Astra reveals CTLA-4 inhibition’s deleterious effect

There was already ample evidence that Astrazeneca’s anti-CTLA-4 MAb tremelimumab was pharmacologically inert, but full data from the Caspian study could show it to be even worse. The trial, in first-line SCLC, was a success for its Imfinzi plus chemo cohort, which extended overall survival versus chemo, but a third arm, adding tremelimumab on top of Imfinzi and chemo, had been kept under wraps. Until today, that is, when Astra revealed that not only had this failed to beat Imfinzi, it failed to extend overall survival versus chemo alone. Of course, this does not necessarily mean that adding tremelimumab causes patients to die more quickly, and one explanation is that its side effects are causing patient drop-outs, leading to a loss of statistical power and failure to show significance. But it does bode ill for the few remaining pivotal tremelimumab-containing studies that have yet to read out; so far the Poseidon trial marks the key positive result, though even here tremelimumab’s role is unclear. Full numerical data from Caspian’s combo cohort should make fascinating reading when they are presented at a scientific meeting, though given the Covid-19 pandemic when this will happen is anyone’s guess.

Selected pivotal studies containing tremelimumab
Trial Cancer type Treatment cohort(s) Enrolment Result/primary completion
Arctic 3rd-line NSCLC Imfinzi +/- tremelimumab 597 Fail
Eagle 2nd-line head & neck Imfinzi +/- tremelimumab 736 Fail
Mystic 1st-line NSCLC Imfinzi +/- tremelimumab 1,118 Fail
Poseidon 1st-line NSCLC Imfinzi + chemo +/- tremelimumab 1,000 Both cohorts positive for PFS, but no inter-cohort comparison given
Neptune TMB-high, 1st-line NSCLC Imfinzi + tremelimumab 953 Fail
Danube 1st-line urothelial Imfinzi +/- tremelimumab 1,126 Fail
Caspian 1st-line SCLC Imfinzi + chemo +/- tremelimumab 988 Imfinzi arm positive for OS, tremelimumab combo arm negative 
Kestrel 1st-line head & neck Imfinzi +/- tremelimumab 823 Jan 2020
Himalaya 1st-line hepatocellular Imfinzi + tremelimumab 1,310 Mar 2020
Strong Various Imfinzi +/- tremelimumab 869 Apr 2021
Nile 1st-line urothelial Imfinzi + chemo +/- tremelimumab 885 Apr 2022
Adriatic SCLC maintenance Imfinzi +/- tremelimumab 600 Feb 2024
Source: & EvaluatePharma.

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