The antibody-drug conjugate (ADC) micvotabart pelidotin (formerly PYX-201) has demonstrated early signals of antitumor activity in patients with head and neck squamous cell carcinoma (HNSCC), raising curiosity about its efficacy in select patient subgroups, according to Glenn J. Hanna, MD.
This ADC, which is under evaluation in patients with multiple tumor types in a phase 1 trial (NCT05720117), delivers a microtubule inhibitor payload and targets Extradomain-B Fibronectin, a noncellular structural component of the tumor extracellular matrix that is highly expressed in malignant tumors.
In the phase 1 trial, among evaluable patients with HNSCC treated within an identified dose range of 3.6 to 5.4 mg/kg (n = 6), micvotabart pelidotin generated a confirmed objective response rate of 50% per RECIST 1.1 criteria.1 Notably, this included 1 confirmed complete response (CR) and 2 confirmed partial responses (PRs).
Based on those findings, the FDA granted fast track designation to this agent on February 27, 2025, for the treatment of adult patients with recurrent or metastatic HNSCC whose disease has progressed following treatment with platinum-based chemotherapy and an anti–PD-(L)1 antibody.2
In an interview with OncLive®, Hanna discussed the ongoing development of micvotabart pelidotin, addressing its single-agent activity and its potential for combinations with PD-1 inhibitors and other immunotherapy agents. He also highlighted the importance of biomarker-driven treatment approaches for HNSCC, including the potential evaluation of micvotabart pelidotin across HPV-positive and HPV-negative patient 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; as well as an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.
OncLive: How does the mechanism of action of micvotabart pelidotindistinguish this agent from other ADCs currently on the market?
Hanna: micvotabart pelidotin is a first-in-concept extracellular-cleaving ADC. What makes this ADC unique is that instead of binding directly to tumor cells, it binds to fibronectin, which is part of the surrounding tumor microenvironment [TME]. This represents a non-cellular targeting mechanism that delivers the ADC payload through the TME, which is distinct from [the mechanisms of action of] most other available ADCs.
How have the pharmacokinetic and pharmacodynamic profiles of this agent translated into early-phase clinical studies?
The early-phase clinical study with micvotabart pelidotin focused on [optimizing] pharmacokinetics, dose, and schedule. The drug demonstrated low levels of free payload in circulation and a long half-life, which allows dosing every 3 weeks. There was consistent target engagement within the tumor extracellular matrix compared with normal tissue when the drug was given to patients with cancer. The dose-escalation portion of the phase 1 study identified a dose-response range beginning around 3.6 mg/kg up to 5.4 mg/kg, with dose-dependent responses starting at 3.6 mg/kg. [Several] of the patients in the study were treated at the 5.4-mg/kg dose.
What key safety and efficacy findings have emerged from the head and neck cancer cohort of the phase 1 trial?
Head and neck cancer has a significant unmet need because, beyond immunotherapy, few new drugs have improved outcomes for recurrent or metastatic disease. The phase 1 trial enrolled almost 80 patients; approximately 9 to 10 had head and neck cancer. From a safety perspective, it was encouraging to see that there were not many off-target grade 3 or higher ADC-related [effects], particularly in the dose range of 3.6 mg/kg to 5.4 mg/kg. There were no major concerns about ocular toxicity, cytopenias like neutropenia, or neuropathy. Some mild skin toxicities were observed and are being further explored, but they were not substantially dose limiting. When comparing micvotabart pelidotin with other ADCs, the safety profile appears favorable; there have not been many cases of eye toxicity, neuropathy, or pneumonitis often seen with other agents.
Regarding efficacy, [2] patients with head and neck cancer had PRs, and at least 1 patient achieved a CR. In follow-up, some responses appear durable, contributing to delays in progression.
What are the next steps for investigating this agent, and where might it have the greatest clinical effect?
Several next steps are underway. First is confirming the dose and further understanding micvotabart pelidotin as a monotherapy. It is clearly an active single agent.
[We also might see the] expansion [of this drug] in head and neck cancer, particularly in the second- or third-line setting for patients with limited options following immunotherapy or chemoimmunotherapy based on the phase 3 KEYNOTE-048 trial [NCT02358031] experience. There is also interest in combining micvotabart pelidotin with PD-1 inhibition. Preclinical data presented at the 2025 AACR Annual Meeting suggest that directing micvotabart pelidotin to TME may help facilitate engagement with CD8-positive T cells when combined with PD-1 blockade. A combination dose-escalation trial is ongoing to evaluate the safety and activity [of this approach].
If safe and effective in the advanced setting, there may be opportunities to move 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 cancer highlights the potential for this approach.
[One aspect of development] for all novel drugs that will be important [to consider] in head and neck cancer is whether there are specific subgroups of patients who benefit [most]. In the emerging phase 1 dataset for micvotabart pelidotin, it seems like patients who are HPV positive and patients who are [HPV] negative benefit from the treatment so far. However, it’ll be important to see whether there’s a narrowing of that signal. Are there specific subsets or biomarkers—for example, in tissue—that we could use to understand if there are patients who are more or less likely to respond?
[Moving forward] I would encourage the company [developing micvotabart pelidotin] consider that. [Drug development companies] will often prioritize steps like biopsies before and during treatment to get some of that valuable data. However, it’s [an] exciting time, and ADCs are primed to enter the clinic for head and neck cancer.
References
- Pyxis Oncology announces favorable preliminary PYX-201 clinical phase 1 part 1 data. News release, 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
- Pyxis Oncology granted FDA fast track designation for PYX-201 monotherapy in patients with recurrent or metastatic head and neck cancer. News release. Pyxis Oncology. February 26, 2025. Accessed August 28, 2025. https://ir.pyxisoncology.com/news-releases/news-release-details/pyxis-oncology-granted-fda-fast-track-designation-pyx-201