Merck's Keytruda falls short of rivals in 1 lung cancer type .
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Jan 07, 2020Surprise! 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.
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. | ||||