ESMO Immuno-Oncology 2025 | Overcoming PD-1-resistance in head and neck cancer with ADCs and bsAbs
Amanda Psyrri, MD, PhD, FACP, National Kapodistrian University of Athens, Athens, Greece, discusses approaches to improve response rates to PD-1 inhibitors in head and neck cancer. Antibody drug conjugates (ADCs) and tumor vaccines such as MRG003 and therapeutic HPV vaccines, like CUE-101, have been assessed in combination with PD-1 blockade to improve outcomes in head-and-neck cancer. Bispecific antibodies including amivantamab, petosemtamab and ficerafusp alfa are additionally under investigation. This interview took place at 2025 European Society for Medical Oncology (ESMO) Immuno-Oncology Congress in London, UK.
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Transcript
Another approach to improve response rate to PD-1 inhibitors involves enhancing tumor immunogenicity with the use of chemo, radiotherapy, intratumoral therapies. One, a more recent approach is antibody drug conjugates. Several ADCs are currently under investigation. Among them, MRG003, becotatug vedotin, targeting EGFR, has demonstrated promising activity. We’ve faced three studies planned in the second line of the current metastatic setting after the progression to platinum and to PD-1 inhibitors...
Another approach to improve response rate to PD-1 inhibitors involves enhancing tumor immunogenicity with the use of chemo, radiotherapy, intratumoral therapies. One, a more recent approach is antibody drug conjugates. Several ADCs are currently under investigation. Among them, MRG003, becotatug vedotin, targeting EGFR, has demonstrated promising activity. We’ve faced three studies planned in the second line of the current metastatic setting after the progression to platinum and to PD-1 inhibitors. Positioning ADCs as an important emerging platform in this disease. Tumor vaccines also may improve the outcomes. Vaccines are used to increase the antigen presentation. Therapeutic HPV vaccines are being evaluated in combination with PD-1 blockade with encouraging activity, particularly in patients with high PD-L1 expression, CPS 20 or higher. A particularly innovative agent is CUE-101, which incorporates two HPV16/18 epitopes and 4-affinity attenuated IL2 molecules. This design enables selective expansion of HPV-specific T cells while minimizing systemic immune toxicity. While CUE-101 demonstrated limited single-agent activity of only 5%, robust responses were observed when combined with anti-PD-1 therapy, irrespective of PD-L1 expression stage. Tumor microenvironment also might play a significant role. We use spatial transcriptomics and we were able to demonstrate that gene expression within the CD45-defined tissue compartment, the leukocyte compartment, is strongly associated with resistance to immune checkpoint inhibition in HNSCC. Results were presented by Gavrilatu et al. at ASCO 2022. Importantly, this signature was dominated by extracellular matrix and stromal genes rather than immune cell-related genes, underscoring the critical role of non-immune stromal components in driving resistance. These findings highlight the importance of spatial context and have renewed interest in anti-stroma therapeutic strategies. Several stroma-targeting approaches have been evaluated, a combination of anti-PD-1 and VEGF, FGF, and vitamin failed to demonstrate survival benefit, but specific antibodies are emerging as a promising strategy. Notable agents under investigation include amivantamab, approved in EGFR mutant lung cancer, which targets EGFR and MET, petosemtamab, which also targets EGFR and LGR5, and ficerafusp alfa, a bispecific antibody, targeting EGFR and EGF beta. These agents aim to modulate tumor cells and immunosuppressive stroma, potentially restoring immune responses. So, in summary, addressing both primary and acquired resistance to immunotherapy is essential to further advance treatment outcomes in head-and-neck cancer. Novel approaches, including ADCs, bispecific antibodies, and therapeutic vaccines offer promising avenues to overcome resistance. Finally, biomarker-driven strategies, particularly those incorporating serial and spatial tissue analysis, will be critical to deepen our understanding of immune escape mechanisms and to guide the rational development of next-generation immunotherapy combinations.
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