FIRST-LINE CLINICAL TRIALS


“Uptake for the Opdualag     will nonetheless require 


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 that 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 European Medicines Agency is also likely to approve Opdualag due to its existing data, Ascierto says. While clearer OS data is still forthcoming, which the EMA is more cognisant of to support a regulatory nod, other data elements are convincing for approval, he adds. Schadendorf agrees, adding that 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 combination’s OS is 52% at five years. Meanwhile, in the Phase II/ III RELATIVITY-047 trial, in the secondary end point 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 combination 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 that it is superior to Opdivo monotherapy in the progression-free survival (PFS) primary end point, 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 the 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-lineline 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 those 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 of 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.”


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