Antitumor activity of STRO-002, a novel anti-folate receptor-α (FRα) antibody drug conjugate (ADC), in patient-derived xenograft (PDX) models and preliminary Phase I dose escalation safety outcomes in patients with ovarian carcinoma (OC)
Denise Uyar, 1 Russell J Schilder, 2 R Wendel Naumann, 3 Fadi S Braiteh, 4 Erika Hamilton, 5 Sami Diab, 6 John Moroney, 7 Richard T Penson, 8 Jennifer Smith, 9 Cristina Abrahams, 9 Michael Palumbo, 9 Venita DeAlmeida, 9 Shannon Matheny, 9 Arturo Molina9.
1Medical College of Wisconsin, Milwaukee, WI; 2Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA; 3Levine Cancer Institute, Carolinas Medical Center, Charlotte, NC; 4Comprehensive Cancer Centers of Nevada, Las Vegas, NV; 5Sarah Cannon Research Institute, Tennessee Oncology, PLLC, Nashville, TN; 6Rocky Mountain Cancer Center, Aurora, CO; 7University of Chicago, Chicago, IL; 8Massachusetts General Hospital, Boston, MA; 9Sutro Biopharma, South San Francisco, CA.
Introduction: FRα is overexpressed in 80% of OC and endometrial carcinoma (EC), with minimal expression in normal tissues. STRO-002 is a novel FRα-targeting ADC designed to circumvent limitations of current ADCs. STRO-002 was generated with Sutro’s cell-free antibody production system (XpressCF™) and site-specific conjugation (XpressCF™) platform, which uses the non-natural amino acid pAMF. STRO-002 has a drug-antibody ratio (DAR) of 4 and contains the proprietary tubulin-targeting 3-aminophenyl hemiasterlin warhead SC209, a potent cytotoxin that is rapidly cleared and a weak substrate for efflux pumps. STRO-002 demonstrated potent cytotoxic activity in multiple FRα-positive tumor cell lines and significant therapeutic efficacy in OC xenograft models. Toxicology studies demonstrate dose-dependent and reversible neutropenia when STRO-002 is administered to cynomolgus monkeys. No ocular toxicity was observed. Herein we report additional preclinical efficacy in PDX models and preliminary safety experience of STRO- 002 in patients (pts) with OC.
PDX model methods: FRα expression was evaluated in EC PDX models by IHC. Single agent efficacy of 10 mg/kg STRO-002 was assessed in models with negative, low (+), medium (++) and high (+++) FRα expression.
Phase 1 trial methods: STRO-002-GM1 is a first-in-human Phase I, open-label, multicenter, dose escalation (Part 1) study with dose expansion (Part 2) to identify the maximum tolerated dose (MTD), and recommended Phase II dose (RP2D) in pts with advanced, relapsed or refractory OC and EC. STRO-002 is given IV over an hour on Day 1 of each 21-day cycle until disease progression.
Results: Statistically significant efficacy was observed in 60% of the FRα-positive PDX models tested, with STRO-002 response appearing to positively correlate with FRα expression levels. Though high FRα PDX models showed the highest response rates, some models with low and medium FRα also exhibited good responses. 5 pts with OC have completed at least one cycle (21 days) of STRO-002 at 3 dose levels: 0.5, 1.0, and 1.8 mg/kg and are evaluable for safety and toxicity. Median age is 63 (r, 52-64). Median ECOG performance status is 0 (r, 0-1). Median # of prior therapies is 6 (r, 2-8). Four pts have received PARP inhibitors. Median number of STRO-002 doses administered is 2 (r, 1-5). 3 additional pts have been treated at the 2.9 mg/kg dose level and continue in the first cycle. No grade ≥ 3 treatment-related adverse events (TRAEs) have been observed. 93% of AEs are grade 1 or 2. The most common TRAEs in ≥20 % of pts includes nausea, vomiting, abdominal pain, fatigue and insomnia. Four grade 3 events occurred in 2 pts after completion of the first cycle and were related to disease progression, including small intestine obstruction, gross hematuria, dehydration and vomiting. 2 pts have discontinued due to disease progression. 6 pts remain on treatment and dose escalation is ongoing.
Conclusions: STRO-002 is the first ADC generated with cell-free protein synthesis technology and site-specific conjugation of a novel hemiasterlin linker-warhead to be tested in pts with solid tumors. The potent anti-tumor activity of STRO-002 in PDX models further supports the clinical development of this agent. The preliminary safety profile in 5 OC pts treated with STRO-002 is encouraging. MTD has not been reached, no DLTs have been observed and dose escalation is continuing. Updated results will be presented. This study is registered with clinicaltrials.gov identifier NCT03748186.