Treme climbs a new mountain

Astrazeneca’s Himalaya study is a surprising hit in first-line liver cancer, but competition is already present.

Astrazeneca’s long-delayed Himalaya study in front-line liver cancer has apparently come up trumps. After Poseidon this is the second trial to suggest that tremelimumab might not, after all, be a write-off, and its success probably owes something to a novel dosing regimen that could avoid treme’s toxicities.

Still, with Roche’s Tecentriq plus Avastin already available, first-line liver cancer is no longer the immuno-oncology white space it once was. And several upcoming phase 3 readouts for Astra’s rivals might make it harder still for the UK company to make a significant dent in this market.

The next relevant readout should come later this year from a Chinese study of Juangsu Hengrui’s camrelizumab, though the big threats in terms of Western datasets are Beigene’s Rationale-301 trial of tislelizumab, and Merck & Co/Eisai’s Leap-002 study of Keytruda plus Lenvima. Both have primary completion dates next May.

Bristol Myers Squibb’s Checkmate-9DW trial of Opdivo plus Yervoy is highly relevant, testing the same anti-PD-1/CTLA-4 mechanism as Himalaya, though it might not yield data until 2023. Notably, however, Opdivo has already failed in first-line liver cancer, as monotherapy in Checkmate-459 – a result that prompted this year’s withdrawal of Opdivo’s second-line label; a Yervoy combo remains available second line.

But Astra can celebrate the fact that, pending full data release from Himalaya, it looks like Imfinzi plus tremelimumab might be approvable in first-line liver cancer. Until the combo’s unexpected success in the NSCLC study Poseidon, which also included chemo, tremelimumab had run up a dismal record of failures, and Astra seemed largely to have deprioritised it.

Selected pivotal studies containing tremelimumab
Trial Cancer type Treatment cohort(s) Enrolment Result/data due
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 Tremelimumab combo arm positive for OS; Imfinzi arm negative for OS (both positive for PFS)
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 for OS
Kestrel 1st-line head & neck Imfinzi +/- tremelimumab 823 Fail
Himalaya 1st-line hepatocellular Imfinzi +/- tremelimumab 1,504 Tremelimumab combo arm positive for OS; Imfinzi arm non-inferior for OS
Adriatic SCLC maintenance Imfinzi +/- tremelimumab 600 H2 2022
Strong Various Imfinzi +/- tremelimumab 1,200 2022 or beyond
Nile 1st-line urothelial Imfinzi + chemo +/- tremelimumab 1,215 2022 or beyond
Source: & EvaluatePharma.

Himalaya also included an Imfinzi-only cohort, but this did not appear to have performed as well, only meeting overall survival non-inferiority, as opposed to the combo’s stated OS benefit, versus Nexavar. This is important, suggesting – as in Poseidon – that the anti-CTLA-4 MAb has an additive benefit, and that the success is not just down to Imfinzi.

Cracking the treme puzzle might be thanks to Himalaya’s use of what Astra calls the Stride regimen, comprising just a single 300mg priming dose of treme together with Imfinzi, followed by Imfinzi alone. Still, this had not been employed in Poseidon.

But data at Asco in 2020 had already suggested the potential of Stride, in Study 22, comprising a mixture of first and second-line liver cancer subjects. This was said to read out positively, and though it had no control cohort it provided a way of handicapping the Himalaya result.

At present the front-line immuno-oncology space has only one US contender, Roche’s Tecentriq plus Avastin having been approved last year on the basis of Imbrave-150; more recently a Tecentriq combo with Exelixis’s Cabometyx failed the Cosmic-312 trial, however.

In China Innovent’s Tyvyt is approved in combination with an Avastin biosimilar called Bevasda.

Keytruda plus Lenvima, meanwhile, got a US complete response letter because, after Tecentriq/Avastin’s approval, the uncontrolled Keynote-524 trial no longer gave sufficient front-line backing. Keytruda retains a second-line label, having failed the potentially confirmatory Keynote-240 trial but succeeded in Keynote-394, a study in Asian patients.

For now Astra can celebrate tapping into treme’s efficacy while avoiding its toxicity; this in itself is a big surprise.

Selected phase 3 studies of anti-PD-(L)1 projects in first-line liver cancer
Project Company Design Study Result
Opdivo Bristol Myers Squibb Vs Nexavar Checkmate-459 Fail
Tecentriq Roche Avastin combo vs Nexavar Imbrave-150 Success; US approval
Tecentriq Roche/Exelixis Cabometyx combo vs Nexavar Cosmic-312 Fail
Tyvyt Innovent Bevasda (Avastin biosimilar) combo vs Nexavar Orient-32 Success; China approval
Imfinzi Astrazeneca +/- tremelimumab vs Nexavar Himalaya Success
Camrelizumab Jiangsu Hengrui Apatinib combo vs Nexavar NCT03764293 Ends Dec 2021
Tislelizumab Beigene Vs Nexavar Rationale-301 Ends May 2022
Keytruda Merck & Co/Eisai Lenvima combo vs Lenvima Leap-002 Ends May 2022
Toripalimab Shanghai Junshi Lenvima combo vs Lenvima NCT04523493 Ends Aug 2023
Opdivo Bristol Myers Squibb Yervoy combo vs Nexavar or Lenvima Checkmate-9DW Ends Sep 2023
HLX10 Shanghai Henlius/Fosun HLX04 (Avastin biosimilar) combo vs Nexavar NCT04465734 Ends Oct 2023

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