  MCC-20487 (NCT04588545): Radiation Therapy Followed by Intrathecal Trastuzumab/Pertuzumab in HER2+ Breast Leptomeningeal Disease (Official Title: Phase I/II Study of Radiation Therapy Followed by Intrathecal Trastuzumab/Pertuzumab in the Management of HER2+ Breast Leptomeningeal Disease)  
JAMA Oncol. 2024 May 23. IF: 28.4 Radiation Therapy Followed by Intrathecal Trastuzumab-Pertuzumab for ERBB2-Positive Breast Leptomeningeal Disease: A Phase 1 Nonrandomized Controlled Trial. Ahmed KA, Kumthekar PU, Pina Y, Kim Y, Vogelbaum MA, Han HS, Forsyth PA. Moffitt Cancer Center, Tampa, Florida; Northwestern University, Chicago, Illinois. Trastuzumab has been studied in the management of ERBB2 (formerly HER2)-positive leptomeningeal disease (LMD) via intrathecal delivery. In a previous phase 1/2 study, Kumthekar et al assessed the safety and efficacy of intrathecal trastuzumab in the management of ERBB2-positive LMD. Trastuzumab and pertuzumab delivered systemically with chemotherapy demonstrated improved overall survival (OS) and progression-free survival (PFS) over chemotherapy with trastuzumab alone in patients with ERBB2-positive breast cancer. Radiation therapy (RT) has a well-defined role in symptom control for LMD and may improve the flow of intrathecal therapies through the cerebrospinal fluid (CSF). In this phase 1 study, we assessed the safety of RT with intrathecal trastuzumab (80 mg) combined with pertuzumab. METHODS The Moffitt Cancer Center Institutional Review Board approved this nonrandomized controlled trial (ClinicalTrial.gov identifier: NCT04588545). Participants provided informed consent. The study followed the CONSORT reporting guideline. Patients were enrolled between December 2020 and May 2023. A modified toxicity probability interval (mTPI-2) or keyboard design was used to determine the recommended phase 2 dose (RP2D). Key eligibility criteria included ERBB2-positive breast cancer with LMD identified with magnetic resonance imaging or CSF analysis, adults' age (≥18 years), life expectancy longer than 8 weeks, left ventricular ejection fraction greater than 50%, Karnofsky Performance Status of 60 or greater, and adequate organ function. Patients could continue treatment with intravenous trastuzumab, pertuzumab, or other ERBB2-directed, hormonal, or systemic agents if controlling systemic disease and LMD developed while receiving these therapies. The intrathecal trastuzumab dose was fixed at 80 mg with a dose escalation of intrathecal pertuzumab. Each cycle was 4 weeks with treatment twice-weekly in cycle 1, weekly in cycle 2, and every 2 weeks thereafter. Because there is no single validated tool to measure response in LMD, primary leptomeningeal assessment was made in a similar fashion to the previous study of intrathecal trastuzumab using cytologic, clinical, and radiographic findings. Radiation therapy was not required per study protocol if patients had received prior RT and the multidisciplinary team determined that additional RT was not needed. Data analysis was performed using JMP, version 17 (SAS Institute). RESULTS This trial included 9 women with a median age of 51 years. Four pertuzumab doses were tested: 10, 20, and 40 mg with 1 patient each and 80 mg with 6 patients. Study therapy was well tolerated with no dose-limiting toxicities (DLTs) identified. The RP2D was determined to be 80 mg using the mTPI-2 design. Toxicities at least partially attributable to study therapy included grade 1 and 2 fatigue (n = 2 and 1), grade 1 headache (n = 2), and grade 1 extremity pain, nausea, paresthesia, and arthralgia (n = 1 each). Two patients developed infected Ommaya reservoirs, which were removed, and were treated with antibiotics. The first patient developed an infection after the first cycle and resumed study treatment after a 3-month treatment break. The second patient developed an infection approximately 24 months after starting treatment and decided to stop therapy after noting stable LMD during these 24 months. To date, the median follow-up is 10.2 months. Median survival has not been reached (95% CI, 3.4 to not reached), with a 12-month OS of 86%. The best leptomeningeal response was a complete response in 2 patients (22%), partial response in 3 patients (33%), and stable disease in 4 patients (44%). The median PFS has not been reached (95% CI, 3.3 to not reached), with a 12-month PFS of 76%. Six patients continue to receive the study therapy. DISCUSSION In this phase 1 nonrandomized controlled trial of RT followed by intrathecal trastuzumab plus pertuzumab for ERBB2-positive breast cancer LMD, the RP2D of pertuzumab was 80 mg with 80 mg of trastuzumab. Additionally, study therapy was well tolerated with no DLTs noted. Finally, intracranial responses appear encouraging, with higher OS than observed for historical control participants. Given the adequate safety profile observed in this phase 1 study, phase 2 is currently open and accruing patients to assess OS. PMID: 38780965 DOI: 10.1001/jamaoncol.2024.1299 原文共享
|
|
|
