A signal-seeking Phase II trial of Durvalumab and Tremelimumab Focused on Advanced, Rare and Less Common Cancers

Immune checkpoint blockade impedes the negative regulatory signals for T-cell response and permits more effective immune detection and eradication of cancer cells. This single-arm phase II clinical trial (ACTRN12616001019493) within the Molecular Screening and Therapeutics (MoST) program evaluates the clinical activity and safety of combination immunotherapy with durvalumab and tremelimumab in patients with advanced cancers, prioritsing rare cancers (<6 per 100,000 annual incidence) and patients having failed standard treatments for their cancer type. MethodsEligible patients were determined by the molecular tumour board based on the absence of actionable genomic findings (n=64) and biomarker enriched (n=48) at screening. Patients received durvalumab 1500 mg and tremelimumab 75 mg every four weeks for 4 cycles, followed by durvalumab alone for another 9 cycles. The primary endpoint was progression-free survival at 6 months (PFS6) and secondary endpoints included objective response, time to progression (TTP) on trial to TTP on prior therapy (TTP2/TTP1>1.3), overall survival and treatment tolerability. ResultsBetween December 2016 and 2019, 112 patients were enrolled on the study. There was a female predominance (55%), most had an ECOG performance status of 0 (66%), aged <65 years (75%), with rare cancers (84%). The PFS6 rate was 32% (95% CI 23 to 40%); 16 of 112(14%) achieved an objective response; TTP2/TTP1>1.3 for 22 of 63 (35%) patients with an evaluable ratio; median overall survival 11.9 months (95% CI 11.0 to 14.8), and there were no new safety concerns. High tumour cell PD-L1 correlated with improved PFS and OS and TMB with PFS alone. More PD-1+CD4+ T-cells and circulating follicular T-helper (cTfh) cells at baseline were strongly associated with better PFS and OS. ConclusionDurvalumab plus tremelimumab demonstrated a signal of clinical activity in treatment-refractory patients with rare cancers. A PFS6 of 32% and 35% of patients achieving a TTP2/TTP1>1.3 suggests an improved disease trajectory on trial. Translational correlates provided insights into biological associations with clinical outcomes across tumour types.