De-escalation in ≥1% PD-L1 metastatic melanoma: the time has come!
Time to revisit dual checkpoint inhibition based on PD-L1 testing in metastatic melanoma.
Today, there is a special flavor in presenting the piece we published with Marco Donia in JAMA Oncology. Why? Simply because this work will allow patients to be spared unnecessary toxicities while achieving similar outcomes.
As a quick background, in the first-line setting of patients with metastatic melanoma, the CheckMate-067 trial had 3 arms:
(1) dual checkpoint inhibition (nivolumab plus ipilimumab) : G3-4 toxicities = 59%
(2) nivolumab alone : G3-4 tox = 24%
(3) ipilimumab alone : G3-4 tox = 28%
The trial tested the dual therapy = (1) and nivolumab = (2) against ipilimumab = (3), and both (1) and (2) were superior to (3). In practice, many clinicians favor dual checkpoint inhibition (1) over nivolumab alone (2). This is based on better response rates, better PFS, better long-term survival. However the trial was not formally designed to compare (1) with (2), and there is no statistical difference in overall survival between the 2 arms.
Immune related toxicities may be long-lasting, disabilitating, and can impair quality-of-life: such differences between dual checkpoint inhibition and nivolumab alone (59% versus 24% in G3-4) are therefore not trivial. For those reasons, we already advocated for a real pragmatic trial comparing the two strategies.
Then comes ≥1% PD-L1 expression
1 - In CheckMate-067 : a post-hoc analysis showed that dual checkpoint inhibition resulted in superior PFS and OS over nivolumab in patients with tumors with <1% PD-L1 expression. However, PFS and OS curves were superimposable in those whose tumors had ≥1% PD-L1 expression.
2 - In the RELATIVITY-047 trial (relatlimab plus nivolumab versus nivolumab) : again, in patients with ≥1% PD-L1 expression, the PFS curves were superimposable.
3 - the lack of benefit of adding ipilimumab to nivolumab in patients with ≥1% PD-L1 wwas observed in the real-life setting in Denmark (n = 1081) by Marco Donia and his colleagues.
There may be some situations where the dual combination may be beneficial even in patients with ≥1% PD-L1 expression, for instance in patients with brain metastasis. Check-out the full paper for other insights, here or below. However, in most patients (nearing half of them), there is now a body of evidence suggesting we could spare them from unnecessary toxicity, while achieving similar outomes.
Marco Donia is a friend. He is an Associate Professor in Copenhagen, Denmark, and a great Clinician-Scientist and researcher. He and his team are making significant inroads in the field. If you haven’t already, you should definitely follow his works, as well as his famous threads on LinkedIn. Here is our piece!
