Abstract P1-18-03: Pertuzumab (P) plus high-dose trastuzumab (H) for the treatment of central nervous system (CNS) progression after radiotherapy (RT) in patients (pts) with HER2-positive metastatic breast cancer (MBC): Primary efficacy analysis results from the phase II PATRICIA study
Authors: Lin Nancy U , Kumthekar Priya , Sahebjam Solmaz , Ibrahim Nuhad , Fung Anita , Cheng Anna , Nicholas Alan , Wang Bei , Pegram Mark 
Published: March 2020

Abstract
Background: There is an unmet need for evidence-based systemic therapies for pts with HER2-positive MBC and progressive brain metastases. Despite assumptions that monoclonal antibodies do not cross the blood-brain barrier, molecular imaging in pts shows localization of 89Zr-trastuzumab to brain metastases. Furthermore, preclinical data support dose-dependent activity of H in intracranial tumor models. The PATRICIA study (NCT02536339) evaluated safety and efficacy of P plus high-dose H in pts with HER2-positive MBC with CNS metastases and CNS progression after RT. Herein, we present results from the primary efficacy analysis of PATRICIA. Methods: PATRICIA was a US-based, phase II, open-label, single arm study. Eligible pts had measurable (≥10 mm) CNS disease that had progressed after CNS-directed RT, in the setting of stable extracranial disease. CNS-directed RT included whole-brain RT (WBRT) or stereotactic radiosurgery (SRS) and must have been completed ≥60 days before study entry. Pts received P (840 mg loading dose, then 420 mg every 3 weeks) and high-dose H (6 mg/kg weekly), which continued until progression (CNS or systemic) or unacceptable toxicity. Pts could continue their existing systemic anti-cancer therapy during the study, with the exception of trastuzumab emtansine (T-DM1) or lapatinib. Switch of other anti-cancer therapy was not permitted during the study. Restaging evaluations including brain MRI were completed every 2 cycles. The primary efficacy endpoint was confirmed objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Secondary endpoints included duration of response (DOR), clinical benefit rate (CBR) in the CNS, and safety. Samples were collected for exploratory pharmacokinetic analyses on Day 1 of weeks 1, 4, 10, and 16. Results: From 15 Dec 2015 to 18 May 2017, 40 pts were enrolled across 16 sites. Median age was 48 (range 34–69) years, with 33% and 67% of pts having an Eastern Cooperative Oncology Group Performance Status score of 0 or 1, respectively. 41% of pts had received prior WBRT only, 28% had received prior SRS only, and 31% had received both. At the data cut off (1 May 2019), of 39 treated pts, 2 remained on study treatment and 37 discontinued treatment, most commonly due to CNS progression (n=27). Median treatment duration was 4.5 (range 0.3–37.3) months. Four pts in the efficacy population (N=37) experienced a confirmed partial response (Table), leading to an ORR of 11% (95% confidence interval [CI], 3–25%). Response durations were 3.2, 3.3, 4.6, and 5.6 months (median DOR 4.6 months). The CBR (complete response + partial response + stable disease [SD] of ≥4 or ≥6 months) was 68% (SD ≥4 months) and 51% (SD ≥6 months). Results from exploratory pharmacokinetic analyses confirmed greater H exposure with the high-dose schedule. The adverse event profile was similar to that previously reported for P and H, with no new safety signals. One pt discontinued treatment due to an adverse event (grade 3 left ventricular dysfunction, considered related to study treatment). No Grade 5 adverse events were reported. Conclusions: The CNS ORR of 11%, ≥6-month CBR of 51%, and lack of any new safety signals suggest that P plus high-dose H may have clinical utility in some pts with HER2-positive MBC with progressive CNS metastases.
Table. Efficacy within the CNS per RANO-BM criteriaEfficacy population (N=37)n (%)95% CIORR*4 (11)3, 25CBR (CR + PR + stable disease [SD] ≥4 months)25 (68)50, 82CBR (CR + PR + SD ≥6 months)19 (51)34, 68Confirmed best response (SD ≥4 months)CR0—PR4 (11)—SD ≥4 months21 (57)—Pts without clinical benefit12 (32)—Confirmed best response (SD ≥6 months)CR0—PR4 (11)—SD ≥6 months15 (41)—Pts without clinical benefit18 (49)—*Confirmed complete response (CR) or confirmed partial response (PR).
Citation Format: Nancy U Lin, Priya Kumthekar, Solmaz Sahebjam, Nuhad Ibrahim, Anita Fung, Anna Cheng, Alan Nicholas, Bei Wang, Mark Pegram. Pertuzumab (P) plus high-dose trastuzumab (H) for the treatment of central nervous system (CNS) progression after radiotherapy (RT) in patients (pts) with HER2-positive metastatic breast cancer (MBC): Primary efficacy analysis results from the phase II PATRICIA study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-03.