A Phase I Study of MEDI4736 (Anti-PD-L1 Antibody) in Combination with Tremelimumab (Anti-CTLA-4 Antibody) in Subjects with Advanced Solid Tumors

Medimmune LLC
Study Design: 
This is a phase I combination study of durvalumab and tremelimumab for patients with metastatic urothelial cancer that has progressed after 1-2 prior treatments (including cisplatinum). Patients were treated with 4 cycles of concurrent durvalumab and tremelimumab and then treated with durvalumab alone for the remainder of the year.
Anti-PD-(L)-1 antibody therapy has activity and approval as a post-platinum therapy for locally advanced and metastatic urothelial cancer. Anti-CTLA-4 agents are approved as second line therapy for urothelial cancers and may have synergistic activity with anti-PD-(L)-1 antibodies. This trial explores the safety and efficacy of the combination of durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) in the metastatic urothelial cancer cohort of the dose-expansion phase for this phase I study of patients with advanced solid tumors.
Overall response rate, progression-free survival, overall survival
This trial demonstrates that combination therapy has manageable toxicity. Although efficacy was observed in all patients, it was better in those with 25% PD-L1 expression. Surprisingly, the addition of tremelimumab did not achieve response rates significantly higher than those seen in single agent anti-PD-(L)-1 trials begging the question, “do we really need to add an anti-CTLA4 antibody?”
A total of 168 patients were analyzed. Overall treatment related adverse events were seen in 75.6% of patients. Pruritus, fatigue, diarrhea, and rash were the most common. However, grade 3 and 4 events were only seen in 28.6% and 0.6% suffered a grade 5 event. The overall response rate (complete and partial responses) was 20.8% for all patients. The response was 29.4% in patients with at least 25% or greater PD-L1 expression in tumor cells and immune cells. The median time to response was 1.8 months and median progression-free survival was 1.9 months. Median overall survival was 9.5 months in all patients. For patients who again had 25% PD-L1 expression, median survival was 18.9 months.