Passing mention of Merck & Co’s Keynote-407 study on Tuesday’s first-quarter earnings call sent the sellside into a panic: was the low profile given at Asco to this trial, testing Keytruda plus chemo in first-line squamous lung cancer, a sign that it had failed?
Perhaps fed up with the ensuing share price decline the group today moved to scotch the doubts, revealing that Keynote-407 had hit an interim overall remission rate (ORR) endpoint, prompting immediate US accelerated approval filing. The trial’s setting is significant, but investors should remember that Keytruda already has a presence even in this tough-to-treat NSCLC histology.
It basically comes down to the way in which checkpoint-blocking antibodies are carving lung cancer into ever smaller niches. Keytruda monotherapy can already be used in first-line squamous NSCLC – if a patient’s tumour expresses PD-L1 at 50% or above.
This is thanks to the Keynote-024 trial, which had recruited NSCLC subjects with squamous as well as non-squamous histologies. This same population was studied in Keynote-042, the study that read out positively last month, and which could expand Keytruda’s addressable market to >1% PD-L1 expressers.
In the first-line NSCLC setting the drug is separately approved in all-comers in combination with chemotherapy, but this applies only to non-squamous disease.
Thus, if today’s revelation about Keynote-407 amounts to a strong enough result to support approval, it will expand the NSCLC population addressable by first-line Keytruda plus chemo to include patients with squamous histology irrespective of PD-L1 expression.
Until more substantial data are presented at Asco analysts will have to keep guessing. Before Tuesday few had even realised that Keynote-407 would feature; Merck had not highlighted the fact, and the Asco abstract titles revealed on April 25 did not mention this trial by name.
Keynote-407’s analysis is somewhat unusual; the hit on ORR, a secondary endpoint, is simply an interim trigger in “an early cohort”, and says nothing about the chances of the trial meeting its much more important co-primary progression-free and overall survival measures.
Still, it would be strange for Merck to go to such lengths to dispel fears about Keynote-407 if it did not view the ORR signal as strong. Evercore ISI’s Umer Raffat today wrote that the interim look did not include PFS or OS, but that the database was being locked today to start this co-primary endpoint analysis.
|1st-line stage IV metastatic NSCLC: the near-term battleground|
|Non-squamous histology||Squamous histology|
|PD-L1 >50%||PD-L1 1-49%||PD-L1 <1%||PD-L1 >50%||PD-L1 1-49%||PD-L1 <1%|
|Keytruda + chemo|
|Keynote-407 (NCT02775435)||NA||NA||NA||+ve for ORR||+ve for ORR||+ve for ORR|
|Keynote-042 (NCT02220894)||+ve for OS||+ve for OS||NA||+ve for OS||+ve for OS||NA|
|Tecentriq + Avastin + chemo|
|Impower-150 (NCT02366143)||+ve for OS & PFS||+ve for OS & PFS||+ve for OS & PFS||NA||NA||NA|
|Tecentriq + chemo|
|Impower-131 (NCT02367794)||NA||NA||NA||+ve for PFS||+ve for PFS||+ve for PFS|
|Opdivo + Yervoy|
|Checkmate-026 (NCT02041533)||Failed in PD-L1 >5%||Failed in PD-L1 >5%|
|Checkmate-227 (NCT02477826)||Positive in TMB-high||Positive in TMB-high|
Where does this leave Keytruda’s closest competitors, Roche’s Tecentriq and Bristol-Myers Squibb’s Opdivo? Tecentriq plus chemo recently showed a PFS advantage in Impower-131, a trial with a near-identical design to Keynote-407 (Tecentriq’s chance to seize a poorly served lung cancer type, March 20, 2018).
Opdivo is in various NSCLC trials that include squamous patients, but its best near-term bet, such as it is, is to rely on Checkmate-227, the trial in squamous and non-squamous NSCLC that it claims showed a benefit for Opdivo plus Yervoy in patients with high tumour mutation burden.
Attention thus turns to Asco. Given the timing Merck’s Keynote-407 abstract probably features nothing beyond the ORR result, but investors might be hoping that it serves as a placeholder for survival data – if these are available by June 3, the date for its presentation.
Whether Merck will want to generate survival data so soon is a separate question. The group might first want to secure accelerated approval based on ORR, safe in the knowledge that this would prove virtually impossible to overturn even if Keynote-407 later failed to improve survival.