When Keytruda and Opdivo battled it out in first-line lung cancer this year the Merck & Co drug ultimately came out on top. Now two more trials are set to read out that could determine how this all-important market shapes up.
Both concern a chemo-combo approach, which increasingly looks like becoming the front-line treatment of choice. The Impower-150 study represents Roche’s first attempt to move Tecentriq from second to first-line use, while Keynote-189 could confirm Merck’s accelerated approval, though given the FDA’s track record the chances of Keytruda losing its US green light are slim.
Rather, this is a case of determining how prescribing patterns evolve. A positive overall survival hit in Keynote-189 should accelerate growth of Keytruda plus chemo in first-line patients irrespective of PD-L1 expression – the setting in which Merck got a surprise nod in May on the back of remission rates seen in cohort G of its Keynote-021 trial.
And, if Keytruda’s first-mover position is strong, the best Roche can hope for is to put pressure on Merck with a strongly positive Impower-150 result; this large, 1,200-patient study tests Tecentriq given with a chemo doublet, with or without Avastin, versus Avastin plus chemo.
Impower-150 has five primary endpoints relating to various cuts of overall and progression-free survival, but it is not known whether these will read out together.
The company has said it expects Impower-150 to read out probably in the fourth quarter, perhaps in the third, but only when the data are cut will it become clear whether they are sufficiently mature to yield medians for both PFS and OS.
At least Impower-150's design is not as convoluted as Astrazeneca’s first-line study of Imfinzi, Mystic, which failed at its first readout – PFS data for a combo with tremelimumab in various cuts of PD-L1 expression.
Still, there is complexity in Impower-150, whose size reflects a desire for sufficient powering. The statistical hurdles for the various data cuts are not clear, and recruitment was not limited to high-PD-L1 expressers, though PD-L1 status will be measured.
|Summary of primary endpoints in Impower-150 (NCT02366143)|
|PFS*||Tumor cell 2/3 or tumour infiltrating cell 2/3||Tecentriq + chemo vs Avastin + chemo|
|PFS*||Tumor cell 2/3 or tumour infiltrating cell 2/3||Tecentriq + Avastin + chemo vs Avastin + chemo|
|PFS*||Tumor cell 2/3 or tumour infiltrating cell 1/2/3||Tecentriq + chemo vs Avastin + chemo|
|PFS*||Tumor cell 2/3 or tumour infiltrating cell 1/2/3||Tecentriq + Avastin + chemo vs Avastin + chemo|
|PFS*||All-comers||Tecentriq + chemo vs Avastin + chemo|
|PFS*||All-comers||Tecentriq + Avastin + chemo vs Avastin + chemo|
|OS||Tumor cell 1/2/3 or tumour infiltrating cell 1/2/3||Tecentriq + chemo vs Avastin + chemo|
|OS||Tumor cell 1/2/3 or tumour infiltrating cell 1/2/3||Tecentriq + Avastin + chemo vs Avastin + chemo|
|OS||All-comers||Tecentriq + chemo vs Avastin + chemo|
|OS||All-comers||Tecentriq + Avastin + chemo vs Avastin + chemo|
|Note: *by Recist v1.1 criteria|
Likewise, Merck’s Keynote-189 recruited all-comers; this 570-patient trial compares Keytruda plus chemo to chemo alone, and looks at PFS as primary endpoint, with OS the key secondary measure. Data are expected in the same timeframe as Impower-150.
While investors, prescribers and regulators alike will be keen to see what survival benefit Keytruda is able to show in first-line NSCLC, it is fair to say that Keynote-189 is not as important as it was before Merck got its surprising accelerated approval based on remission rates seen in the small Keynote-021 trial.
The importance of Keynote-189 diminished further over the weekend, when Merck at Esmo revealed median PFS in Keynote-021’s cohort G: 19.0 months for Keytruda plus chemo versus 8.9 months for chemo alone. And the hazard ratio for OS improved versus the Asco data cut, with reduction in risk of death now running at 41% (p=0.03).
Leerink analysts wrote that Keynote-021 could now itself serve as the confirmatory study for approval of Keytruda plus chemo, provided that Keynote-189 is “directionally positive on OS and statistically positive on PFS”.
Additional threats to Keytruda could come later from Bristol-Myers Squibb’s Checkmate-227 study of Opdivo plus Yervoy and Opdivo plus chemo, and further Mystic readouts. Roche has a number of Impower studies ongoing with various chemo regimens, which could give it multiple shots on goal.
That said, barring a major disaster, Merck’s position in first-line NSCLC looks pretty unassailable.