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.
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|
|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.|