Immunotherapy using combined anti-PD-1/CTLA-4 checkpoint blockade is until date one of the most effective IO regimens across a range of solid malignancies providing superior outcomes compared to anti-PD-1 monotherapy.
CA209-538 was the first clinical trial that investigated this treatment regimen in advanced rare cancers (~30 different histiotypes). Patients with rare malignancies constitute 20% of all cancer diagnoses and represent a patient population of unmet medical need with poor overall survival. Objective responses according to RECIST criteria were observed in around a third of patients in CA209-538 and across a wide range of tumour types. The majority of responses were durable leading to significant survival benefits.
In search of tumor-agnostic biological correlates of response, translational research using tumour tissue and stool specimens of trial participants revealed that tumour mutational burden did not predict for response; however, responses were enriched in patients with PD-L1 positive tumours suggesting that anti-tumour immune responses that were re-invigorated in this patient population by checkpoint blockade may be directed against tumour antigens other than neoantigens. Emphasizing the importance of host factors for an effective anti-tumour immune response, the composition of the gut microbiota pre-treatment was strongly predictive for response to therapy.
A follow up trial MoST-CIRCUIT/CA209-6D6 is currently ongoing and has so far enrolled 175 out of 240 patients with selected rare cancers into four tumour cohorts (high grade neuroendocrine/biliary tract/gynaecological/MSI non-colorectal cancers) at 16 trial sites across Australia. Tumour tissue of all trial participants will be genomically analyzed and will provide one of the largest data sets that correlate clinical outcome with genomic aberrations in a pan-cancer cohort treated with dual checkpoint blockade.