Merus has announced positive interim results from its ongoing Phase II study evaluating petosemtamab, a bispecific antibody, in combination with pembrolizumab (Keytruda) for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). These findings are attracting attention across the oncology community, particularly because the trial focuses on patients whose disease has already progressed on prior PD-1 therapy—a group with limited treatment options and historically poor outcomes.

The Scientific Rationale

Head and neck squamous cell carcinoma is a difficult cancer to treat once it becomes resistant to immune checkpoint inhibitors. Pembrolizumab, which targets PD-1, has been a mainstay of treatment in earlier lines, but many patients eventually relapse or fail to respond. For these patients, therapeutic choices are limited, and prognosis is often grim.

Petosemtamab is designed as a bispecific antibody that simultaneously targets EGFR and cMet, two receptors implicated in tumour growth, survival, and resistance pathways. By engaging both, the drug aims to reduce tumour cell proliferation while potentially restoring sensitivity to immune-based therapies. Pairing this with pembrolizumab seeks to combine direct anti-tumour effects with immune activation, giving the body’s T-cells a renewed opportunity to attack resistant cancer cells.

The Trial Design

The Phase II study enrolled patients with recurrent or metastatic HNSCC, many of whom had already received and progressed on PD-1 therapy. The trial is structured to evaluate both efficacy and safety, with primary endpoints including objective response rate (ORR) and secondary measures such as progression-free survival, duration of response, overall survival, and tolerability.

Patients received regular infusions of petosemtamab alongside standard pembrolizumab dosing. Close monitoring was conducted for adverse events, given the risk of overlapping toxicities from targeting EGFR and cMet together with PD-1 inhibition.

Interim Results

At the interim analysis, the results were encouraging. In this challenging patient population, response rates were higher than expected compared to PD-1 inhibitor retreatment or standard salvage chemotherapy. Several patients achieved partial tumour shrinkage, with some responses lasting multiple months. While not all patients responded, the proportion showing meaningful clinical benefit was greater than typically seen in PD-1 refractory HNSCC.

Importantly, the safety profile was manageable. The most common side effects included skin rash, infusion-related reactions, and mild to moderate fatigue consistent with EGFR-targeted therapies and checkpoint inhibitors. Grade 3–4 adverse events were relatively infrequent and could be managed with supportive care or dose adjustments. No unexpected safety signals emerged.

Why This Matters

These results carry weight for several reasons.

1. Unmet need: Patients with HNSCC who progress after PD-1 inhibitors have very few effective treatment options. The emergence of a new regimen showing efficacy in this population could reshape treatment pathways.
2. Proof of concept for bispecifics in refractory disease: The ability of petosemtamab to enhance pembrolizumab’s activity demonstrates the potential of bispecific antibodies to unlock immune responses in tumours that otherwise evade checkpoint therapy.
3. Durability of responses: While interim, the duration of benefit seen in some patients suggests the combination could offer more than transient relief. Longer follow-up will determine whether this translates into survival benefit.

Remaining Questions

Despite the promise, several uncertainties remain. The current analysis is based on a modest number of patients, and larger trials will be necessary to confirm the findings. The durability of responses and the impact on survival endpoints such as progression-free and overall survival are not yet clear.

Another key question is biomarker identification. Which patients are most likely to respond to the combination? Understanding whether tumour EGFR or cMet expression, immune signatures, or other biomarkers predict benefit will be critical for tailoring treatment.

Finally, long-term safety data are needed, especially for toxicities that may emerge with extended exposure to bispecific antibodies plus checkpoint inhibitors. Regulatory agencies will also expect robust Phase III evidence before considering approval.

Looking Ahead

If the positive trends continue, Merus could move toward a randomized pivotal trial, potentially positioning petosemtamab plus pembrolizumab as a new option for PD-1 refractory HNSCC. Such a trial would compare the combination directly against current salvage treatments, providing the necessary evidence for regulatory submission.

Beyond HNSCC, this strategy could have broader implications. The success of combining a bispecific antibody with a checkpoint inhibitor may inspire similar approaches in other cancers where checkpoint resistance is a major problem, including lung cancer and gastrointestinal malignancies.

For clinical researchers the interim results are a reminder that innovation in trial design and drug combinations can still break ground in areas where treatment options have plateaued. For patients they represent a potential lifeline in a disease where progression often means limited hope.