ideasIdea
Sequence folate-receptor ADCs by payload class
Three FRα ADCs carry different poisons (tubulin, hemiasterlin, topoisomerase). Use them in sequence rather than treating them as interchangeable.
Mirvetuximab (DM4, FRα-high only), luveltamab tazevibulin (hemiasterlin, any FRα), and Rina-S (exatecan, any FRα) share the antigen but not the payload. Cross-resistance between tubulin and TOP1 payloads is expected to be low, and FRα is rarely lost at progression.
Hypothesis
Patients progressing on mirvetuximab retain FRα and respond to a TOP1-payload FRα ADC at rates similar to ADC-naive patients.
Rationale
Payload-specific resistance (tubulin mutations, efflux) does not cross to topoisomerase payloads; FRα PET or repeat biopsy can confirm antigen persistence.
What would test it
Post-mirvetuximab cohort in RAINFOL-02 or a dedicated phase 2 with paired biopsies for FRα and payload-resistance markers.
Maturity
preclinical evidence