1029TiP Phase II trial of pembrolizumab (pembro) and brentuximab vedotin (BV) in patients with metastatic solid malignancies after progression on prior programmed cell death protein (PD)-1 inhibitors (SGN35-033)

Intratumoral regulatory T-cells (Tregs) contribute to resistance to checkpoint inhibitors through various mechanisms (Saleh 2019). Intratumoral Tregs have a unique phenotype expressing higher levels of CD30 than other T-cells and non-tumor infiltrating Tregs in several malignancies including non-small cell lung cancer (NSCLC; De Simone 2016, Vasanthakumar 2017). BV (ADCETRIS®), a CD30-directed antibody-drug conjugate, has been shown to reduce Tregs in clinical trials of classical Hodgkin’s lymphoma and cutaneous T-cell lymphoma, to be uniquely toxic to CD30-expressing Tregs, and to allow for expansion of co-cultured CD8 T-cells in vitro (Romano 2019, Heister 2018 [AACR]). We plan to evaluate pembro with BV (pembro + BV) in pts that have relapsed after, or who are refractory to, PD-1 inhibition. SGN35-033 (NCT04609566) is a multi-cohort, open-label, multicenter, phase II clinical trial evaluating the efficacy and safety of pembro + BV in pts with metastatic NSCLC (EGFR, ALK, ROS1, and BRAF negative) or metastatic cutaneous melanoma after progression on treatment with PD-1 inhibitor therapy. Enrollment will be based on radiographic-confirmed progression on PD-1 inhibitor therapy. Pts must be aged ≥18 years and on PD-1 therapy currently or had their last dose within 90 days prior to enrollment. ∼60 pts will be assigned to 1 of 4 cohorts (15 pts/cohort) based on disease state and diagnosis. Pts will receive 21-day cycles of pembro + BV. Based on antitumor activity and safety data, each cohort may have an expansion phase (up to an additional 40 pts/cohort) to further characterize the safety and antitumor activity. The primary endpoint is objective response rate (ORR) per investigator assessment (RECIST v1.1). Secondary endpoints include duration of response (DOR) and progression-free survival (RECIST), ORR and DOR (iRECIST), and safety. The observed ORR (RECIST v1.1) and 95% confidence interval will be provided for the full analysis set (all pts who are enrolled and received any amount of study drug) using Clopper-Pearson methodology. Enrollment began in January 2021. NCT04609566. Anastasija Pesevska, Prime Global. Seagen Inc. Seagen Inc.