Give Merck & Co 10 out of 10 for effort. The group’s pivotal Keynote-062 study in first-line gastric cancer had yielded ambiguous topline results, yet undaunted Merck came to Asco touting Ketyruda’s potential as an alternative to chemotherapy in these patients.
Close reading of the full Keynote-062 data does not paint a pretty picture, however: at best the trial shows Keytruda monotherapy to be no worse than chemo – in some patients. But hazard ratio boundaries for all the important endpoints veer dangerously over 1.00, suggesting that some Keytruda subjects might be doing worse than those on chemo.
If nothing else this looks like a cry to identify biomarkers to pick out those patients who have a chance of benefiting on Keytruda. As it is, the standing of Merck’s drug in this cancer, where it secured a third-line label in PD-L1 ≥1% patients under accelerated approval in 2017, looks questionable.
Specifically, the cancer in question is not only gastric but also gastroesophageal junction carcinoma, a rarer though similar cancer that occurs at the point where the oesophagus meets the stomach.
It is presumably because the FDA had approved Merck’s drug in PD-L1 ≥1% expressers that the company focused on this same population in designing Keynote-062, a first-line study. This blinded trial randomised 764 subjects to Keytruda, Keytruda plus chemo, or chemo control, and measured overall and progression-free survival in the PD-L1 ≥1% population as co-primary endpoints.
The key positive finding concerned OS for Keytruda monotherapy, which though numerically lower than chemo alone was said to be non-inferior. The combo failed to show superiority on OS versus chemo, and neither monotherapy nor combination improved PFS according to the trial’s statistical plan.
An obvious elephant in the room is Keytruda’s price; why should doctors prescribe a therapy that is more expensive than chemo if it cannot be said to be superior?
Merck’s chief medical officer, Roy Baynes, pointed to Keytruda’s other attributes, such as better tolerability. “Keytruda [monotherapy] doesn’t have the toxicities of chemotherapy,” he told Vantage.
Another problem is the 95% confidence intervals, whose upper bounds exceed 1.00 for OS and PFS in the comparisons for Keytruda combo and monotherapy versus chemo alone. This hints at the possibility of some subjects doing better on chemo alone, though Mr Baynes stressed that in the case of monotherapy the upper bound was under the prespecified non-inferiority boundary of 1.20.
And in the case of PFS there is a remarkable numerical advantage for chemo versus Keytruda monotherapy, though this might be explained by the phenomenon of pseudoprogression. Mr Baynes said immuno-oncology often shows PFS pointing in the wrong direction, and that it is really “an OS story”.
|Summary of Keynote-062 (NCT02494583)|
|Median OS (PD-L1 ≥1%)||12.5mth||10.6mth||11.1mth|
|Upper bound of 95% CI||1.03||1.10|
|Median PFS (PD-L1 ≥1%)||6.9mth||2.0mth||6.4mth|
|Upper bound of 95% CI||1.02||2.01|
|Stats||Not significant||Not significant|
|Median OS (PD-L1 ≥10%)||12.3mth||17.4mth||10.8mth|
|Source: Asco, Dr Josep Tabernero.|
Merck also carried out a prespecified subgroup analysis in a narrower population of subjects, whose tumours expressed PD-L1 at ≥10%, and here Keytruda was seen to prolong OS versus chemo to a “clinically relevant” extent, though this was not tested statistically. Perversely, a smaller benefit was seen for chemo combo.
Mr Baynes said Merck had yet to reveal whether it would file for a first-line label in the ≥1% or the ≥10% PD-L1 expressing population.
Investors and doctors will also want to gauge Keynote-062’s relevance as regards Keytruda’s current availability for gastric cancer, under accelerated approval for third-line treatment. Realistically there is little chance of this being rescinded, though it must be borne in mind that a separate potentially confirmatory study, the second-line Keynote-061 trial, also failed.
On the other hand, a first-line approval on the basis of Keynote-062 might be seen by some as a long shot, notwithstanding claims by the trial's lead investigator, Dr Josep Tabernero, from the Institute of Oncology in Barcelona, Spain.
At today's Asco press conference he insisted that Keytruda could provide a new opportunity for people newly diagnosed with advanced gastric cancer. Yet a final indictment of the study are the survival curves, which for subjects who die in the first 10 months or so show chemo to be better than Keytruda monotherapy.
Perhaps Merck needs to go back to the drawing board and design a new front-line trial in ≥10% PD-L1 expressers, or wait until it discovers additional biomarkers of activity in gastric cancer.