Sigvotatug vedotin (SV), an investigational integrin beta-6 (IB6)─directed antibody-drug conjugate (ADC), plus pembrolizumab: Updated results from the phase 1 study (SGNB6A-001).

8522 Background: IB6 is overexpressed in many tumors, such as non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). SV, an IB6-directed ADC, demonstrated encouraging antitumor activity and manageable safety as monotherapy or in combination with pembrolizumab (SV+P) in advanced NSCLC (aNSCLC) in the ongoing phase 1 SGNB6A-001 study. We report updated results for SV+P. Methods: SGNB6A-001 (NCT04389632) is an open-label, multicenter, dose-escalation and -expansion study evaluating safety, pharmacokinetics, and antitumor activity of SV. SV+P is being evaluated in safety and expansion cohorts of treatment-naive locally advanced, unresectable, or metastatic NSCLC across PD-L1 scores and HNSCC CPS ≥1. Additional cohorts currently enrolling are not included in this analysis. We describe patients (pts) who received SV 1.8 mg/kg AiBW (adjusted ideal body weight) IV Q2W and P 400 mg IV Q6W. Primary endpoint is safety; secondary endpoints include efficacy, such as confirmed objective response rate (cORR) per RECIST v1.1 by investigator. Results: 71 pts across cohorts received ≥1 SV+P dose (37 aNSCLC, 33 HNSCC, 1 esophageal cancer). As of Sep 30, 2025, 34 pts were on treatment. Overall, any-grade (Gr) and Gr ≥3 treatment-emergent adverse events (TEAEs) occurred in 96% and 59% of pts, respectively; treatment-related any-Gr and Gr ≥3 TEAEs occurred in 85% and 44% of pts, respectively. Most common TEAEs ( > 30%) were alopecia, decreased appetite, fatigue, and nausea. In the expansion cohort, 35 pts with aNSCLC were treated, with median follow-up of 10.6 mo (95% CI, 7.6-11.9). In the efficacy-evaluable pts, cORR was 50% in both the PD-L1 TPS < 1% (n = 10) and ≥1% (n = 18) subgroups, with 1 additional partial response (PR) pending confirmation in the PD-L1 TPS ≥1% subgroup (Table). In 5 pts with PD-L1 TPS ≥50%, cORR was 80%, with 1 additional PR pending confirmation. Regardless of TPS, cORR was numerically higher in pts with nonsquamous (n = 19 [53%]) vs squamous (n = 9 [44%]) histology. Conclusions: SV+P continued to show manageable safety and encouraging antitumor activity in treatment-naive NSCLC across PD-L1 TPS and histologies. This supports the ongoing phase 3 SigVie-003 study (NCT06758401) of SV+P vs P for treatment-naive aNSCLC with PD-L1 TPS ≥50% as well as further investigation in the enrolling phase 1 cohorts and future studies. Clinical trial information: NCT04389632 . PD-L1 TPS <1% (n=10) PD-L1 TPS ≥1% (n=18) NSQ(n=19) SQ(n=9) cORR (95% CI), % 50(19 - 81) 50(26 - 74) 53(29 - 76) 44(14 - 79) BOR, % CR 0 6 5 0 PR 50 44 47 44 SD 40 44 42 44 NE/no assessment 10 6 5 11 ORR (95% CI), % 50(19 - 81) 61(36 - 83) 63(38 - 84) 44(14 - 79) DCR (95% CI), % 90(56 - 100) 94(73 - 100) 95(74 - 100) 89(52 - 100) mDOR (95% CI), mo <jats:td colspan="