first-line non-small cell lung cancer patients with a PD-L1 tumour proportion score of 50% or above. The compound is also being explored in novel combinations, including alongside PF-4404, a bispecific antibody directed at both PD-1 and VEGF, in early-stage lung cancers and other tumours where integrin beta-6 is expressed.

Since bringing Seagen into its portfolio, Pfizer has pressed ahead with a wide-ranging antibody-drug conjugate pipeline spanning both approved therapies and candidates in development. Progress is being made across several differentiated antibody-drug conjugate programmes, among them fetrastobart vedotin, a PD-L1 directed candidate currently in Phase 3 for non-small cell lung cancer, additional integrin beta-6 targeted conjugates carrying alternative payloads, and earlier-stage work exploring new targets and payloads including topoisomerase I inhibitors and novel auristatin-based approaches. Taken together, this breadth of activity reinforces the depth of Pfizer’s oncology pipeline and its ambition of delivering eight potential oncology breakthroughs by 2030.

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Related Topics and Keywords

lung cancer, metastatic non-squamous non-small cell lung cancer, Pfizer, sigvotatug vedotin