A fresh Keytruda challenge to Opdivo and small molecules


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.

Clinical evidence

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
Date Region Therapy Indication Notes
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

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter

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