Introduction/Background NaPi2b is a sodium-dependent phosphate transporter broadly expressed in ovarian cancer (OC) and non-small cell lung cancer (NSCLC). ADCs targeting NaPi2b have demonstrated clinical activity, but have been associated with both target- and platform-related toxicities. Platform toxicity with first-generation ADCs included high-grade hematological toxicities, peripheral neuropathy and AST elevation. Dolasynthen is a next-generation platform designed to produce homogeneous ADCs with precise control of the drug-to-antibody ratio (DAR) and site-specific bioconjugation for improved efficacy and reduced platform-related toxicities. XMT-1592 is a DAR 6 Dolasynthen ADC targeting NaPi2b evaluated in a Ph1 trial in refractory cancer patients.

Methodology Eligible OC and NSCLC patients regardless of NaPi2b expression were enrolled in escalating dose cohorts (3.5mg/m2–56mg/m2) IV Q3W. The study used an accelerated titration design for the first 2 dose levels, and standard 3+3 design for the remaining levels. Primary objective was safety/tolerability and to determine the RP2D.

Results 31 patients (28 OC; 3 NSCLC) were enrolled. No DLTs observed. ILD/pneumonitis, fatigue, nausea, anaemia, and headache were the most commonly reported TRAEs. No ≥G3 fatigue, nausea, thrombocytopenia, neutropenia, neuropathy or AST elevations were reported; no treatment-related bleeding events occurred. ILD/pneumonitis occurred in 12 patients (38.7%; 2 Gr3, 1 Gr5) and appeared to be dose dependent. Among evaluable patients, confirmed ORR was 16.7% (5/30), including 1 CR. At the two highest dose levels, ORR was 30.8% (4/13) among evaluable OC patients.

Conclusion Platform toxicities including high-grade neutropenia, thrombocytopenia, neuropathy and AST elevations observed with earlier NaPi2b-targeting ADCs were not observed with XMT-1592. ILD/pneumonitis was the most common TRAE and was consistent with preclinical findings that suggest this observation is likely ‘on target,’ relating to NaPi2b expression in type II pneumocytes. While development of this product candidate has been discontinued by the sponsor due to portfolio reprioritization considerations, alternative dosing regimens may warrant further evaluation given the observed activity.

Disclosures This trial was sponsored by Mersana Therapeutics, Inc.