Lai, Catherine

166 Background: T-DM1 is an antibody-drug conjugate composed of trastuzumab, a stable linker, and the cytotoxic agent DM1. Few T-DM1 data are available in settings approximating clinical practice. We present safety and efficacy data from T-PAS, an expanded access study of T-DM1 in patients (pts) with previously treated HER2-positive MBC. Methods: T-PAS is a US multicenter study of T-DM1 (3.6 mg/kg q3w) in HER2-positive (IHC 3+ or FISH/CISH+) locally advanced or MBC. Key eligibility criteria: prior anthracycline and taxane; prior capecitabine or 5-FU and ≥2 HER2-directed agents (including trastuzumab and lapatinib) for MBC; LVEF ≥50%. Primary endpoint: safety; secondary endpoint: investigator-assessed objective response rate (ORR) in pts with measurable disease. Safety was assessed on day 1 of each cycle; ECHO/MUGA scans were every 12 weeks. Results: This analysis includes 215 pts enrolled in May 2010–Sep 2011 (data cutoff 7/31/2012). Pts received a median of 7 prior systemic MBC therapies (range 1–23) with a median cumulative anthracycline dose of 240 mg/m2(range 6–2645). At baseline, median LVEF was 60% and 50% of pts had investigator-reported cardiovascular disease. Median follow-up was 5.9 months (range 0.1–25.3); median T-DM1 duration was 5.0 months (range 0–23) with 15.8% receiving >18 cycles. ORR was 25.6% (42/164). Rate of grade ≥3 AEs was 43.7% and of SAEs of any grade was 18.1%. Most common all-grade AEs were fatigue (50.7%), nausea (36.3%), and headache (24.2%). Most common grade ≥3 AEs were thrombocytopenia (7.9%), fatigue (4.7%), and increased aspartate aminotransferase and anemia (each 3.7%). There were no grade ≥3 bleeding events. Cardiac dysfunction (primarily asymptomatic decreases in LVEF) was reported in 8 pts (3.7%); 4 were grade ≥3, 3 resulting in T-DM1 discontinuation. Conclusions: In this study that more closely reflects the real-world setting, the safety profile of T-DM1 was similar to that previously reported in conventional clinical trials, with no new safety signals. In this pretreated population (median of 7 prior therapies for HER2-positive MBC), significant activity was observed. Clinical trial information: NCT01120561.

Abstract Background: Central nervous system (CNS) metastases are observed in up to half of patients with HER2-positive metastatic breast cancer (MBC), with incidence likely to continue to rise due to longer survival through improved systemic treatments. While radiotherapy-based approaches can be effective, there are potential short- and long-term toxicities, and patients frequently progress. CNS response to existing systemic therapies has been generally poor, and there is a high unmet need with no approved treatment for CNS metastases in HER2-positive MBC. Combination of the HER2-targeted monoclonal antibodies trastuzumab and pertuzumab provides a more comprehensive blockade of HER2 than either antibody alone, and data from the phase III CLEOPATRA trial suggest that adding pertuzumab to trastuzumab and docetaxel may delay onset of CNS disease. Trastuzumab concentrations in the CNS are increased under conditions of an impaired blood–brain barrier (BBB) and subtherapeutic levels in the CNS may be related to insufficient dosing rather than inability to cross the BBB. The PATRICIA trial is evaluating the addition of pertuzumab with high-dose trastuzumab to a patient's current systemic treatment for HER2-positive MBC patients with CNS progression post-radiotherapy and stable systemic disease. Study design: In this US-based, phase II, open-label, single-arm study, patients will receive intravenous pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks) in combination with intravenous high-dose trastuzumab (6 mg/kg weekly) in addition to their current systemic therapy (except for ado-trastuzumab emtansine or lapatinib) until disease progression or unacceptable toxicity. Eligibility criteria: Patients aged ≥18 years with confirmed HER2-positive MBC with new and/or progressive CNS lesions >60 days after whole-brain radiotherapy or stereotactic radiosurgery for CNS metastases, performance status 0–1, and stable systemic disease will be eligible. Patients must have a baseline left ventricular ejection fraction (LVEF) ≥50%, no significant history of cardiac disease or current use of anthracyclines, life expectancy >12 weeks, and not be pregnant or lactating. Aims: The primary efficacy endpoint will be objective response rate (ORR) in the CNS, assessed by the investigator using RANO–BM criteria. Secondary endpoints will include duration of CNS response, progression-free survival (CNS and/or non-CNS), overall survival, and safety. Pharmacokinetic and patient-reported outcomes will also be evaluated. LVEF will be assessed throughout treatment and follow-up. An interim analysis will be performed when 15 patients have completed 2 cycles, and the study will be stopped if no clinical benefit (complete response, partial response, or stable disease in the CNS) is seen or if two or more patients have congestive heart failure events related to trastuzumab or pertuzumab. Statistical methods: The recruitment target is 40 patients; with 35 evaluable, the 95% confidence interval around an estimated ORR of 20% will be 8.4–36.9%. The trial opens for accrual in Q3 2015. Citation Format: Lin NU, Pegram MD, Lai C, Lacasia A, Stein A, Yoo B, Perez EA. An open-label, single-arm, phase II study of pertuzumab with high-dose trastuzumab for the treatment of central nervous system progression post-radiotherapy in patients with HER2-positive metastatic breast cancer (PATRICIA). [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 OT3-01-04.