Background: The receptor ITGB6 plays a role in tumor pathogenesis and invasiveness, and its overexpression is correlated with poor outcomes. Non-small cell lung cancer (NSCLC), head and neck (HNSCC), and esophageal cancer (EC) are among tumors with high ITGB6 expression (Lyon 2021). SGN-B6A is an ITGB6-directed vedotin ADC with a monomethyl auristatin E (MMAE) payload. SGN-B6A elicits antitumor activity via MMAE-mediated cytotoxicity, bystander effect, and immunogenic cell death. Here, we present updated results of an ongoing phase 1 study with a focus on NSCLC, HNSCC, and EC (Hollebecque SITC 2022). Methods: SGNB6A-001 (NCT04389632) is an open-label, multicenter, dose-escalation/expansion study evaluating the safety, pharmacokinetics, and antitumor activity of SGN-B6A (per RECIST v1.1) in patients (pts) with advanced solid tumors. Dose escalation (Part A) explored continuous weekly and intermittent dosing regimens. Dose was calculated using total body weight (TBW) or adjusted ideal body weight. Dose expansion (Part B) is enrolling pts with NSCLC, HNSCC, and EC. Results: As of 14 December 2022, 148 pts received SGN-B6A, 88 pts in Part A and 60 pts in Part B; enrollment for Part A is complete. In all cohorts (N=148), treatment-emergent adverse events (TEAEs) were observed in 88.5% of pts: 50.7% were Grade ≥ 3 (21.6% related), and 37.2% were serious (8.1% related); 6.1% of pts discontinued treatment due to TEAEs. 3 pts (2.0%) died due to TEAEs; none of the deaths were considered treatment-related. The most common TEAE was fatigue (35.1%); the most common Grade ≥ 3 TEAE was neutropenia (8.1%); the most common TEAEs leading to treatment discontinuation were peripheral sensory neuropathy and pneumonia (1.4% each). Prior lines of therapy and efficacy data for Part A (NSCLC, EC, and HNSCC) and Part B (HNSCC) subsets are summarized. Conclusions: SGN-B6A demonstrated a manageable safety profile, and showed encouraging preliminary antitumor activity and response durability in dose escalation in a heavily pretreated population. Part B dose expansion cohorts in NSCLC, esophageal squamous cell carcinoma (ESCC), and HNSCC are ongoing. Clinical trial information: NCT04389632.

^a Best overall response per RECIST v1.1. CR or PR was confirmed with repeat scan ≥28 days after initial response. + Censored. - Not estimable.