Merck KGaA’s dual immuno-oncology weapon misfires

Bintrafusp alfa’s most important study, head to head against Keytruda in front-line lung cancer, is scrapped.

The only way Merck KGaA’s bintrafusp alfa could have hoped to challenge the mighty Keytruda in first-line lung cancer was head to head, and the German group should be commended for running such a dangerous pivotal study. This does not make the trial’s failure, revealed yesterday, any easier to digest, however.

Bintrafusp, a dual-acting immunotherapy, was an important pillar of the oncology pipelines of Merck KGaA and its partner Glaxosmithkline alike, and the setback is hugely disappointing for both. The project is by no means discontinued, but at best it now looks to be relegated to niche cancer types and combination use.

The surprising thing about the failure of the trial, INTR@PID Lung 037, is that just last October it had passed an interim futility analysis, with enrolment closed at around 300. But yesterday Merck said the data-monitoring committee had now recommended that the study be discontinued, after reviewing “the totality of data”.

With little to go on it is unclear what went wrong. But questions will surely be asked about the rationale of bintrafusp’s mechanism of action: the bispecific fusion protein comprises a Bavencio-like anti-PD-L1 linked to two molecules of TGF-β trap.

The theory ran that such a dual mechanism, active in the tumour microenvironment, could block innate and adaptive immunity. TGF-β is a cytokine associated with local immunosuppression, and the idea was that trapping it in the microenvironment could improve on the activity of PD-L1 blockade alone.

This rationale had been picked up by numerous other companies, including Bristol Myers Squibb, Novartis, Argenx, Scholar Rock, Sanofi and Pfizer (Few TGF-β assets remain unencumbered after Bristol’s Forbius buy, August 25, 2020).

If these players are today taking a long, hard look at their work, perhaps they can take comfort in the fact that bintrafusp is the only asset comprising a dual approach fixed in a single molecule. The competitors are working on standalone TGF-β agents, whose combination with other MAbs might give flexibility.

Selected trials of bintrafusp alfa
Study Setting Primary endpoint(s) Status
INTR@PID Lung 037 1L NSCLC (PD-L1 "high", vs Keytruda, ph3) PFS & OS Terminated for futility in PFS
INTR@PID LUNG 005 Stage III NSCLC (CRT combo ph2, vs CRT + Imfinzi) PFS Ongoing, 2024 primary completion
INTR@PID LUNG 024 NSCLC (chemo combo, uncontrolled ph1/2) Safety Being expanded to add new combos
INTR@PID BTC 055 1L biliary tract cancer (chemo combo ph2/3, vs chemo) OS Enrolment into ph2 part complete; ph3 "on track"
INTR@PID BTC 047 2L biliary tract cancer (single-cohort ph2) ORR Topline data due Q1 2021
INTR@PID CERVICAL 017 2L cervical cancer (single-cohort ph2) ORR Enrolment "nearing completion"
INTR@PID CERVICAL 046 Cervical cancer (+ Avastin or various chemos, ph1) Safety Recently initiated
INTR@PID BREAST 020 HMGA2 +ve TNBC (single-cohort ph2) ORR Recently initiated
INTR@PID UROTHELIAL 152 2/3L urothelial cancer (single-cohort ph1) ORR Recently initiated
CRT: chemoradiotherapy; Source: Merck KGaA &

Merck had put bintrafusp on a faster development track than even Bavencio on the basis of what it called “spectacular” phase I efficacy. But perhaps its tie-up with Glaxo showed that all would not be plain sailing: the up-front fee amounted to a relatively unspectacular $343m. Sellside consensus for 2026 sales was a restrained $504m, according to EvaluatePharma.

In a statement yesterday, Merck said trials in more obscure cancer types, and in combination NSCLC settings, were continuing. But there is no denying that the front-line monotherapy failure knocks a big hole in its immuno-oncology strategy.

Bizarrely, Glaxo did not even announce the setback to the markets, presumably because this did not involve a project discontinuation. But for the UK group it marks yet another major disappointment, after the delay to the approval of dostarlimab, revealed yesterday, and to studies of its Sanofi-partnered Covid-19 vaccine project.

Can any first-line NSCLC immuno-oncology wannabe now seriously threaten Keytruda? Sanofi/Regeneron’s Libtayo is awaiting a US front-line NSCLC verdict on February 28, but this is based on a study whose comparator cohort was not given Keytruda. The Merck & Co drug will emerge from its head-to-head skirmish with bintrafusp even stronger.

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