ESMO 2024 – Regeneron's fianlimab do-over

Regeneron's hopes to beat Bristol Myers Squibb in Lag3 have taken a twist, with the company blaming a "clerical error" for declining results in melanoma patients receiving its contender fianlimab, plus Libtayo, following perioperative PD-(L)1 therapy.

It was these patients who last year helped fianlimab's case, but this year’s ESMO meeting showed much less impressive results. Regeneron is well behind, with pivotal data in first-line melanoma due next year and a trial with a fixed-dose combination expected to complete in 2027. The group will need something special to overtake Bristol, which has had its Lag3/PD-1 combo, Opdualag, approved in melanoma since 2022.

Perioperative waning

Regeneron's data came from a phase 1 trial of fianlimab, with or without Libtayo, in solid tumours. Zooming in on melanoma, the study had already impressed in PD-(L)1-naive patients, and results presented at ASCO 2023 also suggested a benefit in those who had previously received perioperative checkpoint inhibitors but subsequently relapsed; here the ORR was 62%, with eight of 13 patients responding.

The latest update, presented in an ESMO poster this year, concerned long-term follow-up from the same study. While response rates in the other melanoma cohorts held up, in the post-PD-(L)1 group the ORR shrank to 39% (7/18 responses).

During an interview at ESMO Regeneron put this development down to a “technicality”. Essentially, some patients classed as responders by investigator assessment couldn’t be included in the independent analysis, because their disease was deemed unmeasurable at baseline.

“Recist doesn’t do a good job of assessing lymph node disease,” Israel Lowy, Regeneron’s head of translational sciences, oncology, told ApexOnco. “So there were some discrepancies between the baseline assessments done by the blinded [analysis] versus the investigator, which meant there were several patients who couldn’t be accounted for.”

He noted that progression-free survival was a more important endpoint than ORR, and pointed to a PFS analysis showing the PD-(L)1 pretreated patients, along with the overall study population, doing “extremely well”.

Across all cohorts the ORR was 57% and estimated median PFS was 24 months.

With the usual caveats about cross-trial comparisons, fianlimab plus Libtayo could still have an edge over Opdualag, which showed an ORR of 43% and a median PFS of 10.1 months in its pivotal Relativity-047 study.

However, Regeneron needs to get to market first, and this looks some way off. The pivotal trial of fianlimab plus Libtayo in first-line melanoma isn't due to read out until the second half of next year, Lowy said; data had once been expected in 2024.

And the company also hopes to launch with a fixed-dose combination, a phase 3 study of which isn’t set to complete until 2027. However, given that this is open label, Regeneron hopes to use pharmacokinetic and safety data from this trial to support the first-line melanoma filing.

Notable studies of fianlimab in melanoma

Notes: EFS=event-free survival; ORR=overall response rate; pCR=pathologic complete response; PFS=progression-free survival; RFS=relapse-free survival. Source: OncologyPipeline & company communications.

This story has been updated to include comments from Regeneron about filing plans.