AACR – Keytruda set for lung cancer approval but restrictions unclear

The grudge match between Merck & Co and Bristol-Myers Squibb in non-small cell lung cancer has become even fiercer after both companies reported good news on their anti-PD-1 antibodies over the weekend.

Merck’s US filing of Keytruda has come earlier than expected and the antibody’s success now depends on the FDA’s verdict regarding labelling. A restriction to patients expressing the PD-L1 biomarker would mean Keytruda is stuck behind Bristol-Myers’ Opdivo, recently approved in NSCLC, albeit with restrictions of its own. And Opdivo could yet pull even further ahead – a trial aimed at expanding its approval has just been stopped early for efficacy.


Crucial to these drugs’ chances of success are the ways in which the NSCLC market is sliced. Opdivo was approved in the US last month for use in the 30% or so of NSCLC patients with the hard-to-treat squamous form of the disease. Keytruda’s pivotal trial, Keynote-001, recruited patients with both squamous and non-squamous histologies.

But Keytruda is limited in another way. Keynote-001 stratified patients by PD-L1 status, with the best results seen in those with high expression of the biomarker.

Among all 495 Keynote-001 patients the objective response rate was 19.4%, and the median duration of response was 12.5 months. Median progression-free survival was 3.7 months and median overall survival was 12.0 months.

But in the 73 patients with PD-L1 expression in at least 50% of tumour cells, as determined by an assay developed by Dako, the response rate was 45.2% and median progression-free survival was 6.3 months. Median overall survival was not reached.

Results in this group were potentially superior to several first- and second-line options, according to Leerink analysts. Consequently the FDA could decide to approve Keytruda solely for use in the 25-30% of NSCLC patients who are PD-L1-positive.

But there are arguments in favour of a broader label for Keytruda. Expression of the PD-L1 biomarker can change over time, analysts from Bernstein write, and in any case the drugs have the same mechanism; with Opdivo approved in PD-L1-negative NSCLC there is no rationale for denying Keytruda the same approval.


Perhaps a better argument is that Keytruda’s breakthrough therapy designation for NSCLC specifies use in patients who are positive for ALK and EGFR but not PD-L1. However, the fact that Agilent Technologies' Dako unit has submitted a PMA application for a companion diagnostic test would seem to suggest that patients’ PD-L1 status will be material to Keytruda’s success.

Moreover, both drugs are in trials to prove their worth in first-line NSCLC – the current approval and approval application are in the post-chemo setting – that are only enrolling patients that express PD-L1.

FDA approval of Keytruda in second-line NSCLC could come in the third quarter. At around the same time Merck’s Keynote-010 trial will read out. This is much larger than Keynote-001 but has a similar design: both squamous and non-squamous, but only PD-L1-positive patients (Opdivo checks Keytruda’s lung cancer lead, January 12, 2015).

Leerink analysts write that the current lack of randomised survival data is likely to be a disadvantage for Keytruda compared with Opdivo until Keynote-010 reports. And a submission for Opdivo’s use in non-squamous cell cancer is surely on the way after the halt of the Checkmate-057 trial early for efficacy on Friday. 

EvaluatePharma’s consensus forecasts have Opdivo selling $4.9bn in 2020 to Keytruda’s $3.4bn. The FDA’s decision on Keytruda’s labelling could allow this gap to close – or widen it further.

Selected anti-PD-1 studies in NSCLC 
Project  Study   Trial ID  
Keytruda  Keynote-001 NCT01295827
Keytruda  Keynote-010  NCT01905657 
Opdivo  Checkmate-017   NCT01642004 
Opdivo  Checkmate-057  NCT01673867 

To contact the writer of this story email Elizabeth Cairns in London at [email protected] or follow @LizEPVantage on Twitter

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