ICON: A randomized phase IIb study evaluating immunogenic chemotherapy combined with ipilimumab and nivolumab in patients with metastatic hormone receptor positive breast cancer [post]

Jon Amund Kyte, NK Andresen, HG Russnes, Signe Øien Fretland, RS Falk, OC Lingjærde, B Naume
2020 unpublished
Background: Immunotherapy with checkpoint inhibitors (CI) targeting PD-1 or CTLA-4 has emerged as an important treatment modality for several cancer forms. In hormone receptor positive breast cancer (HR+ BC), this therapeutic approach is largely unexplored. We have started a clinical trial, ICON (CA209-9FN), evaluating CI combined with selected chemotherapy in patients with metastatic HR+ BC. The tumor lymphocyte infiltration is predictive for the effect of chemotherapy in BC. In ICON, we use
more » ... . In ICON, we use antracyclins, which are considered as "immunogenic" chemotherapy, and low-dose cyclophosphamide, which has been reported to counter immunosuppressive cells. Methods: ICON is a randomized exploratory phase IIb study evaluating the safety and efficacy of combining nivolumab (nivo; anti-PD-1) and ipilimumab (ipi; anti-CTLA-4) with chemotherapy in subjects with metastatic HR+ BC. Primary objectives are aassessment of toxicity and progression-free survival.The trial will enrol 75 evaluable subjects, randomized 2:3 into two arms (A:B). Patients in Arm A receive only chemotherapy, i.e. pegylated liposomal doxorubicin (PLD 20mg/m2 intravenously every 2nd week) + cyclophosphamide (cyclo; 50 mg per day, first 2 weeks in each 4 week cycle). Patients in Arm B receive PLD + cyclo + ipilimumab (1mg intravenously every 6th week) + nivolumab (240mg intravenously every 2nd week). Patients in arm A will be offered ipi+nivo after disease progression. Discussion: ICON is among the first clinical trials combining chemotherapy with PD-1 and CTLA-4 blockade, and the first in BC. There is a strong preclinical rationale for exploring if antracyclins, which are considered to induce immunogenic cell death, synergize with CI, and for combining PD-1 and CTLA-4 blockade, as these checkpoints are important in different phases of the immune response. If the ICON trial suggests acceptable safety and provide a signal of clinical efficacy, further studies are warranted. The sub-cohort from Arm A receiving ipilimumab/nivolumab without concomitant chemotherapy represents the first BC cohort receiving this therapy. The ICON trial includes a series of translational sub-projects addressing clinically important knowledge gaps. These studies may uncover biomarkers or mechanisms of efficacy and resistance, thereby informing the development of novel combinatory regimes and of personalised biomarker-based therapy. Trial registration: NCT03409198, Jan 24th 2018; https://clinicaltrials.gov/ct2/show/record/NCT03409198
doi:10.21203/rs.3.rs-21888/v1 fatcat:z7dsme6kizeajled6lwkrju7zq