More doubts over TGF-β inhibition

With today’s failure of the second key study of bintrafusp alfa one thing is clear: the idea that inhibiting TGF-β might augment response to checkpoint blockade is at best extremely complex. The Merck KGaA/Glaxosmithkline fusion protein combined this mechanism with PD-L1 blockade, and after flunking a NSCLC study in January it has now failed Intr@pid BTC 047, a trial in second-line cholangiocarcinoma. Scholar Rock, Sanofi, Novartis, Medpacto and Argenx will no doubt evaluate the situation carefully, given that they are all studying similar mechanistic combinations. The fault might lie with bintrafusp: is it trafficked into the tumour microenvironment? Is combining the two mechanisms in a single molecule the right approach? Should its studies enrich for a TGF-β biomarker rather than, like in NSCLC, for PD-L1? Only one bintrafusp study, in breast cancer, enriches for what might be a TGF-β signature – HMGA2. The single-arm cholangiocarcinoma trial showed a 10.1% response rate, which Merck said was just four points above that possible with single-agent immunotherapy. The thinking is that some cancer cells express TGF-β, which induces regulatory T cells and inhibits effector T cells. This idea is by no means dead, but the jury is out on how best to harness it.

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 Expanded to add new combos
Intr@pid BTC 055 1L cholangiocarcinoma (chemo combo ph2/3, vs chemo) OS 2022 primary completion
Intr@pid BTC 047 2L cholangiocarcinoma (single-cohort ph2) ORR 10.1% ORR failed to meet threshold for filing
Intr@pid Cervical 017 2L cervical cancer (single-cohort ph2) ORR Dec 2021 primary completion
Intr@pid Cervical 046 Cervical cancer (+ Avastin or various chemos, ph1) Safety 2022 primary completion
Intr@pid Breast 020 HMGA2 +ve TNBC (single-cohort ph2) ORR 2023 primary completion
Intr@pid Urothelial 152 2/3L urothelial cancer (single-cohort ph1) ORR 2022 primary completion
CRT: chemoradiotherapy; Source: Merck KGaA &

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