Background: Preclinical evidence suggests treatment (tx) with T-DM1 plus an anti-PD1 antibody triggers antitumor immunity. We conducted a phase 1 trial to determine the safety and explore the efficacy of T-DM1 plus pembro. Methods: Eligible patients (pts) had MBC previously treated with trastuzumab (H) and taxane (T), were T-DM1-naïve, and received >1 prior line of tx for MBC or developed recurrence within 6 months (mo) of adjuvant tx. A dose de-escalation (esc) design was used with 6 pts in the dose-finding cohort, followed by an expansion (exp) cohort at the recommended phase 2 dose (RP2D), with mandatory baseline biopsies (bx). The primary endpoint was safety and tolerability. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and clinical benefit rate (CBR: complete response + partial response + stable disease >24 weeks). Associations between immune biomarkers and tx response were explored. Results: 20 pts started protocol tx (6 in dose de-esc cohort; 14 in exp cohort). Median follow-up was 23.5 mo. Pts had median age 54 yrs and median 1 line of prior MBC tx (range 0-2); 100% had received prior T, H, and pertuzumab. There were no dose-limiting toxicities in the dose de-esc cohort; thus full doses of T-DM1 (3.6 mg/kg q21 days) and pembro (200 mg q21 days) were the RP2D. 85% of pts experienced tx-related adverse events (AEs) > grade (gr) 1; 20% of pts experienced gr3 AEs. There were no gr>4 AEs. Gr3 AEs were fatigue; AST increase; ALT increase; pneumonia; pneumonitis; oral mucositis; and vomiting, each in 1 pt. 17 pts had baseline bx; 6 pts had repeat bx after 1 tx cycle. Efficacy results, overall and by PD-L1 Combined Positive Score (CPS; 22C3 staining) and tumor-infiltrating lymphocyte (TIL) status, are shown in the table. Tumors’ antigen presentation will be explored through HLA/dendritic cell marker staining and immune signatures by RNA sequencing. Conclusions: T-DM1 plus pembro was safe and tolerable. The regimen demonstrated clinical activity. Further exploration of immune-related predictive biomarkers is warranted. Clinical trial information: NCT03032107.

Values are listed as estimate (95% confidence interval)