Anti-PD(L)1 can result in durable responses in patients with metastatic triple negative breast cancer (TNBC). However, only a small subgroup of TNBC patients benefit from anti-PD(L)1 with response rates of ± 10% in unselected cohorts. As such, there is an urgent clinical need to identify strategies that render the tumor micro-environment more sensitive to anti-PD(L)1. Preclinical studies have shown that irradiation or low dose chemotherapy may stimulate anti-cancer immune responses. Here we present the first results of a phase II randomized trial of nivolumab after short induction with irradiation or low dose chemotherapy in metastatic TNBC.
Fifty patients with metastatic TNBC who received ≤ 3 lines of palliative chemotherapy were randomly allocated to one of five 2-week induction treatments consisting of 1) 3x8 Gy irradiation of one metastatic lesion or 2) 2x doxorubicin 15mg weekly or 3) cyclophosphamide 50mg daily orally or 4) 2x cisplatin 40mg/m2, weekly or 5) no induction treatment. After this 2-week induction period, all patients received nivolumab 3mg/kg until RECIST 1.1 progression. After 5x10 evaluable patients with paired biopsies (stage I), arms will be closed according to a ‘pick the winner’ concept (Simon’s two-stage design).
To date, 50 patients are evaluable according to RECIST 1.1 with a median follow-up of 4 months (range 1-15). Previous treatments for metastatic disease were 0, 1 or 2+ lines in 20%, 52% and 28%, respectively. The ORR is 22% with 2 CRs (4%) and 9 PRs (18%). Additional two patients had a SD (4%), resulting in a clinical benefit rate (CR+PR+SD>24weeks) of 26%. The median duration of response was 10.9 months (95% CI 7.1-NA). Changes in tumor-infiltrating lymphocytes (TIL) after irradiation or low dose chemotherapy as well as response rates per treatment arm will be presented at the meeting.
This first study in TNBC shows that nivolumab after priming the tumor micro-environment with either irradiation or chemotherapy is feasible and results in a promising response rate that appear higher than expected based on previous PD-1/PD-L1 blockade monotherapy studies in unselected TNBC.
Clinical trial identification
Eudract number: 2015-001969-49
Legal entity responsible for the study
Netherlands Cancer Institute
Dutch Cancer Society, Pink Ribbon, BMS
D. Cullen: D. Cullen is an employee of BMS. R. Salgado: travel support Roche. T.N.M. Schumacher: Stocks Kite pharma, NEON, AIMM therapeutics Employee Kite pharma C.U. Blank: prof Blank is member of the advisory board of BMS. S.C. Linn: Advisory role: Novartis, Cergentis, Philips, AstraZeneca, Roche, Genentech, IBM. All other authors have declared no conflicts of interest.