Weeks after catching up with Merck & Co’s Keytruda by securing its first US approval for melanoma, Bristol-Myers Squibb’s rival Opdivo has shown that it stands a chance of matching it in the much bigger indication of lung cancer, too.
Yesterday’s interim halt for efficacy of Opdivo’s Checkmate-017 trial allays the risk of the US FDA deeming Bristol’s Checkmate-063 data insufficient. Attention now turns to this year’s interim readout of two further NSCLC studies – Checkmate-057 and Keynote-010 – that will show how Bristol and Merck’s respective anti-PD-1 antibodies will initially carve up this market.
Not wanting to be outdone, Merck this morning said it would file Keytruda for second-line treatment of EGFR and Alk-negative lung cancer by the middle of this year; Opdivo’s rolling submission was to have been completed by the end of 2014, though whether it was has not been confirmed.
This is all about first-mover advantage, since eventually analysts expect the two drugs to be evenly matched in terms of efficacy and revenue generation. EvaluatePharma consensus data for sales by indication compute 2020 lung cancer revenues for Keytruda and Opdivo of $3.4bn and $3.6bn respectively.
Heading for approval
Already it was pretty clear that the Bristol drug was heading for approval in NSCLC after the 063 trial read out last October (Bristol checkmates lung study and trades like a biotech, October 31, 2014).
But 063 was a single-arm study that only measured overall response rate. The important thing about the open-label 017 trial is that it compared Opdivo against Taxotere, and its primary endpoint was overall survival – a measure where a sufficient advantage has now been seen for the trial to be halted at its interim analysis.
It had not been clear whether the FDA would approve Opdivo based on the third-line 063 data alone, or whether it would await the readout of 017 with its more robust endpoint and second-line setting. Yesterday’s interim halt makes this point irrelevant.
The question now becomes whether initial indications will differ as to histology. Opdivo’s 063 and 017 successes came in the tough-to-treat squamous tumours, which comprise 30% of NSCLCs, whereas Merck is testing Keytruda in squamous and non-squamous types in the Keynote-010 trial, expected to yield survival data in September.
This is where a third Bristol study comes into play: Checkmate-057 tests Opdivo in second-line non-squamous NSCLC, and is subject to an interim analysis in the first half of 2015. A final twist is that in Keynote-010 selects patients based on their PD-L1 status, whereas Opdivo’s NSCLC studies recruited all comers.
While this might indicate a smaller initial pool of NSCLC patients for Keytruda, Bernstein analysts expect a 2015 approval for the drug in patients irrespective of PD-L1 status. An interim halt in 057 would put Opdivo level with the Merck drug and render the histology question moot.
|Selected anti-PD-1 studies in NSCLC|
|Opdivo||Checkmate-017||272 2nd-line squamous NSCLC pts, vs Taxotere||NCT01642004|
|Opdivo||Checkmate-057||574 2nd-line non-squamous NSCLC pts, vs Taxotere||NCT01673867|
|Keytruda||Keynote-010||920 PD-L1-positive NSCLC pts, any histology, vs Taxotere||NCT01905657|
Opdivo’s actual survival benefit over Taxotere in 017 has not been revealed, and while a positive result had been widely expected the interim halt came as a surprise: Bristol shares were up 4% in early trade today, while Merck rose 1%.
It is thus clear that checkpoint inhibition is still a hot area, notwithstanding the recent surge of enthusiasm in chimaeric antigen receptor (CAR) T-cell therapy. In a flurry of news announcement in the run-up to the JP Morgan healthcare conference, Agenus last week said it had licensed immuno-oncology projects to Incyte for $25m in up-front cash plus a $35m equity investment.
The initial focus of the deal will be assets targeting GITR, Ox40, TIM3 and LAG3. $60m, plus up to $350m in possible milestones, is a great result for Agenus, which had picked up the assets a year ago when it bought a cash-strapped private biotech, 4-Antibody, for just $10-40m in shares.
Such asset appreciation shows that immuno-oncology is set to remain a key investment theme in 2015, and further PD-1 approvals and the search for new checkpoint targets will be its most important aspects.