The response rates seen with nivolumab (anti-PD1) after modulation of the tumour micro-environment using either irradiation or chemotherapy are promising compared to the historical response rates demonstrated in previous PD-1/PD-L1 blockade monotherapy studies in unselected patients with metastatic triple negative breast cancer (TNBC), researchers reported at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.
Marleen Kok, MD, PhD at The Netherlands Cancer Institute (NKI) in Amsterdam, presented findings from the TONIC-trial.This adaptive phase II randomised non-comparative trial(Eudract number:2015-001969-49) allocated patients with metastatic TNBC who received ≤ 3 lines of palliative chemotherapy to one of five 2-week induction treatment arms consisting of either three cycles of 8 Gy irradiation of one metastatic lesion, or two cycles of doxorubicin at 15 mg weekly, or cyclophosphamide at 50 mg daily orally or two cycles of 40 mg/m2 of cisplatin, or to receive no induction treatment. So far, 50 patients were evaluable for response.
Following the 2-week induction, all patients were treated with nivolumab at 3 mg/kg until progression according to iRECIST and RECIST v1.1 criteria. Recruitment to treatment arms will continue until 50 evaluable patients with paired biopsies (pre- and post-induction) are included (stage I). According to a ‘pick the winner’ concept (Simon’s two-stage design) arms will be closed in stage II.
At a median follow-up of 10.8 months (range 1 to 15.7 months), 50 patients are evaluable for response. Twenty percent, 52% and 28% of patients had received 0, 1 or 2+ lines of prior treatment, respectively.
Previously reported trials of single-agent anti-PD-(L)1 immunotherapy in unselected patients with TNBC demonstrated response rates of approximately 5-10%.
The objective response rate (ORR) per RECIST v1.1 with nivolumab for the whole cohort was 22% and 24% for iRECIST, which included 1 (2%) complete responses (CR), and 11 (22%) partial responses (PR). Additionally, stable disease (SD) lasting more than 24 weeks was achieved in 1 (2%) patient, which resulted in a 26% clinical benefit rate (CBR = CR+PR+SD>24 weeks).
In responding patients, the median duration of response was 9 months (95% confidence interval [CI] 5.5-NA). Preliminary analyses suggest that response rate might be higher after induction therapy with doxorubicin or cisplatin.
The investigators also observed that patients with higher leukocyte infiltration and CD8 T cell counts in tumour biopsies were more likely to respond to the treatment.
The authors pointed out that previous research has shown that anti-PD(-L)1 therapy can induce durable responses in patients with metastatic TNBC, but that the response rate is relatively low, about 5-10%, indicating that there is an urgent clinical need to identify strategies that render the tumour micro-environment more sensitive to anti-PD-L1 agents.
They concluded that this is the first study in TNBC to demonstrate that nivolumab after modulating the tumour micro-environment with either irradiation or chemotherapy is feasible and results in a promising response rate that is higher than expected historic date of previous PD-1/PD-L1 blockade monotherapy studies in unselected TNBC.
Giuseppe Curigliano of the Istituto Europeo di Oncologia and University of Milan, Milan, Italy who discussed the study results said that strengths of the study are that it is a very innovative trial exploring combination therapy, it provides data on the effect of chemotherapy and radiotherapy in priming the immune system, as well as TILs quantitative and qualitative assessment. The limits are that we are missing mutational burden before and after exposure to induction agent, TILs before and after induction, and useful another arm for ER-positive and HER2-positive breast cancer.
This trial was funded by the Dutch Cancer Society, Pink Ribbon, and Bristol-Myers Squibb.
LBA14 – Kok M, et al. Adaptive phase II randomized non-comparative trial of nivolumab after induction treatment in triple negative breast cancer: TONIC-trial.