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.

A phase 2 clinical trial assessing the efficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple‐negative breast cancer

“…[27][28][29] Efficacy analyses were conducted in patients who received at least 1 dose of pembrolizumab and had at least 1 measurable unirradiated tumor according to RECIST (version 1.1). The ORR was defined as the percentage of patients with a complete response (CR) or partial response in tumors not targeted by RT.…”

“…In what to the best of our knowledge are the few reports of RT and immunotherapy including patients with breast cancer published to date, various dose regimens have been used with mixed results. 28 Thus, the timing and schedule of RT with respect to checkpoint blockade administration may be critically important. 15 The ORR for the entire cohort was 13.2% and was not reported specifically in the patients with breast cancer, thereby constraining the ability to compare results across studies.…”

“…Modified Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST; version 1.0) was an exploratory endpoint. [27][28][29] Efficacy analyses were conducted in patients who received at least 1 dose of pembrolizumab and had at least 1 measurable unirradiated tumor according to RECIST (version 1.1). A Simon 2-stage optimal design was used to the test the null hypothesis that the true response rate was ≤5% versus the alternative hypothesis that the true response rate was ≥25%, with a type I error rate of 0.05 and type II error rate of 0.20.…”

“…In the phase 2, adaptively designed TONIC trial (Nivolumab After Induction Treatment in Triplenegative Breast Cancer [TNBC] Patients), nivolumab was administered 2 weeks after induction with hypofractionated RT (24 grays in 3 fractions) in patients with mTNBC, resulting in a relatively modest ORR of 10%. 37 Furthermore, in the TONIC trial, the RT was not generally administered in sequential daily fractions. 28 Thus, the timing and schedule of RT with respect to checkpoint blockade administration may be critically important.…”

“…37 Furthermore, in the TONIC trial, the RT was not generally administered in sequential daily fractions. 28 Thus, the timing and schedule of RT with respect to checkpoint blockade administration may be critically important. The importance of sequence is highlighted by preclinical data suggesting that CTLA-4 blockade administered prior to hypofractionated RT is superior to alternative schedules due to the depletion of immune-inhibitory regulatory T cells that restrict CD8 effector cell function and antitumor immunity.…”