It seems Keytruda is cursed to repeatedly have its first-mover advantage quickly snuffed out by Opdivo. The most recent case is US approval in second-line non-small cell lung cancer (NSCLC), in which Merck & Co’s leadership position in non-squamous disease disappeared within a week as Bristol-Myers Squibb’s agent gained approval with an arguably broader label.
The competitive landscape is probably more complicated than questions over use in squamous/non-squamous or PD-L1-positive patients, given that US clinical guidelines and European payers will have as much weight in uptake as the labelled indications. The sell-side has taken the view that NSCLC will be fiercely fought for 2015, but Opdivo will begin to outdistance its rival starting next year (see table below).
The week that was
When the dust settled on a week’s worth of second-line NSCLC approvals, the score looked a bit lopsided: Keytruda won approval in patients both with squamous and non-squamous tumours that have tested positive for the programmed death 1 ligand (PD-L1). Opdivo, which like Keytruda acts on the programmed death 1 pathway, added the non-squamous histology to the previously approved squamous, but importantly in all comers.
|Opdivo vs Keytruda vs atezolizumab in NSCLC (WW sales, $m)|
However, the FDA signalled a preference that Opdivo be directed toward the PD-L1 positive patients in both the language of the announcement and the fact that, on the same day as Opdivo got the nod, the agency granted approval to a PD-L1 diagnostic from Agilent Technologies’ Dako division.
The significance of the PD-L1 biomarker in these immuno-oncology agents has been hotly debated. The Checkmate 057 trial showed it does matter (Asco – The quest for immuno-oncology biomarkers, May 29, 2015). On the other hand, Roche’s recent late-stage lung cancer data from the similarly acting atezolizumab should have done little to dissuade those who believe they should be used regardless of status, as its effectiveness looks almost identical to Opdivo’s in the all-comer population (ECC – Roche looks ready for the PD-L1 lung cancer chase, September 27, 2015).
Roche's data should only reinforce the hypothesis that the immuno-oncology antibodies acting on this PD-1/L1 pathway, Keytruda included, are the same.
Beyond the FDA
US oncologists’ view on this question should be made a little clearer after the National Comprehensive Cancer Network’s NSCLC guideline panel meets next month. The oncologists could, of course, decide to stick to what the label says, but the voices calling for broader use could also easily win the day.
But this is likely a debate for the US alone. In the cost-constrained European markets, Opdivo’s price tag – $31,215 a year in lung cancer in the US, a figure that will likely be similar for Keytruda – will almost certainly drive emphasis in the PD-L1 positive population.
Moreover, the move to use PD-1/L1 agents first line is more likely to be driven by biomarkers. The big trials – Keynote 042 for Keytruda and Checkmate 026 for Opdivo – are in patients testing positive. Bernstein analyst Tim Anderson points out that the first-line market is twice the size of second line, thus making Opdivo’s current edge in all comers less relevant.
The twin FDA approvals are of course big news, but the remaining uncertainties about the most appropriate patients mean that the views of practising oncologists and payers will be as important as the regulators’. These have yet to be fully articulated.