Abstract PD1-06: Open label phase 1b/2 study of ladiratuzumab vedotin in combination with pembrolizumab for first-line treatment of patients with unresectable locally-advanced or metastatic triple-negative breast cancer
Authors: Han Hyo (Heather) , Diab Sami , Alemany Carlos , Basho Reva , Brown-Glaberman Ursa , Meisel Jane , Pluard Timothy , Cortes Javier , Dillon Patrick , Ettl Johannes , Kuemmel Sherko , Sanchez Luis Manso , Oliveira Mafalda , O'Shaughnessy Joyce , Papish Steven , Sinha Rajni , Sterrenberg Danielle , Stringer-Reasor Erica , Tsai Michaela , Vazquez Rafael Villanueva , Wuerstlein Rachel , Wang Yinghui , Wang Zejing , Boni Valentina 
Published: March 2020

Abstract
Background Ladiratuzumab vedotin (LV) is an investigational anti-LIV-1 antibody-drug conjugate with a protease-cleavable linker to monomethyl auristatin E (MMAE). LIV-1 is highly expressed in metastatic triple negative breast cancer (TNBC). LV mediated delivery of MMAE drives antitumor activity through cytotoxic cell killing and has been shown to induce immunogenic cell death (ICD). LV monotherapy has demonstrated encouraging activity in TNBC. Anti-PD-(L)1 agents are emerging as part of the TNBC treatment paradigm and showing promising activity. Combining LV and pembrolizumab (pembro) may result in complementary, as well as synergistic, activity through LV-induced ICD that creates a microenvironment favorable for enhanced anti-PD-(L)1 activity. Methods This ongoing phase 1b/2 study evaluates safety, tolerability, activity, and recommended phase 2 dose of LV + pembro (NCT03310957; 2017-002289-35) in a dose-finding (Part A) followed by expansion phase (Part B) as front-line therapy for TNBC patients (pts). Eligible pts receive LV 2.0 mg/kg or 2.5mg/kg + pembro 200mg every 3 wks. Pts must have TNBC per ASCO/CAP guidelines (absence of HER2, estrogen receptor, and progesterone receptor expression) and are not pre-selected for either LIV-1 or PD-L1 expression. Tumor assessment is performed every 6 weeks per RECIST v1.1. Results As of 23 May 2019, a total of 51 pts have received LV + pembro (7 and 44 pts at LV 2.0 and 2.5 mg/kg, respectively). Nineteen pts enrolled in dose finding (7 and 12 at LV 2.0 and 2.5 mg/kg, respectively) and 32 pts enrolled in dose expansion all at LV 2.5 mg/kg. Median age was 55 yrs (range: 30, 82), ECOG 0/1 was 47%/53%, and invasive ductal carcinoma histology was 69%. All patients were first-line for LA/M TNBC, and 24% of pts had de novo mTNBC at initial diagnosis. Two pts experienced dose-limiting toxicities (DLT) out of 12 pts enrolled at LV 2.5 mg/kg in Part A: Grade 3 colitis and Grade 3 diarrhea. No DLT was observed at LV 2.0mg/kg. Of the 51 pts evaluable for safety (defined as all pts who received any amount of LV or pembro), 44 (86%) reported treatment emergent adverse events (TEAEs). Most common TEAEs across the 2 LV dose levels were nausea (53%); fatigue (45%); diarrhea (43%); alopecia (33%); constipation and hypokalemia (29% each); vomiting (27%); decreased appetite (25%); abdominal pain (24%); decreased weight (22%); and neutropenia and peripheral sensory neuropathy (20% each). Across the 2 dose levels, the most common Grade 3+ AEs were neutropenia (16%); diarrhea, fatigue, hypokalemia, and maculo-papular rash (8% each); and abdominal pain, increased ALT, and urinary tract infection (6% each). The most common SAEs were abdominal pain and constipation (6% each). In this ongoing trial, 26 pts were followed for at least 3 months with an opportunity for 2 post-baseline disease assessments. Among these 26 pts, the confirmed objective response rate was 54% (95% CI, 33.4, 73.4). Two additional pts have a single scan showing PR and are pending confirmatory assessment. Updated data will be provided at the meeting. Conclusion LV + pembro appears tolerable with a manageable safety profile to date. Preliminary efficacy data show encouraging clinical activity as first-line therapy in pts with unresectable LA/M TNBC.
Citation Format: Hyo (Heather) Han, Sami Diab, Carlos Alemany, Reva Basho, Ursa Brown-Glaberman, Jane Meisel, Timothy Pluard, Javier Cortes, Patrick Dillon, Johannes Ettl, Sherko Kuemmel, Luis Manso Sanchez, Mafalda Oliveira, Joyce O'Shaughnessy, Steven Papish, Rajni Sinha, Danielle Sterrenberg, Erica Stringer-Reasor, Michaela Tsai, Rafael Villanueva Vazquez, Rachel Wuerstlein, Yinghui Wang, Zejing Wang, Valentina Boni. Open label phase 1b/2 study of ladiratuzumab vedotin in combination with pembrolizumab for first-line treatment of patients with unresectable locally-advanced or metastatic triple-negative breast cancer [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 PD1-06.