A phase 3, randomized, open-label study to evaluate the efficacy and safety of petosemtamab in combination with pembrolizumab versus pembrolizumab alone as first-line treatment for PD-L1 positive recurrent or metastatic squamous cell carcinoma of the head and neck.

PI: Prof.ssa Lisa Licitra 

The MCLA-158-CL03 study is a clinical trial evaluating the efficacy and safety of Petosemtamab in combination with Pembrolizumab versus Pembrolizumab alone as a first-line treatment for patients with locally recurrent and/or metastatic squamous cell carcinoma of the head and neck who have not yet received prior treatment. 

Petosemtamab is a bispecific antibody that targets two proteins: EGFR (Epidermal Growth Factor Receptor) and LGR5 (Leucine-rich repeat-containing G-protein coupled Receptor 5), both of which are overexpressed (i.e., abnormally expressed) on the surface of squamous tumor cells. As a biologic drug, it blocks the EGFR receptor, inhibiting the growth and progression of tumor cells while promoting apoptosis, or programmed cell death. Petosemtamab also specifically targets LGR5, a critical marker involved in the regulation of stem cell proliferation and differentiation, essential for tissue regeneration. 

Pembrolizumab is a humanized monoclonal antibody that acts by binding to the PD-1 (Programmed Cell Death-1) protein, thereby inhibiting the interaction between PD-1 and its ligands (PD-L1 and PD-L2), and stimulating immune system cells to eliminate cancer cells. 

The study, conducted in accordance with international ethical guidelines, is considered experimental, as Petosemtamab is not yet approved by health authorities for the treatment of head and neck cancer. However, the potential impact of Petosemtamab has already been demonstrated in previous clinical trials, supporting the biological and clinical rationale that this treatment may improve prognosis in this patient population. 

By contrast, Pembrolizumab is a drug that has long been approved by the U.S. Food and Drug Administration (FDA) and by the Italian Medicines Agency (AIFA) for the treatment of head and neck cancer. 

The aim of this study is to improve overall survival in patients with locally recurrent and/or distant metastatic disease, and to achieve better oncologic responses with the combination of the investigational drug Petosemtamab and Pembrolizumab, compared to Pembrolizumab monotherapy. 

Eligibility for enrollment in the study depends on various factors, including patient characteristics (demographic data, cancer history, and comorbidities), lab results, and radiologic parameters, which will be assessed through specific screening tests before treatment begins. These tests will be performed at this institution and follow clearly defined timelines. 

This is a randomized, open-label study.   

- The term "open-label" means that the patient, physician, and study staff all know which drug is being administered.   

- The term "randomized" means that the drugs included in the study will be assigned randomly, like flipping a coin. Assignment to one treatment arm or the other (Petosemtamab + Pembrolizumab versus Pembrolizumab alone) will occur through a computerized process called "randomization", which randomly assigns patients to treatment without any influence from the investigator or the patient. There is a 50% chance of being assigned to the experimental arm and a 50% chance of being assigned to the control arm: 

  - Arm 1 (Experimental): Administration of Petosemtamab + Pembrolizumab   

  - Arm 2 (Control): Administration of Pembrolizumab alone 

Dosing and administration: 

- Petosemtamab is administered at a fixed dose via intravenous infusion every two weeks, preceded by anti-allergic premedication.   

- Pembrolizumab is administered at a fixed dose via intravenous infusion every six weeks. 

Patients will be monitored for oncologic response through clinical visits and instrumental examinations. Additionally, patients will be monitored for potential adverse effects caused by the investigational therapy with Petosemtamab and/or the immunotherapy with Pembrolizumab. Treatment can lead to toxicity, often known in advance, requiring symptomatic treatment (e.g., corticosteroid therapy) and targeted strategies to reduce the intensity of side effects (e.g., treatment pauses, dose reductions, etc.). To ensure patient safety regarding treatment-related toxicities, all participants will be closely monitored. 

Treatment will continue until maximum response is achieved and will follow specific timelines and procedures outlined in the protocol. However, treatment may be discontinued in the event of disease progression, unacceptable toxicity, or—as is always the case in clinical trials—based on the decision of the investigator and/or the patient (who will continue to have access to medical care and will not forfeit any legal rights or benefits). 

The study team involved in the MCLA-158-CL03 trial is available for further detailed information about the study (email: amo@istitutotumori.mi.it).