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

J A Kyte, N K Andresen, H G Russnes, S Ø Fretland, R S Falk, O C Lingjærde, B Naume, J A Kyte, N K Andresen, H G Russnes, S Ø Fretland, R S Falk, O C Lingjærde, B Naume

Abstract

Background: Immunotherapy with checkpoint inhibitors (CPI) 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 CPI 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 anthracycline, 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 20 mg/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 (1 mg intravenously every 6th week) + nivolumab (240 mg 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 anthracyclines, which are considered to induce immunogenic cell death, synergize with CPI, 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 cross-over patients from Arm A receiving ipilimumab/nivolumab without concomitant chemotherapy represent 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://ichgcp.net/clinical-trials-registry/NCT03409198.

Keywords: Anthracycline; Breast cancer; CTLA4; Checkpoint inhibitor; Cyclophosphamide; Hormone receptor positive; Immunogenic cell death; Immunotherapy; PD-1.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

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Fig. 1
Study design

References

    1. Robert C, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384(9948):1109–1117. doi: 10.1016/S0140-6736(14)60958-2.
    1. Larkin J, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34. doi: 10.1056/NEJMoa1504030.
    1. Gibney GT, et al. Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma. Clin Cancer Res. 2015;21(4):712–720. doi: 10.1158/1078-0432.CCR-14-2468.
    1. Rizvi NA, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–128. doi: 10.1126/science.aaa1348.
    1. Ferris RL, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856–1867. doi: 10.1056/NEJMoa1602252.
    1. Hellmann MD, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093–2104. doi: 10.1056/NEJMoa1801946.
    1. Emens LA. Breast cancer immunotherapy: facts and hopes. Clin Cancer Res. 2018;24(3):511–520. doi: 10.1158/1078-0432.CCR-16-3001.
    1. Schmid P, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108–2121. doi: 10.1056/NEJMoa1809615.
    1. Nanda R, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 2020;6(5):1–9. doi: 10.1001/jamaoncol.2019.6650.
    1. Schmid P, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810–821. doi: 10.1056/NEJMoa1910549.
    1. Sistigu A, et al. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med. 2014;20(11):1301–1309. doi: 10.1038/nm.3708.
    1. Rugo HS, et al. Safety and antitumor activity of pembrolizumab in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Clin Cancer Res. 2018;24(12):2804–2811. doi: 10.1158/1078-0432.CCR-17-3452.
    1. Dirix LY, et al. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res Treat. 2018;167(3):671–686. doi: 10.1007/s10549-017-4537-5.
    1. Barroso-Sousa R, et al. A phase II study of pembrolizumab in combination with palliative radiotherapy for hormone receptor-positive metastatic breast cancer. Clin Breast Cancer. 2020;20(3):238–245. doi: 10.1016/j.clbc.2020.01.012.
    1. Tolaney SM, et al. Randomized phase II study of eribulin mesylate (E) with or without pembrolizumab (P) for hormone receptor-positive (HR+) metastatic breast cancer (MBC) J Clin Oncol. 2019;37:1004–1004. doi: 10.1200/JCO.2019.37.15_suppl.1004.
    1. Bezu L, et al. Combinatorial strategies for the induction of immunogenic cell death. Front Immunol. 2015;6:187.
    1. Kroemer G, et al. Natural and therapy-induced immunosurveillance in breast cancer. Nat Med. 2015;21(10):1128–1138. doi: 10.1038/nm.3944.
    1. Apetoh L, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13(9):1050–1059. doi: 10.1038/nm1622.
    1. Voorwerk L, et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat Med. 2019;25(6):920–928. doi: 10.1038/s41591-019-0432-4.
    1. Nolan E, et al. Combined immune checkpoint blockade as a therapeutic strategy for BRCA1-mutated breast cancer. Sci Transl Med. 2017;9(393):eaal4922. doi: 10.1126/scitranslmed.aal4922.
    1. Pfirschke C, et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity. 2016;44(2):343–354. doi: 10.1016/j.immuni.2015.11.024.
    1. Goldman JW, et al. Nivolumab (N) plus ipilimumab (I) as first-line (1L) treatment for advanced (adv) NSCLC: 2-yr OS and long-term outcomes from CheckMate 012. J Clin Oncol. 2017;35(15):9093–9093. doi: 10.1200/JCO.2017.35.15_suppl.9093.
    1. Rau KM, et al. Pegylated liposomal doxorubicin (Lipo-Dox(R)) combined with cyclophosphamide and 5-fluorouracil is effective and safe as salvage chemotherapy in taxane-treated metastatic breast cancer: an open-label, multi-center, non-comparative phase II study. BMC Cancer. 2015;15:423. doi: 10.1186/s12885-015-1433-4.
    1. Jehn CF, et al. Biweekly pegylated liposomal doxorubicin (Caelyx) in heavily pretreated metastatic breast cancer: a phase 2 study. Clin Breast Cancer. 2016;16(6):514–519. doi: 10.1016/j.clbc.2016.06.001.
    1. Munzone E, Colleoni M. Clinical overview of metronomic chemotherapy in breast cancer. Nat Rev Clin Oncol. 2015;12(11):631–644. doi: 10.1038/nrclinonc.2015.131.
    1. Rossi D, et al. Neoadjuvant chemotherapy with low dose of pegylated liposomal doxorubicin plus weekly paclitaxel in operable and locally advanced breast cancer. Anticancer Drugs. 2008;19(7):733–737. doi: 10.1097/CAD.0b013e3283043585.
    1. Dellapasqua S, et al. Pegylated liposomal doxorubicin in combination with low-dose metronomic cyclophosphamide as preoperative treatment for patients with locally advanced breast cancer. Breast. 2011;20(4):319–323. doi: 10.1016/j.breast.2011.02.014.
    1. Ghiringhelli F, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother. 2007;56(5):641–648. doi: 10.1007/s00262-006-0225-8.

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