The novel integrin beta-6 (IB6)-directed antibody-drug conjugate sigvotatug vedotin has demonstrated encouraging early efficacy in non-small cell lung cancer (NSCLC), prompting its advancement to phase 3 clinical development. The agent, formerly known as SGN-B6A and now designated PF-08046047 under Pfizer's pipeline, represents a potential first-in-class integrin β6 ADC therapy.
Phase 1 Trial Results Show Promising Activity
Data from the phase 1 SGNB6A-001 trial revealed that sigvotatug vedotin achieved a confirmed overall response rate (ORR) of 19.0% (95% CI, 12.3%-27.3%) as monotherapy in NSCLC patients (n = 116). The responses included 3 complete responses and 19 partial responses. Notably, among patients with nonsquamous, taxane-naive NSCLC (n = 42), the confirmed ORR increased to 31.0% (95% CI, 17.6%-47.1%), consisting of 2 complete responses and 11 partial responses, with a median progression-free survival of 6.4 months (95% CI, 4.5-10.5).
The combination of sigvotatug vedotin with pembrolizumab showed even more promising results, with a confirmed ORR of 42.9% (95% CI, 21.8%-66.0%) for frontline treatment of NSCLC patients (n = 21), as presented at the 2025 ASCO Annual Meeting.
Mechanism of Action and Target Rationale
Sigvotatug vedotin is an ADC that specifically targets integrin αvβ6-positive tumor cells through an engineered antibody with high specificity. The agent utilizes a protease-cleavable linker to deliver the microtubule inhibitor MMAE (monomethyl auristatin E) with a drug-to-antibody ratio of four. When internalized, MMAE disrupts microtubules, inhibits cell division, and leads to tumor cell death.
Integrin β6 represents an attractive therapeutic target as it is minimally expressed in healthy adult tissues but becomes upregulated during embryogenesis, tissue repair, and carcinogenesis. According to Rachel E. Sanborn, MD, medical director of the Thoracic Oncology Program at Providence Cancer Institute, "Preclinical studies have shown that blocking IB6 can lead to a blockade of downstream signaling pathways, which can inhibit tumor migration as well as invasion."
The target is highly expressed in various solid tumors, including NSCLC, head and neck cancer, and esophageal cancer, and is associated with poor prognosis. Upregulated IB6 levels correlate with tumor progression and higher-grade, more aggressive tumors. The protein can activate the TGF-beta complex, converting it to tumor-promoting signaling pathways, and facilitates tumor invasion as well as epithelial to mesenchymal transition in cancer cells.
Safety Profile and Tolerability
In the phase 1 trial, the most common grade 3 or higher adverse events with sigvotatug vedotin included dyspnea, fatigue, and neutropenia, primarily reflecting chemotherapy toxicities from the MMAE payload. Three patients experienced pneumonitis when used in combination with pembrolizumab; however, none were grade 3 or higher in severity.
Phase 3 Development Program
Based on these encouraging results, sigvotatug vedotin has advanced directly to phase 3 trials, bypassing phase 2 development. The phase 3 Be6A Lung-01 trial is an open-label, global, randomized study enrolling patients with nonsquamous NSCLC who have received prior treatment with one line of platinum-based chemotherapy and an anti-PD-1 or anti-PD-L1 immune checkpoint inhibitor.
Patients with actionable genomic alterations are permitted to enroll, provided they have received at least one line of appropriate targeted therapy along with platinum doublet chemotherapy. Prior anti-microtubule agents like taxane chemotherapies are excluded. The study randomizes patients 1:1 to receive sigvotatug vedotin administered on days 1 and 15 of a 28-day cycle versus standard-of-care docetaxel given intravenously every 21 days. The primary endpoint is overall survival, with secondary endpoints including confirmed ORR and progression-free survival.
Future Development and Clinical Impact
The inclusion of patients with actionable genomic alterations in the phase 3 trial reflects the belief that the agent's mechanism and target are not specific to particular genomic alterations, potentially offering activity similar to or better than traditional chemotherapy agents like docetaxel.
Additionally, the Be6A Lung-02 trial is exploring sigvotatug vedotin plus pembrolizumab compared with pembrolizumab alone for first-line treatment of patients with PD-L1-high, advanced NSCLC, indicating the potential for earlier-line incorporation.
As Sanborn noted, "We have extremely limited therapeutic options in this setting for patients who have such a significant need, so any agent that demonstrates a significant benefit over docetaxel in a randomized phase 3 trial is going to be met with enthusiasm." The development of sigvotatug vedotin represents part of the broader evolution in integrin-targeted cancer therapy, moving beyond earlier small-molecule inhibitors and blocking antibodies toward next-generation approaches that directly induce tumor cell death.
