Testing Early Treatment In Head And Neck Cancer Without Compromising Curative Care

By Selda Samakoglu, MD, Ph.D., Chief Medical Officer, Aveta Biomics

When we add an investigational treatment before surgery or chemoradiotherapy, we need a convincing reason for doing so and a clear plan for knowing when it should stop. The patient still has to reach the treatment intended to cure them, safely and on time. That concern has shaped our development of APG-157 for head and neck squamous cell carcinoma.

The weeks after diagnosis are often filled with staging, multidisciplinary discussions, treatment planning, and preparation for surgery or chemoradiotherapy. This work is necessary, but the disease can change while it is underway. Observational CT studies have confirmed tumor growth between diagnostic and treatment-planning scans,¹ and we believe early intervention may have a role during this interval — provided we can show that it helps without compromising definitive care.

For our part, we are testing whether oral APG-157 treatment before surgery or chemoradiotherapy can provide early disease control and whether the associated immune changes contribute to longer-term benefit. The biological rationale gives us a reason to investigate, but the clinical trial will establish what that means for patients.

Keeping Definitive Treatment On Schedule

In developing the APG-157 30-01 Phase 3 protocol, we had to address the concern that treatment before surgery could delay or jeopardize curative care. The protocol therefore determines when patients are reassessed, when APG-157 must be stopped, and how sites record the timing of definitive treatment.³

Cohort A specifies six weeks of neoadjuvant treatment before surgery. Cohort B specifies approximately four weeks of induction before chemoradiotherapy. Definitive treatment should begin within 21 days after the last dose, with an earlier transition when clinically indicated. These windows are limits for study conduct, and they should never become a reason to postpone care that could appropriately start sooner.

However, we also need to be candid about the time this approach may add. That depends on when surgery or chemoradiotherapy could otherwise have begun. Sites record both the planned and actual dates, along with the reasons for any delay. Progression, toxicity, a scheduling problem, and an unrelated medical condition call for different actions, and those matter when we assess safety and feasibility.

Flexibility is inherent. For example, imaging is scheduled for Week 4 but can be performed earlier if there is a clinical concern. A rise in circulating tumor DNA, or ctDNA, also calls for prompt imaging under the protocol. If progression, intolerance, or deterioration threatens timely definitive treatment, then APG-157 must stop, and the patient should move promptly to surgery or chemoradiotherapy. Neither completing the investigational course nor waiting for central review should hold up that decision.

At the same time, an independent data monitoring committee reviews events and patterns across sites that could compromise curative treatment. Depending on the findings, the protocol provides for mitigation measures, a pause in enrollment, or study termination. These safeguards need to work in day-to-day site practice, including when a patient's condition changes between scheduled visits.

What We Learned From An Earlier Phase Study

The Phase 2A study included 24 participants evaluable for efficacy and reported four objective responses. Short-course treatment was generally well tolerated, with no reported Grade 3 or higher treatment-related adverse events or delays to definitive therapy.^2,3 That was encouraging, but it was a small, single-arm study that also included earlier-stage disease. We cannot assume the same findings will translate into benefit for the locally advanced populations in Phase 3.

The timing of the observed activity and the ability to proceed to definitive care helped define the Phase 3 treatment windows: six weeks of neoadjuvant treatment before surgery and approximately four weeks of induction before chemoradiotherapy. Exploratory evidence of innate immune activation and M1 macrophage polarization also supported evaluating up to one year of maintenance after chemoradiotherapy in Cohort B, with the aim of sustaining immune activity and helping control residual micrometastatic disease.^2,3

One participant's response assessment offers a useful example of how easily a summary can lose important detail. The sum of the target-lesion diameters did not change after treatment. A new lesion, however, meant that the overall response was classified as progressive disease.⁴ A description limited to stable target lesions would have left out the finding that determined the patient's overall response.

Stable disease has defined response thresholds and can include some growth. However, we need to be clear about whether we are discussing the primary tumor, the measured target lesions, or the overall assessment, including new lesions.

Clinical-to-pathological downstaging needs similar attention. Imaging before treatment and pathology after surgery answer different questions. A lower pathological stage is an observation worth investigating, but in an uncontrolled study it cannot, on its own, establish an effect of the drug.

The same limitation applies to longer-term outcomes. Patients receive definitive surgery or radiotherapy after APG-157, and so randomized comparison is needed to determine what the added treatment contributes to their outcomes.

Surgery And Chemoradiotherapy Raise Different Questions

AVTA 30-01 uses two cohorts because the treatment settings differ. Cohort A evaluates APG-157 before surgery in resectable, locally advanced oral cavity or oropharyngeal cancer. Postoperative management is then based on pathological risk. Cohort B evaluates induction and maintenance around definitive chemoradiotherapy in protocol-defined oropharyngeal cancer when curative-intent surgery is unsuitable. This includes selected patients for whom surgery would cause unacceptable functional impairment. Each cohort has its own randomization and statistical evaluation, with event-free survival as the primary endpoint.³

The surgical cohort also has to account for the current standard of care. In the U.S., perioperative pembrolizumab is approved for eligible adults with resectable, locally advanced HNSCC whose tumors have a PD-L1 combined positive score of at least 1.⁵ Cohort A focuses on patients for whom that strategy is medically unsuitable under the study's defined criteria. Sites must document eligibility and obtain the required review before randomization. Patient preference or cisplatin ineligibility alone is not sufficient.

In Cohort B, four weeks of induction are followed by chemoradiotherapy and, for eligible patients, up to one year of maintenance. APG-157 is not given concurrently with chemoradiotherapy. Maintenance can begin only after adequate recovery and within the protocol's timing window. We are testing the hypothesis that continued immune modulation may help control residual disease. Because induction and maintenance are evaluated together, the trial cannot independently establish how much benefit comes from each.

Interpreting Biomarkers Alongside Clinical Outcomes

The biomarker work gives us a way to investigate what is happening during treatment. Exploratory tissue analyses in the APG-157 program have supported further study of changes in immune-cell infiltration.² In Phase 3, ctDNA measures are secondary biological activity endpoints; event-free survival remains the primary measure of efficacy.³

Interpreting ctDNA requires attention to the assay, whether ctDNA was detectable at baseline, when samples were collected, and which samples are missing. Consistent collection and a prespecified analysis are essential for meaningful comparisons across patients and treatment arms. Even a substantial fall in ctDNA does not establish cure or, by itself, justify reducing treatment.

The randomized study can examine how biomarker changes relate to clinical outcomes. Whether ctDNA could eventually serve as a surrogate is a separate question that would require further validation and regulatory agreement. Measuring it prospectively in a large trial does not establish that role.

A Future With Comprehensive Cancer Care

The promise of an earlier intervention matters only if it respects the care a patient already needs. In head and neck cancer, timing can determine whether a patient reaches surgery or chemoradiotherapy safely and without avoidable delay. That is why we must remain attentive not only to whether APG-157 shows activity but also to whether it fits responsibly into an already demanding course of care. The aim is not to ask patients to accommodate an investigational therapy but to learn whether an added intervention can offer meaningful benefit while preserving the rhythm, judgment, and urgency of curative care.

References:

1. Dejaco D et al. Specific growth rates calculated from CTs in patients with head and neck squamous cell carcinoma. BMJ Open. 2019;9:e025359. https://doi.org/10.1136/bmjopen-2018-025359
2. Wang MB et al. Neoadjuvant APG-157 monotherapy in patients with locally advanced squamous cell carcinoma of head and neck: A phase IIA, single arm trial. J Clin Oncol. 2025;43(suppl 16):6087. https://doi.org/10.1200/JCO.2025.43.16_suppl.6087
3. AVTA 30-01 Protocol. Version 1.0, 13 March 2026. Sections 2.2.3, 3.1–3.3, 4.1, 5.1, 5.3, 6.7.1, and 8.1.7; Table 12.
4. AVTA 20-01 study data. Listing 16.2.6.1, dated 30 June 2026. Overall response assessment for the participant with unchanged target-lesion measurements and a new lesion.
5. FDA. Approval of neoadjuvant and adjuvant pembrolizumab for resectable locally advanced HNSCC, 12 June 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-and-adjuvant-pembrolizumab-resectable-locally-advanced-head-and-neck

About The Author:

Selda Samakoglu, MD, Ph.D., is the chief medical officer of Aveta Biomics. She is a medical oncologist and physician-scientist with more than 20 years of experience in academia, clinical medicine, and biopharmaceutical development. Her work includes monoclonal antibodies, small molecules, oncolytic viruses, and cell-based immunotherapies, with experience advancing programs from early clinical development through regulatory approval.