Combination immunotherapy in patients with rare cancers.
BEHREN A. 1,2, GUNJUR A. 1,10, KEE D. 3,4, MARKMAN B. 5,6, MICHAEL M. 4, UNDERHILL C. 7, CARLINO M. 8, JACKETT L. 9, DUARTE J. 1, QUIGLEY L. 1, OSTROUSKA S. 1, PALMER J. 1, ADAMS D. 10, LAWLEY T. 11, CEBON J. 1,3, KLEIN O. 1,3
1 Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Melbourne, Australia; 2 Department of Medicine, University of Melbourne, Melbourne, Australia; 3 Department of Medical Oncology, Austin Health, Melbourne, Australia; 4 Department of Medical Oncology, Peter McCallum Cancer Centre, Melbourne, Australia; 5 School of clinical Science, Monash University, Melbourne, Australia; 6 Department of Medical Oncology, Alfred Health, Melbourne, Australia; 7 Albury-Wodonga Regional Cancer Centre, Albury-Wodonga, Australia; 8 Blacktown Hospital and the University of Sydney, Sydney, Australia; 9 Department of Anatomical Pathology, Austin Health, Melbourne, Australia; 10 Experimental Cancer Genetics, Wellcome Sanger Institute, Hinxton, United Kingdom; 11 Microbiotica Limited, Cambridge, United Kingdom
CA209-538 is a prospective multicentre Phase II clinical trial sponsored by the Olivia Newton-John Cancer Research Institute investigating the efficacy of combined immune checkpoint blockade (CTLA-4/ipilimumab and PD-1 blockade/nivolumab) in a range of rare cancers (NCT02923934, n=120). Participants received the anti-PD-1 antibody nivolumab and the anti-CTLA-4 antibody ipilimumab every three weeks for four doses, followed by nivolumab (3 mg/kg IV) every two weeks and continued for up to 96 weeks, until disease progression or unacceptable toxicity. While approximately 20% of the study population progressed on or before the first evaluation at 12 weeks, the entire trial population achieved an overall response rate (ORR) and the clinical benefit rate (CBR) of ~ 30% and 50% respectively.
Patients with rare cancers have limited therapeutic options, low survival and are often excluded from clinical trials and biomarker studies due to the low incidence (<6 per 100,000 individuals). However, while incidence is low for each individual rare cancer, collectively they comprise of almost 25% of all cancer diagnoses. To identify biomarkers for rare cancer patients responding to combination immunotherapy we evaluated baseline and on-treatment collected biospecimen including PBMCs, stool, sera/plasma and tumour tissue for markers of response including cancer-specific autoantibodies, cytokine levels, microbiome, PD-L1 status, baseline tumor gene-expression and tumour mutational burden (TMB).