Need to know:
- The approval of Opdualag in first-line melanoma is considered a major step in the checkpoint inhibitor space as it’s the first time in years that a new approach has secured FDA approval.
- There is likely to be a domino effect, with ongoing trials’ forthcoming data now likely to be compared to Opdualag’s results as an efficacy and safety barometer. The use of monotherapy as an active comparator in forthcoming trials may now also be out of date.
- While Opdualag is an advance, there are still unanswered questions, specifically relating to how it fits into the broader treatment spectrum, with available therapies still likely to be ideal for certain subpopulations.
Ongoing first-line melanoma clinical trials may now have to at least match the efficacy and safety profile of Bristol Myers Squibb’s recently approved Opdualag combination to be considered a success, experts say. Further, clinical trials currently being designed are now less likely to use a checkpoint inhibitor monotherapy as an active comparator, with two combos available in the market, they add. There is still some argument of sticking to a monotherapy comparator, but there is work to be done to optimise this design, some note.
Uptake for the Opdualag combo is likely to be swift owing to its convincing efficacy data so far and its positive side-effect profile, experts also say. Yet there are still questions, particularly as to where Opdualag would fit into the treatment spectrum, since there is still clinical value to available front-line melanoma therapies. These options are BMS’s own combo of anti-CTLA-4 antibody Yervoy (ipilimumab) plus the anti-PD-1 antibody Opdivo (nivolumab), and Opdivo alone.
On 18 March, BMS’s Opdualag secured FDA approval in adult and paediatric patients 12 years of age or older with unresectable or metastatic melanoma. An EMA approval is also likely, even if the regulatory body is more interested in overall survival (OS) data, which Opdualag needs more of.
Opdualag, which is a combination of LAG-3-blocking antibody relatlimab + Opdivo, was heralded as a step forward in the checkpoint inhibitor space as relatlimab’s mechanism may open the door to a new approach.
Melanoma clinical trials need to reflect Opdualag data
It is no longer feasible to have monotherapy as a head-to-head comparator due to availability of the two combos, says Opdualag investigator Dr Paolo Ascierto, melanoma unit director at the National Tumor Institute, Fondazione G Pascale in Naples. All forthcoming data will be compared to Opdualag results by the melanoma community, adds Opdualag investigator Dr Dirk Schadendorf, department of dermatology director at the University Hospital Essen, Germany.
There are patients receiving anti-PD1/PD-L1 monotherapy in the adjuvant setting, which also argues the case for a combo as an active comparator arm in first-line trials, Ascierto says. These trials will have to separate patients who received an anti-PD1/PD-L1 in the adjuvant setting and those who have not, he adds.
Monotherapy comparator still in melanoma clinical trials?
It could be argued that a single-agent active comparator can still be used in future first-line trials, notes Dr Ahmad Tarhini, cutaneous clinical and translational research director at the Moffitt Cancer Center. Monotherapy approaches are still efficacious in certain patients as well as having better safety profiles than combo approaches, he explains. Yet, there would be the need to single out these specific patients who should get monotherapy in the first place, he adds.
It is not so clear which patients would benefit more with a monotherapy, says Dr Ryan Joseph Sullivan, medicine associate professor, Harvard Medical School. Perhaps biomarkers can help find these patients, he notes.
While biomarkers are being investigated by the industry, older patients and those with underlying autoimmune disease may be ideal candidates for monotherapy, he adds. Patients with low tumour burden and ones with tumour sites confined in lymph nodes would be ideal for monotherapy, Tarhini notes.
But using a single-agent active comparator in first-line trials will not reflect what is happening in the melanoma space, Sullivan notes. “Trials need to reflect what’s done in the field.”
Indeed, uptake is likely to be swift for Opdualag among clinicians, Sullivan says, adding there is no new learning curve in terms of administration of an infusion therapy, much like other checkpoint inhibitors. Opdualag’s positive safety profile is too hard to ignore to not be considered by clinicians, Ascierto says.
EMA approval likely to follow
The EMA is also likely to approve Opdualag due to its existing data, Ascierto says. While clearer OS data is still forthcoming, for which the EMA is more cognizant about to support a regulatory nod, other data elements are convincing for approval, he adds. Schadendorf agrees, adding the EMA will nonetheless require additional reporting on OS. That said, until BMS reports OS data in Europe, there could be difficult negotiations for reimbursement in many countries, delaying access, he adds.
Nevertheless, new drugs in first-line melanoma are still welcome as there is still room for improvement, particularly on OS, Ascierto says. In the Phase III CHECKMATE-067 trial studying Opdivo + Yervoy, the combo’s OS is 52% at five years. Meanwhile, in the Phase II/III RELATIVITY-047 trial, in the secondary endpoint of OS, Opdualag’s is 55.8% at 36 months.
Opdualag’s OS trajectory is currently trending positively despite salvage therapy potentially blurring the data, Tarhini says. Opdualag patients who have access to Opdivo + Yervoy will likely be prescribed the second combo as well if needed as a form of salvage therapy, he explains.
FDA approval logical
The FDA approval of Opdualag was supported by its Phase III registrational data showing it is superior to Opdivo monotherapy in the progression-free survival (PFS) primary endpoint, Ascierto says. In RELATIVITY-047, Opdualag offered 10.1 months median PFS versus 4.6 months with Opdivo alone (p=0.0055).
Opdualag has an edge over Opdivo + Yervoy in terms of safety, Sullivan says, adding: “That’s a big deal.“ In RELATIVITY-047, there were no new safety events with Opdualag compared with Opdivo alone, although Grade 3 and 4 drug-related adverse events were 18.9% with Opdualag and 9.7% with Opdivo. Opdualag is not dramatically more toxic than Opdivo monotherapy, in context of Opdivo + Yervoy being more toxic than Opdivo alone, he explains.
Unanswered questions remain
Yet there are still several unanswered questions regarding Opdualag, which may be answered once it has broader use. Sullivan says there is the question of whether Opdivo + Yervoy has been displaced as a standard in front-line melanoma. There are situations where Opdivo + Yervoy’s higher toxicity risk may be worthwhile for certain patients, such as those with brain metastasis, with rapidly progressing disease, or who are very symptomatic, he notes.
Patients with high tumour burden and ones with mucosal and acral melanoma will also likely stick with Opdivo + Yervoy, Ascierto and Schadendorf add. “I wouldn’t use the new combo where [Opdivo + Yervoy] is the clear standard,” Sullivan notes.
There is also the question of if Opdualag should be used in patients who have progressed from Opdivo + Yervoy in the front-line setting, Sullivan says. Inversely, there is the question if Opdualag failure patients would be responsive to Opdivo + Yervoy, Schadendorf adds. Sullivan says: “We need more data—but there is the temptation to offer [Opdualag] to everyone.”