Genmab takes its Profound buy into endometrial

Genmab has said it plans to have three phase 3 trials of its ProfoundBio-originated ADC rinatabart sesutecan under way by the end of 2025, and details of the second, Rainfol-03, have just emerged on clinicaltrials.gov.

The new study, due to start in October, heralds an expansion from ovarian into endometrial cancer, specifically patients who have progressed on an anti-PD-(L)1 MAb and platinum-based chemo. Further chemo is the current standard of care in this second-line setting, with dismal outcomes; Genmab will hope to do better, especially after posting a 50% response rate in relapsed endometrial cancer in phase 1/2 at ASCO.

Few options

Post-PD-(L)1/chemo patients generally go on to receive single-agent chemo, which has shown an ORR of less than 16%, median progression free-survival of less than five months, and median overall survival of less than a year.

Rina-S, a folate receptor alpha (FRα)-targeting ADC that Genmab gained via its $1.8bn takeover of ProfoundBio, has shown early signs that it could do better, specifically from the Rainfol-01 trials in various solid tumours; data in post-PD-(L)1/chemo endometrial cancer patients, with a median of three prior lines of therapy, were presented in an ASCO poster.

Among 22 evaluable patients receiving 100mg/m² of rina-S, the confirmed ORR was 50%. At 120mg/m² this was a slightly less impressive 47%; in any case, 100mg/m² was selected at the go-forward dose, and presumably this is what will be tested in Rainfol-03, although the clinicaltrials.gov entry gives no dosing details.

The Rainfol-01 investigators also noted that activity was seen regardless of FRα expression levels, although data on this weren’t presented. This is something that will be closely watched in phase 3 – as well as whether the promising response rate translates into longer survival in a rigorously controlled trial.

As for adverse events, rina-S was primarily linked with cytopenias and low-grade gastrointestinal side effects. There were no signals of ocular toxicity, neuropathy or interstitial lung disease, which can be seen with ADCs. There were two deaths, both at the higher dose, one due to septic shock deemed related to rina-S, and one due to acute kidney injury deemed unrelated.

Competition

The most advanced FRα-targeting ADC is AbbVie’s Elahare, gained via that group's $10bn acquisition of ImmunoGen. In a phase 2 investigator-sponsored trial in endometrial cancer, an Elahere/Keytruda combo produced an ORR of 38%; however, ocular toxicities of any grade were seen in over half of patients.

None of the many other FRα-targeting ADCs is being investigated in a specific endometrial cancer trial, according to OncologyPipeline.

Genmab also has pivotal plans in first-line endometrial cancer. This setting could be harder to crack, with Merck & Co’s Keytruda, GSK’s Jemperli and AstraZeneca’s Imfinzi all approved alongside chemo; Keytruda and Jemperli irrespective of mismatch repair status.

Separately, Genmab's ProfoundBio buy has run into problems elsewhere, with the discontinuation this week of the PTK7-targeting ADC GEN1107. Rina-S was the main driver of the deal, though, and this latest trial initiation shows it's still going strong; meanwhile, the biggest upcoming event for rina-S will be readout of the pivotal Rainfol-02 trial in its lead indication, platinum-resistant ovarian cancer, due next year.

Phase 3 trials of rina-S

Source: OncologyPipeline, clinicaltrials.gov & company Q2 2025 presentation.