ASH 2025 – Adcetris good, follow-ons not so much

It’s not been a great month for Pfizer’s attempts to develop a follow-on to its blockbuster Adcetris. First one similarly acting ADC, PF-08046045, was discontinued after recruitment delays, and now a related project, coded PF-08046044, is gone too, Pfizer has quietly revealed.

ASH played host to an update to ‘044’s phase 1 study, and the results were an unpleasant wake-up call: a significant uptick in toxicity has been seen since initial data were unveiled at the EHA conference. The molecule remains listed in the R&D pipeline shown on Pfizer’s website, but asked by ApexOnco the group stated: “Pfizer made a business decision to deprioritise the programme.”

All this work is derived from Seagen, which Pfizer bought for $43bn, and which brought with it the Takeda-partnered anti-CD30 ADC Adcetris, marketed for lymphoma. ‘045 (SGN-35T) was similar to Adcetris but with a different linker, while ‘044 (SGN-35C) used a modified linker, camptothecin payload in place of auristatin, and different drug-to-antibody ratio.

Déjà vu

Pfizer revealed in its third-quarter update that ‘045 had been discontinued, after the project’s phase 1 study had been scaled back, with just 22 patients enrolled out of a planned 150.

A similar thing happened with ‘044, whose phase 1 study had once planned to enrol 210 lymphoma patients, but which managed to recruit only 57, according to clinicaltrials.gov. While Pfizer hasn’t publicly stated the scrapping of ‘044, it told ApexOnco that the discontinuation wasn’t due to “safety concerns, regulatory request, or any study conduct issues”.

This might be the case formally, but behind the scenes things had clearly not been going well, and ASH revealed plenty of reasons why ‘044 looked uncompetitive. At EHA in June Pfizer was reporting a 6% rate of treatment-related adverse events, but at ASH this climbed to 19%, with dose delays rocketing from 14% to 42%.

How PF-08046044's phase 1 dataset has evolved

Notes: *9% at any grade; **efficacy-evaluable denominator was 27. Source: OncologyPipeline & ASH.

The effect was likely driven by Pfizer ramping up ‘044 dosing; the EHA dataset related to 0.6-2.5mg/kg, but ASH took this up to 4.0mg/kg. Strangely, the response rate improvement amounted to just seven points, and it seems surprising that Pfizer felt the need to drive responses meaningfully over the already respectable 70% it reported at EHA.

3.2mg/kg was deemed maximally tolerated after two of three 4.0mg/kg patients developed grade 4 neutropenia and febrile neutropenia, and this was dose-limiting, City of Hope’s Dr Swetha Thiruvengadam told ASH. G-CSF was administered to manage neutropenia, though it wasn’t used as primary prophylaxis.

What next?

Anyone looking for the next ricochet of Pfizer’s latest discontinuation will no doubt want to see what other projects the company has that, like ‘044, also use the valine-lysine-glycuronide linker and topoisomerase 1 inhibitor payload.

One is SAR445953 (PF-08046050), an anti-CEACAM5C ADC licensed to Sanofi, whose phase 1 study is continuing to recruit a planned 494 patients. Meanwhile, an anti-CD228 ADC, PF-08046031, uses a payload-linker similar to '045, and its phase 1 trial once had a target population of 185 but is now marked “active, not recruiting”, having enrolled just 11.

This story has been updated to correct the description of PF-08046031.