Surprise! There’s a tumour in which Keytruda doesn’t work

The Merck & Co drug’s failure in small-cell lung cancer prompts a theory and leaves the way clear for Roche and Astrazeneca.

Keytruda’s domination of the anti-PD-(L)1 market sometimes seems so comprehensive that it is surprising to see it flunk a clinical trial. Yesterday this is what happened, with the Keynote-604 study failing to show an overall survival benefit in first-line small-cell lung cancer.

The setback seems particularly galling because two competitors that are in desperate pursuit of Keytruda – Roche’s Tecentriq and Astrazeneca’s Imfinzi – have already succeeded in this tumour type. And the disparity has already seen one bank turn to scientific papers for an answer.

Citing a retrospective analysis published in Jama, Leerink has argued that in tumours characterised by poor PD-L1 expression and less fit patients – of which SCLC is one – there is evidence that PD-L1 inhibitors like Tecentriq and Imfinzi work better than PD-1-targeting drugs like Keytruda.

Yesterday’s disclosure that Keytruda had failed Keynote-604, and the earlier failure of Bristol-Myers Squibb’s Opdivo in Checkmate-451, appear to back such a hypothesis. A less sophisticated view holds that PD-1 drugs overall are better than PD-L1s, though this is massively skewed by the timing of study readouts.

Failed studies of anti-PD-(L)1 antibodies across various cancer types
  Keytruda Opdivo Tecentriq Imfinzi Bavencio
  (anti-PD-1) (anti-PD-1) (anti-PD-L1) (anti-PD-L1) (anti-PD-L1)
Urothelial     Imvigor-211 (2L)    
Colorectal     Imblaze-370 (3L)**    
Gastric Keynote-061 (2L)
Keynote-062 (1L)***
       
Glioblastoma   Checkmate-143 (2L)
Checkmate-498 (1L)
Checkmate-548 (1L)
    Javelin Gastric 300 (3L)
NSCLC   Checkmate-026 (1L)   Arctic (3L)
Mystic (1L)*
Javelin Lung 200 (2L)
SCLC Keynote-604 (1L) Checkmate-331 (2L)
Checkmate-451 (1L)*
     
Head & neck Keynote-040 (2L)     Eagle (2L)*  
Ovarian         Javelin Ovarian 100 (1L)
Hepatocellular Keynote-240 (2L) Checkmate-459 (1L)      
TNBC Keynote-119 (2L)        
*CTLA-4 combo; **Cotellic combo; ***data inconclusive. 1L=1st line; 2L=2nd line; 3L=3rd line.

Tecentriq is already approved for first-line SCLC on the basis of the Impower-133 trial, and last year Imfinzi matched its result in the Caspian study (World Lung 2019 – Astra’s achievement in SCLC unlikely to be a game changer, September 9, 2019).

Both these anti-PD-L1 drugs showed 12 to 13 months of median overall survival, yielding around a 30% reduction in risk of death versus chemo alone. In Keynote-604 the absolute survival benefit has not been disclosed, but Merck said the 20% relative reduction in risk of death was insufficient to hit statistical significance.

There was a statistical benefit in progression-free survival, Keynote-604’s co-primary endpoint, but this is unlikely to be enough for approval given the availability of Tecentriq and Imfinzi’s Caspian result. Merck stock was off 2% this morning.

Irrespective of the first-line failure, Keytruda retains its third-line SCLC label with the backing of remission rates seen in the Keynote-028 and 159 studies. And the front-line developments likely have little relevance for Pharmamar’s Zepsyre, which was recently filed for second-line SCLC and licensed to Jazz.

It is hard to gauge how much Keytruda could lose in sales; EvaluatePharma’s sales by indication consensus forecasts shows $748m of 2024 revenue coming from SCLC, but it is not clear how much of this comprises first-line use. Keytruda’s next significant test is the Keynote-355 readout in first-line triple-negative breast cancer.

Selected first-line SCLC trials
Drug Company Study Setting mOS result
Opdivo Bristol-Myers Squibb Checkmate-451* Monotherapy, vs placebo 10.4mth vs 9.6mth (HR=0.84, failed)
+ Yervoy, vs placebo 9.2mth vs 9.6mth (HR=0.92, failed)
Tecentriq Roche Impower-133 On top of chemo, vs chemo 12.3mth vs 10.3mth (HR=0.70, p=0.007)
Imfinzi Astrazeneca Caspian On top of chemo, vs chemo 13.0mth vs 10.3mth (HR=0.73, p=0.005)
+ tremelimumab + chemo, vs chemo Due 2020
Keytruda Merck & Co Keynote-604 On top of chemo, vs chemo (HR=0.80, failed)
*First-line maintenance setting.

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