A phase 1, multicenter, open-label, first-in-human study of DS-6157a in patients (pts) with advanced gastrointestinal stromal tumor (GIST).
Authors: George Suzanne , Heinrich Michael C. , Somaiah Neeta , Van Tine Brian Andrew , McLeod Robert , Laadem Abderrahmane , Cheng Ben , Nishioka Satoshi , Kundu Madan Gopal , Qian Xiaozhong , Lau Yvonne Y. , Tran Brittany , Kumar Prasanna , Dosunmu Ololade , Shi Julia , Naito Yoichi 
Published: June 2022

11512 Background: GPR20 is selectively and abundantly expressed in GISTs, the most common sarcoma of digestive tract. DS-6157a is an anti-GPR20 antibody-drug conjugate with a novel tetrapeptide-based linker and DNA topoisomerase I inhibitor exatecan derivative (DXd). The target drug-to-antibody ratio is ̃8. The DXd payload, when released, inhibits topoisomerase I and induces cell apoptosis. Methods: This study conducted in the US and Japan was designed to include a dose-escalation (Part 1) and a dose-expansion (Part 2) in adult pts with advanced GIST (NCT04276415). Part 1 evaluated safety, tolerability, efficacy, and pharmacokinetics (PK) to determine the maximum-tolerated dose (MTD) and/or recommended dose for expansion. Key eligibility criteria included ECOG PS of 0 or 1, measurable disease per RECIST v1.1, and adequate bone marrow, hepatic, and renal function. DS-6157a was administered every 3 weeks as monotherapy. Pts had tumor assessments per RECIST 1.1 every 6 weeks (wks) for 36 wks, then every 9 wks thereafter. Results: At data cutoff, 34 pts were available for full analysis: median treatment duration was 9.9 wks (range, 3-56 wks) and 5 pts (14.7%) were ongoing; median age 60.5 years (y) (range, 29-81 y); 19 pts (56%) were male; 47% of pts were Asian and 47% were white. Baseline GPR20 expression was highly prevalent, and dose-dependent PK exposure was confirmed within the range of dose levels. The MTD was 6.4 mg/kg. One pt with SDH-deficient GIST with both SDH B and NF1 mutations, had a confirmed PR with shrinkage of -75%; 18 pts (53%) experienced stable disease and 10 pts (29%) experienced progressive disease as best response. Median progression-free survival across all dose levels was 3.6 months (95% CI, 1.6, 6.9). Treatment-emergent AEs (TEAEs) occurred in all pts and treatment-related TEAEs (TRAEs) in 32 pts (94%). The most common (≥25%) all-grade (Gr) TEAEs were nausea (82%), decreased appetite (59%), fatigue (47%), anemia (44%), constipation (38%), decreased platelets (35%), and vomiting (32%). Gr ≥3 TRAEs occurred in 14 pts (41%); the most common were decreased platelets (21%) and anemia (18%). Serious TEAEs (SAEs) occurred in 9 pts (27%) and related SAEs in 4 pts (12%). Related Gr 4 SAEs in 2 pts included abnormal hepatic function, neutropenia, thrombocytopenia and leukopenia. There was 1 treatment related death (hepatic failure). Further investigations are on-going to understand the modest clinical efficacy observed. The study did not proceed to Part 2, because the data from Part 1 did not meet efficacy targets. Conclusions: DS-6157a was generally well tolerated with early signs of moderate clinical activity. While there were no objective responses in pts with KIT-mutant GIST, tumor shrinkage was observed in all 4 pts with KIT wild-type GIST treated at different doses, including a confirmed PR at the MTD in a pt with SDH-deficient GIST with both SDH B and NF1 mutations. Clinical trial information: NCT04276415.