What’s next for relatlimab?

The Lag3 inhibitor is now approved in melanoma, but Bristol looks unlikely to stop there in its search for a safer Yervoy.

If in relatlimab Bristol Myers Squibb was looking for a less toxic drug than Yervoy to complement Opdivo then the first pillar of this strategy is in place. The Opdivo/relatlimab combo, now trademarked Opdualag, was last week approved for front-line melanoma, with no delay and no nasty label surprises.

Investors will naturally now want to know what Bristol has up its sleeve. An analysis by Evaluate Vantage has pinpointed nine additional studies in over 4,000 patients that should give a clue as to whether relatlimab might augment Opdivo or replace Yervoy in the established drugs’ approved uses, and maybe in new indications, beyond metastatic melanoma.

Of course, publicly Bristol is not about to give up on Yervoy, a drug whose sales rose 20% last year to $2bn despite its association with numerous adverse reactions, many on account of immune system activation.

But analysts at Mizuho, for instance, already see Opdualag replacing Opdivo monotherapy in first-line melanoma, and capturing a significant chunk of the Opdivo/Yervoy combo’s share here. This view is driven by Opdualag’s preferable safety profile, though the analysts stress that head-to-head comparison of long-term survival data will be needed for Opdualag to be considered in preference to Opdivo plus Yervoy in this setting.

Lung cancer

Perhaps the next really big readout for relatlimab is a front-line NSCLC trial combining the drug with Opdivo with or without chemo, and comparing these regimens against Opdivo alone. This will measure progression-free survival as a co-primary endpoint, but it is not clear whether in itself it could back a regulatory filing.

One difficulty is that this study does not appear to use an appropriate comparator drug. Opdivo monotherapy is not approved for front-line NSCLC, though it is available as a Yervoy combo in ≥1% PD-L1 expressers, or as a Yervoy plus chemo combo in all-comers.

Meanwhile, the Relativity-098 trial, which might yield data in 2025, is a phase 3 study designed to extend Opdualag’s use into adjuvant melanoma, where Opdivo and Yervoy are both approved as monotherapies, but where competition exists in the form of Merck & Co’s Keytruda.

Selected Bristol-sponsored relatlimab studies
  Approved therapy?
Trial Condition Design Enrolment Opdivo Yervoy Opdivo + Yervoy
NCT01968109 Solid tumours Relatlimab +/- Opdivo 1,499 NA NA NA
Relativity-098* Adjuvant stage III-IV melanoma Opdivo + relatlimab vs Opdivo 1,050 Y Y N
Relativity-047 1st-line melanoma** Opdivo + relatlimab vs Opdivo 714 Y Y Y
Checkmate-358 Various tumours, incl neoadjuvant Opdivo +/- relatlimab, Yervoy or Darzalex 584 NA NA NA
NCT04623775 1st-line NSCLC Opdivo + relatlimab +/- chemo vs Opdivo 520 N N Y
Relativity-073 2nd-line hepatocellular carcinoma Opdivo + relatlimab vs Opdivo 250 N^ N Y
NCT03662659 Gastric/GEJ cancers Opdivo + relatlimab + chemo vs Opdivo + chemo 274 Y N N^^
NCT02061761 R/r B-cell malignancies Relatlimab +/- Opdivo 107 N N N
Relativity-069 Classical Hodgkin & non-Hodgkin lymphoma Opdivo + relatlimab (uncontrolled) 68 Y~ N N
Relativity-059 Solid tumours (China study) Opdivo + relatlimab (uncontrolled) 12 NA NA NA
Notes: *phase 3 study; **approved Opdualag indication; ^approval in this indication was withdrawn; ^^awaiting approval for oesophageal squamous cell carcinoma; ~approved in 3rd-line classical Hodgkin lymphoma. Source: product labels & clinicaltrials.gov.

Also not to be underestimated is a solid tumour trial with a primary completion date of September this year, the biggest Bristol-sponsored relatlimab study, according to clinicaltrials.gov. This enrolled patients with a variety of solid tumours, and interestingly tests relatlimab monotherapy as well as an Opdivo combo.

Formally this is a phase 1/2 study primarily testing overall responses and adverse events, but it could provide Bristol with vital insight into which additional cancers to focus on. Notably, this began in 2013 seeking to enrol just 168 subjects, but today has an enrolment target of 1,499.

Relativity-047, the trial that backed Opdualag’s metastatic melanoma approval, showed a 19% rate of serious treatment-related adverse events, versus 59% in Opdivo/Yervoy’s pivotal Checkmate-067 study. The potential for this kind of safety advantage alone explains Bristol’s investment into a programme whose phase 2 and 3 studies comprise over 5,000 patients.

Yervoy US approval summary
Approval date Therapy Indication Supporting trial(s)
Not approved* Yervoy or chemo combo 1st-line oesophageal squamous cell carcinoma Checkmate-648 study
2 Oct 2020 Opdivo combo 1st-line mesothelioma Checkmate-743 study
26 May 2020 Opdivo combo 1st-line Alk & EGFR -ve NSCLC Checkmate-9LA study
15 May 2020 Opdivo combo 1st-line PD-L1 +ve (≥1%), Alk & EGFR -ve NSCLC Checkmate-227 study part 1a
10 Mar 2020 Opdivo combo 2nd-line liver cancer Checkmate-040 study
10 Jul 2018 Opdivo combo 2nd-line MSI-H or mismatch repair-deficient colorectal cancer  Checkmate-142 study
16 Apr 2018 Opdivo combo 1st-line intermediate or poor risk renal cancer Checkmate-214 study
30 Sep 2015 & 23 Jan 2016 Opdivo combo 1st-line melanoma  Checkmate-067 & 069 studies
28 Oct 2015 Monotherapy Adjuvant stage III melanoma CA184-029 study
25 Mar 2011 Monotherapy 2nd-line melanoma MDX010-20 study
Note: *28 May 2022 Pdufa date. Source: product labels.

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