Neoadjuvant ipilimumab and nivolumab in combination with paclitaxel following anthracycline-based chemotherapy in patients with treatment resistant early-stage triple-negative breast cancer (TNBC): A single-arm phase 2 trial.
Authors: Loi Sherene , Francis Prudence A. , Zdenkowski Nicholas , Gebski Val , Fox Stephen B. , White Michelle , Kiely Belinda Emma , Woodward Natasha E. , Hui Rina , Redfern Andrew David , Calvert Raewyn , Rennie Lauren , Boyle Frances M. ,   Breast Cancer Trials-Australia and New Zealand
Published: June 2022

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Background: We examined the efficacy and safety of neoadjuvant ipilimumab and nivolumab combined with paclitaxel following suboptimal response to anthracycline-based chemotherapy in patients with early-stage TNBC. Methods: This single arm multicentre phase 2 study enrolled 34 patients in 8 sites. Patients were aged ≥18 years with previously untreated stage 3 TNBC and were required to have ≥15mm of tumor remaining or 10mm of tumor with one positive lymph node after 4 cycles of anthracycline-based therapy. A suboptimal response subset at baseline was defined as < 50% reduction in tumor volume after initial anthracycline-based chemotherapy. Patients received neoadjuvant ipilimumab 1mg/kg IV 6 weekly for 2 doses and nivolumab 240mg every 2 weeks for 6 doses, with weekly paclitaxel at 80mg/m2 for 12 weeks, followed by surgery. Nivolumab (480mg 4-weekly) continued post operatively for further 9 months. Primary endpoint was pathological complete response (pCR) in breast and axilla, with secondary endpoints pCR in the suboptimal responders, pCR in PD-L1 positive patients (≥1% by SP142 assay), clinical response in the breast (ORR by RECIST), event-free (EFS) and overall survival (OS). Results: Between December 2018 and April 2020, 34 patients were enrolled, 33 were evaluable for the primary endpoint. Median age was 46.6yrs. At diagnosis, all patients were clinical stage III (AJCC v8), 16/34 (47%) were node positive, 8/31 (26%) were PD-L1 positive. At study entry (following anthracycline-based chemo), the median tumor size by ultrasound was 28mm (12-62). 16/33 (48%) were considered suboptimal responders. The pCR rate (ypT0ypN0) was 24.2% (95% CI, 11.09-42.26) in all evaluable, 37.5% [3/11] in PD-L1+ and 23% [5/22] in PD-L1- patients. In patients with suboptimal anthracycline response (< 50% tumor reduction), the pCR rate was 18.8% (95% CI, 8.52-75.51) (3/16). ORR in the breast was 57.6% (19/33) in all evaluable patients and 43.7% (8/20) in the suboptimal responders. The number of patients with residual cancer burden (RCB) class 0,1,2,3 was 8 (24%), 1 (3%), 19 (57.5%) and 5 (15%) respectively. With 14 months median follow up, 12-months EFS was estimated at 85% and OS 94%. For patients with pCR vs non-pCR, the hazard ratio (HR) for EFS was 0.62, 12 mo EFS was 100% vs 75%. In the neoadjuvant phase, 15/33 (45%) patients experienced at least one grade 3-4 adverse event. Most common immune-related event was grade 1 or 2 pneumonitis 9/33 (27%), which generally occurred with fever after the first dose of ipilimumab, and resolved. There was one case of grade 3 colitis. Conclusions: In these high risk patients, the addition of ipilimumab and nivolumab to neoadjuvant paclitaxel resulted in promising ORR and pCR rates, regardless of PD-L1 status. Rates of low grade pneumonitis were high. Follow up continues. Clinical trial information: ACTRN12617000651381.