Understanding differences between EMA and FDA positions - Different indications for OPDUALAG® in Europe and USA and the reason why:
On September 15 2022, the European Commission (EC) authorised OPDUALAG® for the treatment of melanoma with tumour cell PD-L1 expression < 1%. Remarkably, the indication (SmPC 4.1) granted by the EC based on the positive CHMP opinion of July 2022 is different from the indication granted by the US FDA.
The indication wording in Europe is: Opdualag is indicated for the first line treatment of advanced (unresectable or metastatic) melanoma in adults and adolescents 12 years and older with tumour cell PD-L1 expression <1%.
The indication wording in USA is: OPDUALAG is a combination of nivolumab, a programmed death receptor-1 (PD-1) blocking antibody, and relatlimab, a lymphocyte activation gene-3 (LAG-3) blocking antibody, indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.
Why this difference?
OPDUALAG® is a combination of the antibodies relatlimab and nivolumab. Nivolumab has previously been authorised for the treatment of melanoma (as OPDIVO®); relatlimab is authorised only in combination with nivolumab in OPDUALAG®. Both antibodies are checkpoint inhibitors and work as immunotherapy of cancer, with nivolumab directed against PD-1 (programmed death receptor-1) and relatlimab against LAG-3 (lymphocyte activation gene-3).
At variance with the European decision to restrict the indication to patients whose tumors have a low (<1%) PD-L1 expression, the FDA granted a broader indication without the need for a PD-L1 assay. Both indications can be justified:
Adding relatlimab to the treatment with nivolumab clearly and obviously increased PFS. In FDA’s prescribing information, the Kaplan-Meier curve clearly illustrate the superiority of OPDUALAG over nivolumab alone - obviously supporting the broader indication granted by FDA.
On the other hand, when CHMP looked at subgroups with a cut-off at 1% PD-L1, it seemed that the overall positive result is driven by the subgroup with tumour cell PD-L1 expression smaller than 1% - which is why EMA preferred the more restricted indication: OPDUALAG is indicated for the first line treatment of advanced (unresectable or metastatic) melanoma in adults and adolescents 12 years of age and older with tumour cell PD-L1 expression <1%. (https://www.ema.europa.eu/en/documents/smop-initial/chmp-summary-positive-opinion-opdualag_en.pdf)
Kaplan-Meier plot of PFS per BICR by baseline PD-L1 expression – All randomised subjects (28-Oct-2021 DBL)
Interestingly, this observation, that a second checkpoint inhibitor, which is added to nivolumab, works best in patients with low PD-L1 is not completely new. We have seen a similar subgroup effect for the combination of nivolumab (OPDIVO®) and ipilimumab (YERVOY®) we have seen a similar subgroup effect (https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf).
When the combination of nivolumab (OPDIVO®) and ipilimumab (YERVOY®) was approved for the treatment of melanoma, CHMP considered this subgroup difference important enough to justify the following addition to the indication (SmPC 4.1): Relative to nivolumab monotherapy, an increase in progression-free survival (PFS) and overall survival (OS) for the combination of nivolumab with ipilimumab is established only in patients with low tumour PD-L1 expression (see sections 4.4 and 5.1).
It looks like there’s a kind of ceiling effect for these checkpoint inhibitors, and if this ceiling has already been reached by nivolumab alone - in patients with high PD-L1 expression - another checkpoint inhibitor apparently will not add much benefit. With relatlimab, the second example after ipilimumab, for such a subgroup difference, it may seem reasonable to consider similar effects for future combinations of checkpoint inhibitors, at least with other anti-LAG-3 monoclonal antibodies, such as fianlimab. It might even be advisable to look for similar subgroup effects in trials combining other checkpoint inhibitors as well.