It was almost exactly a year ago that highly positive results for two Braf/Mek inhibitor combinations in first-line melanoma were revealed – only to be overshadowed shortly afterwards by stunning Opdivo data.
Yesterday investors were again reminded of mounting pressure on the small-molecule approach, with US approval of Opdivo combined with Yervoy in the first-line setting, albeit for now in patients without the Braf mutation. The key lies in three upcoming US FDA action dates for immunotherapies – in patients irrespective of Braf status – that threaten to push Braf/Mek combos into oblivion.
The first is on November 27, when Opdivo faces an FDA decision on whether it should be moved from second to first-line use in melanoma all-comers. Then Merck & Co’s rival anti-PD-1 MAb Keytruda will face an FDA action date in first-line melanoma on December 19.
And on January 23 the Opdivo plus Yervoy regimen will see a verdict on approval in this broad setting, a decision that was recently given priority review.
If these turn out positive, as seems likely, melanoma doctors faced with an untreated patient will no longer have to be guided by their Braf status. Currently a patient with Braf-mutated melanoma should in the first instance be given a Braf inhibitor.
Other factors will come into play, and one school of thought says an aggressive Braf-mutated tumour should first be treated with a Braf/Mek combo – even with the formal availability of immunotherapies in this setting (Esmo – Mek combo competitors fight, but battle could be elsewhere, September 29, 2014).
|Selected phase III first-line melanoma studies|
|Tafinlar + Mekinist||Novartis||Combi-v||Braf-mutated pts||NCT01597908|
|Zelboraf + cobimetinib||Roche||CoBrim||Braf-mutated pts||NCT01689519|
|Opdivo||Bristol-Myers Squibb||Checkmate 066||Braf wild-type pts||NCT01721772|
|Opdivo + Yervoy||Bristol-Myers Squibb||Checkmate 069||Primary endpoint in Braf wild types||NCT01927419|
|Opdivo + Yervoy||Bristol-Myers Squibb||Checkmate 067||All comers||NCT01844505|
|Keytruda||Merck & Co||Keynote-006||All comers||NCT01866319|
Yesterday’s approval related to Bristol’s Checkmate 069 study, which while recruiting all-comers measured a primary endpoint (overall response) only in Braf wild types. Standalone Opdivo was filed in first-line use based on Checkmate 066, a study in Braf wild types stopped early for efficacy last year, and the PDUFA date has been delayed to November 27 to consider a label in all patients.
Meanwhile, the Checkmate 067 trial – in first-line melanoma patients irrespective of Braf status – will serve as the basis for the January 23 decision on broad use of Opdivo plus Yervoy. At Asco Bristol-Myers Squibb reported promising progression-free survival data from this, but overall survival results are not yet available.
As things stand it is hard to draw firm conclusions across several trials. The Combi-v study yielded median overall survival of 25.6 months for Novartis’s Tafinlar plus Mekinist, while the Cobrim trial of Roche/Exelixis’s Zelboraf plus cobimetinib has yet to reach a median figure, though the two studies’ progression-free survival benefits look similar.
Beyond efficacy it will also be vital to remember cost, and that of Opdivo plus Yervoy looks to come in at roughly $256,000 per patient per year. Tafinlar and Mekinist cost $91,200 and $104,400 respectively.
And the convenience of a pill versus an antibody infusion is obvious, but so is that of potentially not even needing to check a patient’s Braf status before commencing treatment. All these factors will determine the continuing relevance of Braf/Mek inhibitors in the face of immuno-oncology’s onslaught.
According to EvaluatePharma consensus 2020 sales forecasts for Tafinlar have slid from $736m to $674m since April, while those for Zelboraf have been cut 29% to $306m in the past year. It looks like the sellside is starting to assume the inevitable.