Adcetris gives Pfizer its first post-Seagen surprise

The positive outcome of the Echelon-3 trial will see Adcetris filed in diffuse large B-cell lymphoma, Pfizer said today. That’s a stark contrast to the view of Adcetris’s originator, Seagen, whose acquisition Pfizer closed in December, and which a month before then had deprioritised this study and deemed it “no longer registrational”.

What could have caused such a divergence of opinions? It’s possible that Pfizer is pedalling hard to justify the $43bn it spent on Seagen, and wants to make the most of the Echelon-3 readout, its first post-takeover success. But a little-noticed fact is that the study's deprioritisation came shortly after its design was changed.

The clue lies in an amendment to Echelon-3’s clinicaltrials.gov entry done on 15 September last year. This saw the trial’s target enrolment cut from 400 to just 225 patients, as well as changing its primary endpoint from PFS to OS.

A reason for this might have been an independent review committee opinion that PFS looked unlikely to be met. Today Pfizer toplined the result as “statistically significant and clinically meaningful improvement” for OS, but for PFS (now a secondary endpoint) it only claimed a “positive outcome”.

Eighth use?

Depending on the nature of the OS win and on whether the FDA accepts this as a positive result the indication studied in Echelon-3, third-line or later diffuse large B-cell lymphoma, could become Adcetris’s eighth approved use. The drug is established in several Hodgkin’s disease settings, and has rare types of CD30-positive and T-cell lymphomas on its label too.

Echelon-3 combined Adcetris with Revlimid and Rituxan, and compared this triplet against Revlimid and Rituxan, a doublet approved for previously treated follicular and marginal zone lymphomas. Patients had to have progressed on at least two earlier therapy lines, and to have been ineligible for stem cell transplant or Car-T therapy.

This relapsed/refractory DLBCL setting was the first notable approved use for autologous CD19-directed Car-T therapy, and more recently has seen the entry of anti-CD20 T-cell engagers. In light of such developments perhaps the setting of Echelon-3 was starting to become irrelevant in the real world. 

A separate question concerns the importance of CD30 – Adcetris’s target – in DLBCL. In a small academic DLBCL trial Adcetris had generated ORRs of 73% in CD30-positive patients, but only 46% in those whose cancers didn’t express the antigen.

Yet the OS benefit in Echelon-3 was significant “regardless of CD30 expression”, Pfizer said today. Another issue for the FDA, therefore, will be to look at the extent to which CD30-expressers drove the outcome of all-comers in Echelon-3, and whether there is significant activity versus Revlimid/Rituxan in non-expressers.

Either way, Echelon-3 has given Pfizer an unexpected gift. The company can hardly be blamed for wanting to capitalise on it.

Approved uses for Adcetris

Note: cHL=classical Hodgkin lymphoma; DLBCL=diffuse large B-cell lymphoma; pcALCL=primary cutaneous anaplastic large-cell lymphoma; PTCL=peripheral T-cell lymphoma; sALCL=systemic anaplastic large-cell lymphoma. Source: OncologyPipeline & prescribing information.