ASCO 2023 – in Lag3 Regeneron could beat Bristol Myers Squibb

With ASCO around the corner Regeneron is working hard to maintain enthusiasm in the Lag3 mechanism, after interest was recently rekindled by promising lung cancer data on Immutep’s eftilagimod alpha. A just unveiled Asco abstract confirms the leading activity of Regenron’s MAb, fianlimab.

A fianlimab plus Libtayo combo had already impressed at last year’s ESMO, with 64% ORR in front-line melanoma beating Bristol Myers Squibb’s Opdualag on a cross-trial basis. But the ASCO data are intriguing for another reason: the combo looks active in melanoma patients who have already progressed on PD-(L)1 blockade in the perioperative setting.

Earlier iterations of this dataset had already shown promise, and the additional results comprise a still small subset of just 13 of the 98 patients in the fianlimab phase 1 study in question.

But this is nevertheless an important group, as all 13 had received anti- PD-(L)1 in the neoadjuvant or adjuvant setting but subsequently relapsed. Yet eight of the 13 responded to fianlimab plus Libtayo, including one complete remission, with an estimated median PFS of 11.8 months, the just unveiled ASCO abstract shows.

Regeneron’s last report, at ESMO, was of 64% ORR among 80 purely first-line melanoma subjects, and this has held up across all 98. mPFS across the trial stands at 15.3 months; though this is lower than ESMO’s 24 months that number looked unreliable, and in any case on a cross-trial basis the data look better than the 10.1-month mPFS on Opdualag’s label.

Why could fianlimab plus Libtayo be better than Opdualag? Differences in MAb design is one possibility, as is that fianlimab has been dosed up to 1.6g every three weeks, with the only relevant added toxicity being adrenal insufficiency. In contrast, the dose of Bristol’s anti-Lag3 relatlimab in the Opdualag combo is 160mg every four weeks.

Fianlimab + Libtayo in 1st-line melanoma

Source: ASCO abstract with 1 Nov 2022 cutoff.

Two phase 3 melanoma studies of fianlimab plus Libtayo, one front line and the other in the adjuvant setting, are under way against Merck & Co’s Keytruda, and should yield data in 2025. There are also phase 2/3 trials in first-line NSCLC adding fianlimab on top of Libtayo (in PD-L1 ≥50% expressers) and on top of Libtayo and chemo.

If pivotal studies yield a registrational dataset a further consideration will be how to combine fianlimab and Libtayo. Bristol notably launched relatlimab plus Opdivo as part of the Opdualag fixed-dose combo, and Regeneron is heading in a similar direction, citing multiple advantages to such a fixed-dose formulation.

The competition includes Lag3 x PD-1 bispecifics being investigated by Macrogenics (tebotelimab) and Roche (RO7247669). For now Regeneron is  pinning its hopes on the straight MAb approach of fianlimab, given that a bispecific additionally has to juggle the balance of affinities for two separate targets.

Either way, with numerous other competitors on its heels, not least Merck’s own favezelimab, it is key for Regeneron to keep posting sector-leading data.