Keytruda’s US approval for first-line melanoma irrespective of patients’ Braf status allows Merck & Co to narrow the gap against Bristol-Myers Squibb’s Opdivo, but it also shows how the US and European regulators’ views have diverged.
Both anti-PD-1 MAbs are already approved in this setting in Europe, but with Opdivo the US FDA refused to follow suit when it slapped Bristol with a complete response letter last month (see table below). And a separate question is where the Keytruda approval leaves small-molecule Braf/Mek inhibitors from Novartis and Roche.
Opdivo’s failure to secure US approval in first-line Braf-mutated melanoma patients seemed to give renewed hope for the small-molecule approach in this patient subgroup (US regulator slows down the immuno-oncology runaway train, November 30, 2015).
Novartis’s Tafinlar and Mekinist, and Roche/Exelixis’s Zelboraf and Cotellic, are approved for treating melanoma harbouring the activating Braf mutation that is present in some 40% of cases. Doctors tend to like these small-molecule drugs on account of their simplicity and the solid effect they bring about in these patients, especially in aggressive disease.
Whether the availability of Keytruda to this population hits small-molecule agents’ sales will be down to physicians. On one hand, small molecules are simple and effective, but on the other Keytruda now offers a first-line melanoma option without even needing to test a patient’s Braf status.
Comparing clinical evidence here is difficult, even before considering the fact that drawing conclusions from unrelated studies is fundamentally unsound.
Median progression-free survival with Mekinist/Tafinlar and Zelboraf/Cotellic is between nine and 11 months in this setting. The Keytruda approval was based on Merck’s Keynote-006 trial versus Yervoy, in which some 36% of participants had Braf-mutated melanoma; however, the data for this subgroup have not been split out.
The case of Opdivo is stranger still. Studies forming the basis for its EU approval in first-line Braf-positive disease were Checkmate-066 and 037; but the former was specifically in Braf wild-type patients, while the latter looked at second-line disease.
In announcing the US complete response letter Bristol said it had sought US approval on the basis of Checkmate-066 as well as some unspecified data relating to Opdivo in Braf-positive metastatic melanoma. Ultimately the issue will be resolved in real practice, as well as perhaps in the readout of an NCI-sponsored study comparing different treatment sequences in Braf-positive melanoma.
Moreover, as of October doctors have had the option of treating Braf-mutated melanoma first line with Opdivo plus Yervoy, and this immunotherapy approach has been listed in US National Comprehensive Cancer Network guidelines for some time, with Braf/Mek inhibitors only “preferred” if needed for early response.
Were it not for Yervoy’s notorious toxicity, any advantage Keytruda had over Opdivo would be purely academic.
|Anti-PD-1 MAb approvals in major Western markets|
|Opdivo (Bristol-Myers Squibb/Ono)|
|27 Nov 2015||US||Monotherapy||1st-line Braf-positive melanoma||Complete response letter|
|24 Nov 2015||US||Monotherapy||2nd-line renal cell carcinoma||First anti-PD1 to show OS benefit in renal cancer|
|24 Nov 2015||US||Monotherapy||1st-line Braf-W/T melanoma||Checkmate-066 study|
|9 Oct 2015||US||Monotherapy||2nd-line non-squamous NSCLC||Checkmate-057 study|
|1 Oct 2015||US||Yervoy combo||1st-line Braf-W/T melanoma||1st I-O combo in cancer; Checkmate-069|
|20 Jul 2015||EU||Monotherapy||2nd-line squamous NSCLC||–|
|19 Jun 2015||EU||Monotherapy||1st & 2nd-line melanoma regardless of Braf status||Checkmate-066 & 037 studies|
|4 Mar 2015||US||Monotherapy||2nd-line squamous NSCLC||Checkmate-017 study|
|22 Dec 2014||US||Monotherapy||2nd-line melanoma||First US approval; Checkmate-037 study|
|Keytruda (Merck & Co)|
|18 Dec 2015||US||Monotherapy||1st-line melanoma regardless of Braf status||Keynote-006 study|
|2 Oct 2015||US||Monotherapy||2nd-line PD-L1-positive NSCLC||Keynote-001 study|
|22 Jul 2015||EU||Monotherapy||1st & 2nd-line melanoma regardless of Braf status||Keynote-001, 002 & 006 studies|
|4 Sep 2014||US||Monotherapy||2nd-line melanoma||First anti-PD-1 agent to get US approval; Keynote-001 study|