Opdualag sets its sights on lung

Yesterday’s revelation that the phase 2 first-line NSCLC Relativity-104 study of Bristol Myers Squibb’s Opdualag would feature as an ESMO late-breaker came on the same day that a phase 3 trial in this setting appeared at long last on the clinicaltrials.gov registry.

Remarkably, Bristol had once planned to begin this phase 3 study, now known as Relativity-1093, by the end of 2021; but an apparent gating factor to that move was the result of Relativity-104, a trial that itself has been delayed by over two years. It’s promising that Opdualag is making progress beyond melanoma, but intervening setbacks in other cancer types continue to weigh heavy.

These setbacks have included clinical study failures in colorectal, gastric and liver cancers, casting doubt on Bristol's ability to move Opdualag beyond the first-line melanoma setting of its first and so far only approval. That too has been set back, as the EMA refused to follow the FDA with a broad label, and restricted the drug to PD-L1 low expressers only.

Lung relevance

The first-line NSCLC opportunity has become important especially given the failure of Merck & Co’s rival anti-Lag3 MAb favezelimab in the Keytruda combo Keynote-495 trial, but clearly Bristol has wanted to generate sufficient mid-stage backing before launching a pivotal programme.

It might be assumed that such backing now exists, given ESMO’s decision to grant Relativity-104 a late-breaker slot on 14 September. Nothing has so far been revealed about this trial’s results, which at one point had been expected in early 2022. Later investor decks had Relativity-104 as a 2023 readout, before this slipped into the current year.

The delay to the phase 3 study is even more striking. All the way back at Bristol’s first-quarter 2021 financials presentation the group’s chief medical officer, Samir Hirawat, stated: “By the end of the year we can initiate a phase 3 programme in [NSCLC] if we have tolerability that is demonstrated in that early trial that we're looking at.”

An obvious reason for the three-year delay therefore is that such backing has not been forthcoming – until now.

104 vs 1093

If Relativity-104 is about to yield positive data at ESMO it’s worth considering how that trial’s design compares against that of Relativity-1093, which according to the US trials registry is to begin on 20 September.

Both studies combine Opdualag with platinum chemo, and enrol stage IV NSCLC patients who haven’t had prior systemic treatment in the metastatic setting. But there the similarities end: while Relativity-104 enrolled patients irrespective of PD-L1 expression levels, the phase 3 trial sets 1-49% as a recruitment criterion.

It might therefore be assumed that Relativity-104 hasn’t shown a benefit for Opdualag in ≥50% PD-L1 expressers. There’s also a key difference in the comparator arm: Opdivo plus chemo in Relativity-104, and Keytruda plus chemo in Relativity-1093. Logically phase 3 has overall survival as primary endpoint, versus ORR and safety in the phase 2 trial.

At present the reasons behind the design differences can only be guessed at; the long-awaited ESMO data will provide at least some answers.

Selected Opdualag trials in key settings

Source: OncologyPipeline.

ESMO will take place in Barcelona, Spain, on 13-17 September 2024.