Ozuriftamab Vedotin Makes Strides Toward Phase 3 Analysis in HPV-Associated OPSCC

The ROR2-targeted agent ozuriftamab vedotin (CAB-ROR2-ADC; BA3021; Oz-V) may headline a new era of antibody-drug conjugates (ADCs) specifically benefitting patients with treatment-refractory human papillomavirus (HPV)–associated oropharyngeal squamous cell carcinoma (OPSCC), according to Alan L. Ho, MD, PhD.

Findings from a phase 2 trial (NCT05271604) showed that among 12 evaluable patients with p16-positive disease who received Oz-V every 2 weeks, the overall response rate (ORR) was 42%, and the disease control rate was 92%.¹ Additionally, the median progression-free survival (PFS) with this dosing schedule was 4.7 months (95% CI, 2.4-13.9), and the median overall survival (OS) was 11.6 months (95% CI, 4.7-not evaluable).

Previously, in July 2024, Oz-V received FDA fast track designation for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) who have experienced disease progression on or after platinum-based chemotherapy and a PD-(L)1 inhibitor.²

In an interview with OncLive^®, Ho discussed the unique elements of Oz-V that may contribute to its efficacy and tolerability in OPSCC, key findings from the trial, and where research with the agent in this population is headed next.

Ho is chief of the Head and Neck Oncology Service and an attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive: What is the mechanism of action of Oz-V, and how is this agent unique compared with the mechanisms of action of other ADCs?

Ho: Oz-V is a unique ADC. There are several unique features about the agent itself. The first is the target. The target for Oz-V is ROR2. That’s a transmembrane receptor for the Wnt family of ligands, which is involved in cancer cell proliferation, migration, and invasion. That protein is overexpressed in many different malignancies, including [both HPV-positive and HPV-negative] head and neck cancers. However, there’s also evidence that ROR2 is enriched in patients with HPV-positive tumors and is driven by the viral antigens E6 and E7, so although there’s a rationale for pursuing ROR2 as a target in all head and neck cancers, there’s an intriguing rationale for HPV-positive cancers, beyond that target. That’s a target of interest for an ADC.

Oz-V is also a unique ADC in the way it targets ROR2. It’s been engineered to conditionally bind ROR2 only in low-pH microenvironments, whereas it doesn’t bind in neutral pH environments, thereby preferentially binding ROR2 within the tumor microenvironment and not necessarily in normal tissue. This theoretically widens the therapeutic window for ADC action.

The other features of the ADC are [that] it has a monomethyl auristatin cytotoxic payload and a cleavable linker, so it has bystander effects, and the drug to antibody ratio is 4. It’s also shown strong efficacy, preliminarily, in a cohort of patients with HNSCC, which led to its FDA [fast track] designation for that indication.² There’s evidence that the target ROR2 is enriched within p16-driven head and neck cancers, which are predominantly oropharyngeal squamous cell carcinomas.

What were the key efficacy findings from the phase 2 trial evaluating Oz-V in OPSCC?

The agent so far has been investigated in a cohort of 40 patients with head and neck cancer, and among 12 evaluable patients with p16-positive OPSCC, it elicited a 42% ORR, and the median OS was 11.6 months.¹ This is promising activity in a cohort of patients [who] were heavily pretreated; [approximately] two-thirds of those patients had been previously treated with 3 or more lines of prior therapy. Based upon that activity, the plan now is to investigate Oz-V in a phase 3 randomized trial in patients with OPSCC.

In the phase 2 trial, we investigated 2 different [dosing] schedules to evaluate which would be the safer, more tolerable approach. There was a 2-week-on, 1-week-off approach and an every-other-week approach. The every-other-week dosing was the safer, more tolerable version. [At that dose], only 15% of [patients experienced] grade 3 treatment-related adverse effects [TRAEs] vs 30% at the other schedule. The other schedule also had a 10% grade 4 TRAE incidence.

[Oz-V was] well tolerated at the every-other-week schedule. The toxicities we’ve been looking out for include fatigue, anemia, and cumulative peripheral neuropathy from the cytotoxic payload itself, but we’ve been happy with having a fairly tolerable regimen to offer to patients, which is important in heavily pretreated patients with OPSCC, who have received a lot of different therapies in the past.

What details of the phase 3 trial would you like to share with colleagues who might be looking to enroll patients in this study?

We’re excited by the efficacy and safety profiles of the agent in OPSCC from the preliminary data of both ORR and PFS, but what we really want to demonstrate is that it’s superior to the standard-of-care [SOC] options we have for patients and [we want to] get this to be a therapeutic that’s available for all patients. The phrase 3 registration trial is focused on enrolling patients with unresectable, recurrent OPSCC. These are going to be previously treated patients. All patients would have to have received PD-1–directed therapy, as well as platinum therapy in the recurrent/metastatic disease setting, and they can have had up to 3 prior lines of treatment to qualify. Those eligible patients will be randomly assigned to 1 of 2 arms: the SOC arm, which would allow treatment with cetuximab, methotrexate, or docetaxel, vs the experimental arm, [in which patients would receive] Oz-V. Patients will be treated until progression, toxicity, or withdrawal, with the primary end points being OS and ORR. Hopefully, we’ll get this phase 3 study open soon.

References

1. Wong W, Thomas J, Adkins D, et al. Phase 2 trial of ozuriftamab vedotin (Oz-V), a conditionally binding ROR2-targeting ADC, in patients with treatment refractory HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Presented at: 2026 Multidisciplinary Head and Neck Cancers Symposium; February 19-21, 2026; Palm Desert, CA. Abstract 5.
2. BioAtla granted FDA fast track designation for ozuriftamab vedotin (CAB-ROR2-ADC) for treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck. News release. BioAtla, Inc. July 23, 2024. Accessed April 30, 2026. https://ir.bioatla.com/news-releases/news-release-details/bioatla-granted-fda-fast-track-designation-ozuriftamab-vedotin