Petosemtamab and Pembrolizumab: A Promising Pair in HNSCC Treatment


In an interview, Cesar Augusto Perez, MD, delved into the findings from a phase 2 study evaluating petosemtamab plus pembrolizumab in patients with recurrent/metastatic head and neck squamous cell carcinoma.

Cesar Augusto Perez, MD

Cesar Augusto Perez, MD

When given in combination with pembrolizumab (Keytruda) in the first-line setting, petosemtamab (MCLA-158) demonstrated clinically meaningful activity and showed a manageable safety profile among patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC).1

A phase 2 study (NCT03526835) sought to assess the combination in the first line for the treatment of patients with recurrent/metastatic PD-L1-positive HNSCC with an ECOG performance status of 0 to 1 and measurable disease. Patients were given petosemtamab at a dose of 1500 mg intravenously (IV) once every 2 weeks in a 28-day cycle along with 400 mg of IV pembrolizumab 400 once every 6 weeks until progressive disease or toxicity.

The primary end points of the study were overall response rate (ORR), safety, and tolerability, and secondary end points included duration of response, progression-free survival, overall survival, pharmacokinetics, immunogenicity, and biomarkers.

Findings presented at the 2024 American Society of Clinical Oncology Annual Meeting showed that the ORR was 67% (95% CI, 45%-84%) among those given the combination. Sixteen of 24 patients responded, 13 of which were confirmed, and 3 which were unconfirmed. These responses were seen regardless of human papilomavirus (HPV) status and across PD-L1 combined positive score (CPS) subgroups. For safety, no new safety signals were identified. However, infusion-related reactions (IRRs) were observed in 38% of patients. Grade 3 IRRs were seen in 7% of patients, and there were no grade 4 or 5 IRRs.

This combination represents a new potential first- and best-in-class treatment for the first-line treatment of patients with HNSCC, according to Cesar Augusto Perez, MD.

“There are phase 3 trials now being designed and those will hopefully open soon with petosemtamab and pembrolizumab in patients with head and neck cancer that are PD-1-positive in the first-line setting. Definitely watch out for those for that trial and for those results, because they might be practice-changing, hopefully,” Perez, hematologist and medical oncologist at Florida Cancer Specialists & Research Institute’s Lake Nona Cancer Center, told Targeted OncologyTM in an interview.

In the interview, Perez delved into the findings from a phase 2 study (NCT03526835) evaluating treatment with petosemtamab plus pembrolizumab for the first-line treatment of patients with recurrent/metastatic HNSCC.

Head and neck cancer image: © -

Head and neck cancer image: © -

Targeted Oncology: What was the rationale behind studying this combination?

Perez: Data of petosemtamab were already presented last year in patients that were refractory to platinum and refractory to checkpoint inhibitors. These patients were naive to EGFR inhibitors in the metastatic setting. Petosemtamab demonstrated an encouraging response rate of 37% as a single agent in this refractory population. The treatment was fairly well tolerated. Most of the adverse events were infusion-related reactions, and there were some EGFR-related toxicities such as rash. But the response rate in this particular population was pretty impressive. The median duration of response was, I think, 5.6 months. Because of the tolerability, there is not really a lot of overlap in toxicities with checkpoint inhibitors. It was logical to think that the combination will be something worth pursuing in patients that were treatment-naive in the recurrent/metastatic setting.

What background can you provide regarding this phase 2 study?

This is a phase 2 trial that was based on the activity seen already of petosemtamab in patients with head and neck cancer that had progression of disease on platinum and checkpoint inhibitors. In that population, there was a report last year with a response of around 37%. This trial used petosemtamab in combination with pembrolizumab for patients with a squamous cell carcinoma of the head and neck who had disease that was PD-L1-positive. All [patients were] treatment-naive in the recurrent or metastatic setting. The study could enroll patients that were HPV-negative and HPV-positive, so it was regardless of HPV status. The results were actually very encouraging. The data is still fairly early, so it is not mature, but the results presented were very encouraging.

What did the patient population look like?

The median age for patients with head and neck cancer was 64 years old. There were patients with several different subsites of the head and neck. I think it is important to know that around 31% of the patients had oropharyngeal squamous cell carcinoma. From this, there were 8 patients in total with HPV-related squamous carcinoma, so p16-positive. The trial did include patients that had HPV-related disease, which was important because there is always a question of how much activity the EGFR antibodies have in patients with HPV-related disease or if the activity is mainly seen in the HPV-negative patient populations. It is kind of a controversial area.

Please discuss the efficacy findings.

In terms of efficacy, 67% of the patients developed a response, so there was a response rate of 67%. In total, there were 24 patients that had evaluable disease by RECIST 1.1, there was 1 patient with a complete response, 12 patients with a partial response, and there were also 3 patients with an unconfirmed partial response. There were patients with responses with HPV-negative and HPV-positive disease, and they also were divided among the CPS scores. There were 10 patients with CPS between 1 to 19, and 14 patients with CPS of 20 [or higher]. And there were responses in both subsets. In CPS 1 to 19, 60% of patients responded and patients with CPS more than 20, there was a 71% response rate, which is obviously very encouraging.

In terms of the duration of response, most of the patients were still in response at the data cutoff. I think 1 of the things that I learned from these molecules that is very interesting is that you can see responses pretty early, which is something that we are not used to seeing in checkpoint inhibitors. Usually, we have to wait a little bit longer. But for unknown reasons, the activity of this antibody can be seen pretty early on during the treatment course, which is very important for patients who are symptomatic, and that is important, because some patients have a life-threatening disease in the immediate term, so we try not to lose patients, and the good thing about this antibody is that we can see activity early on. And as a single agent, we saw the same thing as in the combination arm.

What were the safety findings observed?

There were treatment-related [adverse events (AEs)] in 45 patients. Most of them were grade 1 to 2. Forty percent of the patients had treatment-emergent AEs which were grade 3 or more. From these, some of them were grade 3 infusion-related reactions in 7%. The infusion-related reactions in the whole population were 38%, but 7% were grade 3. There were no grade 4 or 5 infusion-related reactions, which is obviously an important and interesting thing. The most common AEs observed were rash and acneiform dermatitis; this is an EGFR-related AE, and also fatigue and some skin fissures. There were some other less common AEs [like] constipation, folliculitis, and nausea.

What should a community oncologist take away from this research?

I think that community oncologists, and the whole oncology community in general, have to watch out for this agent. Certainly, the response rate of petosemtamab together with pembrolizumab is encouraging. There was a 67% overall response rate in this cohort. It is early on, but certainly, the response rate is a lot higher than what we are used to seeing in this population. These were all patients with PD-1 CPS more than 1, which is important. And there were no new safety signals for the combination. The main AEs were infusion-related reactions, but it is something that with some measurements, including slowed down infusion and some premedications, have been ameliorated in terms of the grade.

Again, it is a promising approach in the first-line setting. There are phase 3 trials now being designed and those will hopefully open soon with petosemtamab and pembrolizumab in patients with head and neck cancer that are PD-1-positive in the first-line setting. Definitely watch out for those for that trial and for those results, because they might be practice-changing, hopefully.

Fayette J, Clatot F, Braña I, et al. Petosemtamab (MCLA-158) with pembrolizumab as first-line (1L) treatment of recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC): phase 2 study. J Clin Oncol. 2024;42(suppl 16):6014. doi:10.1200/JCO.2024.42.16_suppl.6014
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