First-in-Idea ADC Micvotabart Pelidotin Exhibits Early Antitumor Exercise in HNSCC

The antibody-drug conjugate (ADC) micvotabart pelidotin (previously PYX-201) has demonstrated early alerts of antitumor exercise in sufferers with head and neck squamous cell carcinoma (HNSCC), elevating curiosity about its efficacy in choose affected person subgroups, in response to Glenn J. Hanna, MD.

This ADC, which is underneath analysis in sufferers with a number of tumor sorts in a part 1 trial (NCT05720117), delivers a microtubule inhibitor payload and targets Extradomain-B Fibronectin, a noncellular structural part of the tumor extracellular matrix that’s extremely expressed in malignant tumors.

In the part 1 trial, amongst evaluable sufferers with HNSCC handled inside an recognized dose vary of three.6 to five.4 mg/kg (n = 6), micvotabart pelidotin generated a confirmed goal response price of fifty% per RECIST 1.1 standards.¹ Notably, this included 1 confirmed full response (CR) and a pair of confirmed partial responses (PRs).

Based on these findings, the FDA granted quick observe designation to this agent on February 27, 2025, for the therapy of grownup sufferers with recurrent or metastatic HNSCC whose illness has progressed following therapy with platinum-based chemotherapy and an anti–PD-(L)1 antibody.²

In an interview with OncLive^®, Hanna mentioned the continued growth of micvotabart pelidotin, addressing its single-agent exercise and its potential for combos with PD-1 inhibitors and different immunotherapy brokers. He additionally highlighted the significance of biomarker-driven therapy approaches for HNSCC, together with the potential analysis of micvotabart pelidotin throughout HPV-positive and HPV-negative affected person subgroups.

Hanna is director of the Center for Cancer Therapeutic Innovation (Early Drug Development Program) and the Center for Salivary and Rare Head and Neck Cancers at Dana-Farber Cancer Institute; in addition to an affiliate professor of medication at Harvard Medical School in Boston, Massachusetts.

OncLive: How does the mechanism of motion of micvotabart pelidotindistinguish this agent from different ADCs presently available on the market?

Hanna: micvotabart pelidotin is a first-in-concept extracellular-cleaving ADC. What makes this ADC distinctive is that as a substitute of binding on to tumor cells, it binds to fibronectin, which is a part of the encircling tumor microenvironment [TME]. This represents a non-cellular focusing on mechanism that delivers the ADC payload by the TME, which is distinct from [the mechanisms of action of] most different obtainable ADCs.

How have the pharmacokinetic and pharmacodynamic profiles of this agent translated into early-phase medical research?

The early-phase medical examine with micvotabart pelidotin targeted on [optimizing] pharmacokinetics, dose, and schedule. The drug demonstrated low ranges of free payload in circulation and an extended half-life, which permits dosing each 3 weeks. There was constant goal engagement inside the tumor extracellular matrix in contrast with regular tissue when the drug was given to sufferers with most cancers. The dose-escalation portion of the part 1 examine recognized a dose-response vary starting round 3.6 mg/kg as much as 5.4 mg/kg, with dose-dependent responses beginning at 3.6 mg/kg. [Several] of the sufferers within the examine have been handled on the 5.4-mg/kg dose.

What key security and efficacy findings have emerged from the pinnacle and neck most cancers cohort of the part 1 trial?

Head and neck most cancers has a major unmet want as a result of, past immunotherapy, few new medicine have improved outcomes for recurrent or metastatic illness. The part 1 trial enrolled virtually 80 sufferers; roughly 9 to 10 had head and neck most cancers. From a security perspective, it was encouraging to see that there have been not many off-target grade 3 or increased ADC-related [effects], significantly within the dose vary of three.6 mg/kg to five.4 mg/kg. There have been no main issues about ocular toxicity, cytopenias like neutropenia, or neuropathy. Some delicate pores and skin toxicities have been noticed and are being additional explored, however they weren’t considerably dose limiting. When evaluating micvotabart pelidotin with different ADCs, the security profile seems favorable; there haven’t been many instances of eye toxicity, neuropathy, or pneumonitis typically seen with different brokers.

Regarding efficacy, [2] sufferers with head and neck most cancers had PRs, and at the least 1 affected person achieved a CR. In follow-up, some responses seem sturdy, contributing to delays in development.

What are the subsequent steps for investigating this agent, and the place would possibly it have the best medical impact?

Several subsequent steps are underway. First is confirming the dose and additional understanding micvotabart pelidotin as a monotherapy. It is clearly an energetic single agent.

[We also might see the] enlargement [of this drug] in head and neck most cancers, significantly within the second- or third-line setting for sufferers with restricted choices following immunotherapy or chemoimmunotherapy primarily based on the part 3 KEYNOTE-048 trial [NCT02358031] expertise. There can be curiosity in combining micvotabart pelidotin with PD-1 inhibition. Preclinical information introduced on the 2025 AACR Annual Meeting counsel that directing micvotabart pelidotin to TME might assist facilitate engagement with CD8-positive T cells when mixed with PD-1 blockade. A mix dose-escalation trial is ongoing to guage the security and exercise [of this approach].

If secure and efficient within the superior setting, there could also be alternatives to maneuver micvotabart pelidotin—alone or with immunotherapy—into the neoadjuvant setting. The [June 2025 FDA] approval of [perioperative] pembrolizumab [Keytruda] for resectable, high-risk head and neck most cancers highlights the potential for this method.

[One aspect of development] for all novel medicine that shall be essential [to consider] in head and neck most cancers is whether or not there are particular subgroups of sufferers who profit [most]. In the rising part 1 dataset for micvotabart pelidotin, it looks like sufferers who’re HPV constructive and sufferers who’re [HPV] damaging profit from the therapy to date. However, it’ll be essential to see whether or not there’s a narrowing of that sign. Are there particular subsets or biomarkers—for instance, in tissue—that we might use to know if there are sufferers who’re kind of prone to reply?

[Moving forward] I might encourage the corporate [developing micvotabart pelidotin] contemplate that. [Drug development companies] will typically prioritize steps like biopsies earlier than and through therapy to get a few of that beneficial information. However, it’s [an] thrilling time, and ADCs are primed to enter the clinic for head and neck most cancers.

References

1. Pyxis Oncology declares favorable preliminary PYX-201 medical part 1 half 1 information. News launch, Pyxis Oncology. November 20, 2024. Accessed August 28, 2025. https://ir.pyxisoncology.com/news-releases/news-release-details/pyxis-oncology-announces-favorable-preliminary-pyx-201-clinical
2. Pyxis Oncology granted FDA quick observe designation for PYX-201 monotherapy in sufferers with recurrent or metastatic head and neck most cancers. News launch. Pyxis Oncology. February 26, 2025. Accessed August 28, 2025.