US regulator slows down the immuno-oncology runaway train


It would be an exaggeration to call Friday’s US complete response letter for Opdivo anything more than a minor setback, though it represents the first sign of the FDA putting a barrier in front of the anti-PD-1 runaway train.

This small blip came in a week during which the Bristol-Myers Squibb drug extended its lead over Merck & Co’s Keytruda by some margin (see table below). Still, the US regulator’s reluctance to approve it in first-line melanoma patients harbouring the Braf mutation shows that there might after all be life in small-molecule approaches from Roche, Novartis and Exelixis.

These small-molecule combinations – namely Novartis’s Tafinlar plus Mekinist, and Roche/Exelixis’s Zelboraf plus Cotellic, were making headway in their approved indication of Braf-mutated melanoma. But the question was to what extent a patient’s Braf status would be relevant given the onslaught of the anti-PD-1s (More pressure mounts on the Braf/Mek combo, October 2, 2015).

Not lost yet

Now it seems that all is not lost for the small molecule combos. On Friday the US regulator said it would need additional data before approving Opdivo in first-line, Braf-mutated patients, putting it at odds with its European counterpart, which has approved both Opdivo and Merck’s rival, Keytruda, in first-line melanoma irrespective of Braf status.

The US complete response letter was the first setback for Opdivo, which has stormed through indications and lines of therapy since first getting US approval 11 months ago, for second-line melanoma. The past week alone saw it get the US nod for first-line disease – in Braf wild types – and renal cell cancer, a brand new use.

Keytruda is still indicated only for melanoma and lung cancer, and its US melanoma label is restricted to second-line patients. The FDA did approve Keytruda before Opdivo, but that was Merck’s only advantage; the Bristol drug actually got its first green light in Japan, in July 2014.

Opdivo also leads in NSCLC, since it is now approved in non-squamous as well as squamous patients irrespective of PD-L1 status; Keytruda got the green light in NSCLC irrespective of histology, though patients’ tumours had to test positive for PD-L1, as determined by a Dako companion diagnostic.

It is not clear how long this anomaly will persist, especially given the poor predictive power of the PD-L1 biomarker.

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 First I-O combo in cancer; Checkmate-069 study
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)
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

As far as combinations go, only Opdivo has formally been approved together with Bristol’s Yervoy, though of course Yervoy’s standalone availability means that it can theoretically be combined with Keytruda.

As a recent EP Vantage report pointed out, combinations are the next stage of immuno-oncology’s advance. Yervoy is already being studied in 21 trials combining it with Opdivo, though Merck is running its own studies with Ketyruda (Merck & Co shows the way in immuno-oncology combinations, November 23, 2015).

Combo use represents a separate part of the equation, and Merck will undoubtedly work hard not to lose ground.

EP Vantage has published a broad overview of the current landscape for anti-PD-1/PD-L1 combination therapeutics. A free copy of the report is available by download.

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

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