Abstract OT3-01-05: PANACEA (IBCSG 45-13/BIG 4-13): A phase Ib/II trial evaluating the efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant, HER2-positive, metastatic breast cancer
Authors: Loi S , Andre F , Maibach R , Hui R , Bartsch R , Jerusalem G , Gombos A , Campone M , Bonnefoi H , Bachelot T , Curigliano G , Biganzoli L , Giobbie-Hurder A 
Published: May 2016

Abstract
Background
Preclinical and correlative clinical data suggest that HER2-positive breast cancer could be amenable to immunotherapeutic approaches. We hypothesize that immune evasion contributes to tumor growth and progression in HER2-positive tumors and anti-PD1 restores T cell cytotoxicity reverting trastuzumab resistance.
Eligibility criteria
Patients with HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast cancer with disease progression during treatment with trastuzumab or subsequent anti-HER2 therapy of not more than 3 lines.
HER2 overexpression and PD-L1 expression confirmed in central laboratories based on tissue obtained within 1 year prior to study entry.
Objective
The primary objectives of this phase Ib/II study are to determine the recommended dose (RP2D) of pembrolizumab in combination with standard dose trastuzumab, and to evaluate the efficacy and safety profile of the drug combination in patients with PD-L1 positive, HER2 overexpressing unresectable loco-regional or metastatic breast cancer.
Trial design
The phase Ib portion of the trial will use a standard 3+3 design to determine the RP2D of standard-dose trastuzumab with three pembrolizumab dose levels: 2 mg/kg, 10 mg/kg, or a fall-back dose of 1 mg/kg. A Simon optimal two-stage design will be used in the phase II portion to assess the primary outcome of objective response. Pembrolizumab at the RP2D will be given with trastuzumab (6 mg/kg i.v. every 3 weeks) until disease progression or lack of tolerability. The null hypothesis that the true objective response rate (ORR) is 7% will be tested against a one-sided alternative rate of 22%. In the first stage, 17 patients will be enrolled. If there are zero or one responses, enrollment will stop. Otherwise, 23 additional patients will be accrued. The null hypothesis will be rejected if 6 or more objective responses are observed in 40 evaluable patients. This design has a type-I error of 0.05 and 85% power. If the null hypothesis is true, the probability is 0.66 that enrollment will stop at the end of the first stage.
Two concurrent analyses of the data will take place at the end of the first stage. One analysis will assess ORR using the criteria described above. The second will be a detailed review of safety data.
Statistical methods
Primary and secondary endpoints will be based on patients enrolled in the phase II trial. ORR will be presented with a two-sided 90% confidence interval calculated using the method of Atkinson and Brown. The distributions of time-to-event secondary endpoints, such as duration of response and time to progression, will be summarized using the method of Kaplan-Meier.
Present accrual and target accrual
As of 3 June 2015 11 patients have been screened for HER2 and PD-L1 positivity, and 3 successfully enrolled, completing the first dose cohort. Target enrollment of this phase Ib/II trial is 6-46 evaluable patients. Discussions are ongoing to include a PD-L1 negative cohort.
Contact information
Conducted by the International Breast Cancer Study Group and the Breast International Group in collaboration with Merck Sharp & Dohme Corp.
Citation Format: Loi S, Andre F, Maibach R, Hui R, Bartsch R, Jerusalem G, Gombos A, Campone M, Bonnefoi H, Bachelot T, Curigliano G, Biganzoli L, Giobbie-Hurder A. PANACEA (IBCSG 45-13/BIG 4-13): A phase Ib/II trial evaluating the efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant, HER2-positive, metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-05.