Immuno-oncology is Merck & Co’s world – everyone else just lives in it. US approval of Keytruda in first-line non-small cell lung cancer in combination with chemotherapy for now makes this the PD-1 to beat, especially given setbacks to rivals from Bristol-Myers Squibb and Roche.
What was once a neck-and-neck duel for dominance of this space has turned decidedly against Bristol’s Opdivo, reflected in investor reaction to yesterday’s post-market announcement. Merck shares rose 3% in post-market trading – reflecting the belief that a potential outcome was a three-month delay – while Bristol shares sank 1%.
The chemo-combo approval opens the door to wider use of Keytruda in the first-line setting since, unlike its first-line monotherapy approval, patients need not show any expression of PD-L1. Combining with chemo can turn the tumour immunogenic and make it amenable for checkpoint blockade (Event – Merck’s daring bid for lung cancer domination, April 28, 2017).
Winning approval on the small Keynote-021 data was not guaranteed, but Merck’s stealthy submission on that basis at least suggested confidence that it would be sufficient – regulators would surely have made it clear that it had no chance if the data were not robust. Confirmation that a filing has been accepted in Europe on the back of the same data suggests approval could come in another important region later this year.
Analysts were quick to caution that approval did not mean that Merck would own the entire first-line lung cancer space – Bernstein’s Tim Anderson noted that the combination with Alimta applied to only 25% of first-line NSCLC. More broadly, Mr Anderson said, it is endorsement of the chemo combo approach that the FDA was willing to approve Keytruda on a smaller phase II study.
Squandering a lead
The first-line lung cancer space was thrown wide open last last summer when Bristol-Myers Squibb’s Opdivo failed to beat chemo in the hotly awaited Checkmate-026 study.
The shock failure saw many competitors scrambling to amend and enlarge trials to increase chances of success (Roche powers up for first-line lung duel, February 2, 2017). While both Keytruda and Opdivo are approved in second-line lung cancer, the Merck drug later became the first anti-PD-1 MAb to gain a first-line label – albeit only in patients with 50% or greater PD-L1 expression.
Roche has made chemo the cornerstone of its combo effort, and Impower-150, which adds Avastin into the mix, will be the first of four such studies to read out.
A separate challenge was thought to be imminent from Bristol itself, based on pooled data from the uncontrolled Checkmate-012 and 568 trials of various Opdivo combos, including with Yervoy and chemo, but this early-filing effort was abandoned in January.
A third threat to Keytruda could come from Astrazeneca’s combination of Imfinzi and tremelimumab. The twice-amended Mystic trial has given Astra several shots on goal – assuming sufficient powering remains – and this complex study could yield progression-free survival data in mid-2017.
However, it is not clear what PD-L1 cutoffs the UK company is using; if it were to show a benefit in >25% PD-L1 expressers that would still leave others a chunk of the market to go after. But success is not a foregone conclusion – Evercore ISI’s Umer Raffat recently said he doubted that Mystic would show a PFS benefit, but admitted that overall survival benefit in PD-L1-high patients was possible.
This points to the difficulties of interpreting survival data in immuno-oncology: PFS can be ruined by pseudoprogression, where the tumour grows before shrinking, while an overall survival benefit can be masked by failing placebo patients switching to active treatment.
There is much to play for here. But the Merck has earned the lead thanks to competitor missteps and fortunate clinical outcomes – now is the time for it to consolidate that advantage.