Sigvotatug vedotin (SV), an investigational integrin beta-6 (IB6)–directed antibody‒drug conjugate (ADC), and pembrolizumab combination therapy: Initial results from an ongoing phase 1 study (SGNB6A-001).

3010 Background: IB6, a tumor-associated membrane protein, is overexpressed in many solid tumors, including 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 a monotherapy in patients (pts) with advanced NSCLC in SGNB6A-001, an ongoing phase 1 study (Peters, ASCO 2024). Due to immunogenic cell death induction and innate immune system activation, SV activity may be enhanced when combined with pembrolizumab (P; SV+P). We report initial results of SV+P in pts with advanced solid tumors. Methods: SGNB6A-001 (NCT04389632) is an open-label, multicenter, dose-escalation and dose-expansion phase 1 study evaluating the safety, pharmacokinetics (PK), and antitumor activity of SV. Part C is evaluating safety of SV+P in pts with advanced solid tumors; part D is currently enrolling to evaluate SV+P in treatment-naive pts with locally advanced, unresectable, or metastatic NSCLC and HNSCC. Pts receive SV 1.8 mg/kg by adjusted ideal body weight IV Q2W and P 400 mg IV Q6W. Primary endpoint is safety; secondary endpoints include efficacy and PK. Results reported here are from parts C and D. Results: As of Nov 26, 2024, 31 pts received ≥1 dose of SV+P in parts C and D (19 NSCLC, 11 HNSCC, and 1 esophageal); median (95% CI) follow-up was 2.9 (1.6-5.0) months, and 26 pts remain on treatment. Median (range) age was 65 (34-80) years, 61% were male, and 52% had ECOG PS 0. Of pts with NSCLC, 12 (63%) had non-squamous tumors and 11 (58%) had tumors with PD-L1 TPS ≥1. All pts with HNSCC had tumors with PD-L1 CPS ≥1. Any-grade (Gr) and Gr ≥3 treatment-emergent adverse events (TEAEs) occurred in 87% and 35% of pts, respectively. Most common TEAEs are shown in the Table. Any-Gr and Gr ≥3 immune-mediated TEAEs occurred in 61% and 10% of pts, respectively. Pneumonitis/interstitial lung disease occurred in 3 pts (9.7%), with no Gr ≥3 events. Renal TEAEs led to discontinuation of both SV and P in 2 pts (6%); 3 other pts discontinued treatment (1 progressive disease, 2 consent withdrawal). There were no treatment-related deaths. In 7 efficacy-evaluable pts with TPS≥1 NSCLC, 1 confirmed (c) complete response (CR), 1 c partial response (PR), and 2 PRs pending confirmation were observed (ORR 57%; cORR 29%). In 8 efficacy-evaluable pts with 1L HNSCC, 2 cCR and 1 cPR were observed (cORR 37.5%). Conclusions: SV+P demonstrated manageable safety and encouraging preliminary efficacy. These data support the ongoing phase 3 Be6A-Lung-02 study (NCT06758401) comparing SV+P vs P as first-line treatment for pts with PD-L1 high (TPS≥50) advanced NSCLC. Clinical trial information: NCT04389632 . All Treated Pts (n=31) TEAEs Any Gr (>25%)n (%) Gr ≥3 n (%) Fatigue 13 (42) 1 (3) Decreased appetite 13 (42) 3 (10) Nausea 12 (39) 0 Alopecia 11 (35) 0 Asthenia 9 (29) 2 (6) Decreased weight 8 (26) 0 Dysgeusia 8 (26) 0