Adaptive phase II randomized trial of nivolumab after induction treatment in triple negative breast cancer (TONIC trial): Final response data stage I and first translational data.

Abstract

1012 Background: Anti-PD(L)1 can result in durable responses in patients with metastatic triple negative breast cancer (TNBC). However, only a subgroup of TNBC patients benefits from anti-PD(L)1 with response rates of 5-10% in unselected cohorts. Strategies to render the tumor micro-environment (TME) more susceptible to anti-PD(L)1 might include stimulation of anti-cancer immune responses by induction treatment with irradiation or low dose chemotherapy. Methods: In stage I (non-comparative Simon’s two stage design) 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 2) 2x doxorubicin 15mg weekly flat dose3) cyclophosphamide 50mg daily orally 4) 2x cisplatin 40mg/m2 weekly 5) no induction treatment. After this induction period, all patients received nivolumab until iRECIST progression. After at least 5x10 evaluable patients with paired biopsies (stage I) arms will be closed according to a ‘pick the winner’ concept taking into account safety, clinical responses and immunological correlates. Results: Stage I has been closed with 66 patients available for response evaluation. Previous treatments for metastatic disease were 0, 1 or 2+ lines in 23%, 45% and 32%, respectively. For the total group the ORR is 20% with 2 CRs and 11 PRs. In addition, two patients had SD for > 24 weeks (3%), resulting in a clinical benefit rate of 23%. ORR on nivolumab after induction with irradiation, doxorubicin, cyclophosphamide and cisplatin were 8% (1/12), 35% (6/17), 8% (1/12) and 23% (3/13), respectively. In the nivolumab-only cohort the ORR was 17% (2/12). Analyses of changes in the TME, gene expression and TCR sequencing induced by irradiation, low dose chemotherapy and nivolumab will be presented at the meeting as well as the design of stage II according to the ‘pick the winner’ strategy. Conclusions: This basket trial shows that short term induction with irradiation or low dose chemotherapy before nivolumab is feasible. Final clinical and translational results of stage I will be presented at ASCO 2018. Clinical trial information: NCT02499367.