What future for Lag3 blockade?

With Opdualag facing increasing doubts about its ability to break into cancers beyond its approved indication of melanoma, matters won't be helped by the fact that the Bristol Myers Squibb drug can't even broaden its use in melanoma itself.

Thursday's failure of the phase 3 Relativity-098 study, in which Opdualag couldn't beat Opdivo alone on recurrence-free survival in the adjuvant treatment of stage III-IV melanoma, means that Opdualag won't progress beyond its sole approved indication of first-line melanoma. The setback follows at least five other failures in key clinical trials.

These include various treatment settings in colorectal, liver and gastric cancers. Not only that, but Bristol's decision to push into the all-important setting of first-line NSCLC, where the Relativity-1093 study in 1-49% PD-L1 expressers began last October, looks highly questionable.

As for Relativity-098, Bristol hasn't revealed the extent of Opdualag's flop, but suggested that adjuvant uses in general might be a non-starter for Lag3 blockade, since “patients whose tumours are completely resected may not have sufficient antitumor T cells in place for Opdualag to have its maximal effect".

Opdivo monotherapy is approved in adjuvant stage III-IV melanoma on the basis of the Checkmate-238 study, which at a seven-year update showed median RFS of 61.1 months. Presumably Opdualag was looking unlikely to beat this in Relativity-098.

Doubts

Opdualag, a fixed-dose combination of Opdivo's active ingredient with the anti-Lag3 antibody relatlimab, is the only industry project with Lag3 activity to reach the market.

Since its approval in 2022, however, doubts have set in about Lag3's promise as a hot new immuno-oncology mechanism – apparently confirmed by the setbacks that followed. These include last year's quiet discontinuation of Roche's PD-1 x Lag3 bispecific tobemstomig, though this asset hadn't progressed beyond mid-stage clinical trials.

A much bigger shock came at the end of last year, when Merck & Co discontinued its anti-Lag3 MAb favezelimab, which was in pivotal development. That move came after a phase 3 failure in colorectal cancer, and earlier phase 2 disappointments in SCLC and NSCLC.

All these developments will be closely watched by Regeneron, which has claimed to have a better approach than Opdualag in its own anti-Lag3 MAb fianlimab, combined with Libtayo. However, readout of two vital phase 2/3 studies of fianlimab, in first-line NSCLC and melanoma, has slipped from 2024 into the first half of this year.

Selected Opdualag trials in key settings

Source: OncologyPipeline.