ESMO Immuno-Oncology 2025 | First-in-human study of INCA32459, a LAG-3/PD-1 bsAb in advanced cancers
Jesus Fuentes-Antras, MD, NEXT Oncology Madrid, Hospital Universitario Quirónsalud Madrid, Madrid, Spain, discusses the first-in-human Phase I study of INCA32459 (NCT05577182), a bispecific antibody (bsAb) targeting PD-1 and LAG-3 in patients with select advanced malignancies. INCA32459 demonstrated a manageable safety profile consistent with immune checkpoint inhibitors, linear pharmacokinetics, and evidence of T-cell activation. Early efficacy was observed, including complete and partial responses in heavily pretreated tumors. This interview took place at 2025 European Society for Medical Oncology (ESMO) Immuno-Oncology Congress in London, UK.
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Transcript
This was a first in human phase one trial studying these molecules in patients with selected malignancies and focused on melanoma particularly. This was a PD-1/LAG3-B-specific, which is one of the novelties, not just the targeting of both signals, but doing it with a B-specific, which is different from other approaches, which are already validated. I think, in a nutshell, the rationale is there to target LAG-3 as a co-inhibitory signal, which is co-expressed with PD-1 in T cells, which are exhausted...
This was a first in human phase one trial studying these molecules in patients with selected malignancies and focused on melanoma particularly. This was a PD-1/LAG3-B-specific, which is one of the novelties, not just the targeting of both signals, but doing it with a B-specific, which is different from other approaches, which are already validated. I think, in a nutshell, the rationale is there to target LAG-3 as a co-inhibitory signal, which is co-expressed with PD-1 in T cells, which are exhausted. So what we want to do here is essentially to overcome immune resistance, either primary or secondary. This trial enrolled approximately 50 patients. Most of them, well, not most, but in the highest proportion were melanoma, triple negative breast cancer, nasopharyngeal carcinoma. And we saw from a safety perspective that there was not a big difference compared to previous targeting of PD-1, for instance, the PD-1-/PD-L1 axis. Essentially, I can recall the DLT was achieved, and we saw two cases of myocarditis, which were fortunately quickly resolved with steroids. And the rest of the side effects were easy to manage, not limiting, and again, not very different from what’s already established. And in regards to efficacy, this trial showed approximately a 20% overall response rate and approximately 40,45% of DCR patients achieving stability. And we may consider these results in light of the fact that two-thirds of the patients had previously received and progressed to immune checkpoint inhibitors, which makes them particularly valuable. Finally, I think from a PKPD perspective, there were no relevant signals in the sense that PD-1 occupancy was observed, PKs were linear. I mean, there was nothing really extraordinary from that. So suggesting that pursuing further development of the agent would be a good idea and good potential. Unfortunately, this trial was stopped early, but this was essentially due to a sponsor’s decision and in line with their pipeline strategy, but not due to safety concerns or other issues in terms of efficacy or pharmacodynamics.
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