Surprise! There’s a Tumour in which Keytruda doesn’t Work. Este Fracaso de Merck en el intento de poder Tratar en Primera Línea el Cáncer de Pulmón Micricitico podría dar un Giro Descomunal a todo lo Establecido .

Merck's Keytruda falls short of rivals in 1 lung cancer type .

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Jan 07, 2020

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

Jacob Plieth

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.