Background Preclinical and clinical data suggest that HER2-positive (HER2+) breast cancer (BC) will be amendable to immunotherapeutic approaches. We evaluated pembrolizumab with trastuzumab in patients (pts) with trastuzumab-resistant HER2+, PD-L1 positive (PD-L1pos), unresectable loco-regional or metastatic BC and a parallel cohort of pts with HER2+, PD-L1 negative (PD-L1neg) BC during the phase II study.

Methods: Pts with advanced BC and progression on prior trastuzumab-based therapies, ECOG 0-1, and a metastatic tumor biopsy in the last year were eligible. HER2 positivity and quantity of tumor-infiltrating lymphocytes (TILs) on H&E slide were centrally evaluated. PD-L1 score was assessed by Merck central lab. Tumor imaging was performed at weeks 12, 18, 24 and every 12 weeks, thereafter. Primary endpoints were safety of the combination (phase Ib) and objective response rate (ORR) per RECIST 1.1 (phase II). Secondary endpoints were PFS, duration of response, and OS. Phase Ib was a 3+3 dose-escalation of 2 pembrolizumab doses (2mg/kg, 10mg/kg) Q3W. In phase II, pts received pembrolizumab 200mg Q3W for 24 months or until disease progression. Clinically stable pts with progression were allowed to continue pembrolizumab until confirmation on subsequent assessment. Pts with isolated CNS progression were also allowed to continue pembrolizumab after local treatment. Planned total enrollment was 61 pts. For the phase II PD-L1pos cohort, a Simon two-stage design (N=40; proceed if ≥2/17 respond) was used which had 85% power to compare ORR of 7% vs. 22% (1-sided α=0.05). For the PD-L1neg cohort, a single-stage design with 15 pts had >95% power to compare ORR of 1% vs. 20% (1-sided α=0.14). NCT02129556.

Results: 6 pts enrolled in phase Ib between April and July 2015; no DLTs were observed. The PD-L1pos cohort enrolled 40 pts between August 2015 and September 2016. The PD-L1neg cohort enrolled May 2016 to April 2017, stopping after 12 pts due to low rate of PD-L1 negativity, maintaining >90% power to detect the target difference in ORR. PD-L1 testing labs changed in April 2016. Prior to this time, QualTek PD-L1 positive was defined as ≥1% on tumor or TILs. Using the Dako 22C3 antibody, positive was defined as tumor PD-L1 combined positive score (CPS)≥1%.

146 pts were screened to enroll 58 pts. Of screened pts, median stromal TILs was 1% (mean: 4.8%, SD: 9.1%, range: 0 to 60%; n=127); 52% of pts were PD-L1pos, with higher positivity rates while using the Dako assay compared with Qualtek (65% vs. 43%, p=0.009). Median TILs of pts in the PD-L1pos cohort was 2% (mean: 8.1%, SD: 11.2%, range: 0 to 40%) and 0% (mean: 1.2%, SD: 2.2%, range: 0 to 5%) in the PD-L1neg cohort.

Of enrolled pts, median age was 51yrs (range: 28-72), 69% had visceral metastases. 29% of pts received prior pertuzumab, 72% had prior T-DM1, 40% prior lapatinib. 38% of pts were ER-positive, 62% were ER-negative. Median TILs in enrolled ER pos and ER neg pts were 1.5% and 2.0%, respectively. PD-L1 positivity rates were also not significantly different by ER status (p=0.5).

Final safety data and efficacy results will be presented at the meeting.

Citation Format: Loi S, Giobbe-Hurder A, Gombos A, Bachelot T, Hui R, Curigliano G, Campone M, Biganzoli L, Bonnefoi H, Jerusalem G, Bartsch R, Rabaglio-Poretti M, Kammler R, Maibach R, Smyth MJ, Di Leo A, Colleoni M, Viale G, Regan MM, Andre F. Phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive metastatic breast cancer: Results from the PANACEA (IBCSG 45-13/BIG 4-13/KEYNOTE-014) study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS2-06.