Frontline Petosemtamab Doublet Elicits Responses in Recurrent/Metastatic HNSCC


Key Takeaways

  • The combination therapy achieved a 67% ORR, with efficacy observed regardless of HPV status and PD-L1 expression.
  • Most treatment-emergent adverse events were grade 1 or 2, with 40% of patients experiencing grade 3 or higher events.
Petosemtamab Combo | ©Lars Neumann-

Petosemtamab Combo in HNSCC

©Lars Neumann-

The combination petosemtamab (MCLA-158) plus pembrolizumab (Keytruda) showcased early clinical efficacy with a tolerable toxicity profile when used in the first-line setting for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), according to data from a phase 2 study (NCT03526835) presented during the 2024 ASCO Annual Meeting.1

At a median follow-up of 3.58 months (range, 0.5-10.3), the doublet elicited an investigator-assessed overall response rate (ORR) of 67% (95% CI, 45%-84%) by RECIST 1.1 criteria, which comprised one complete response, 12 partial responses (PRs), and 3 unconfirmed PRs.

Moreover, the ORR achieved with the combination in those with human papillomavirus (HPV)–related, or p16-positive, tumors was 75% (n = 3/4); in those with p16-negative tumors, this rate was 65% (n = 13/20). In those with a PD-L1 combined positive score (CPS) ranging from 1 to 19, the ORR with the regimen was 60% (n = 6/10); in those with a PD-L1 CPS of 20 or higher, this rate was 71% (n = 10/14).

“Petosemtamab combined with pembrolizumab in the first line demonstrated a 67% response [rate], regardless of HPV status and regardless of PD-L1 expression. We had a favorable safety profile, including manageable infusion-related reactions [IRRs],” Jérôme Fayette, MD, of the Department of Medical Oncology at Leon Berard Center of University of Lyon, in Lyon, France, said in a presentation of the data. “Petosemtamab is a potential first- and best-in-class treatment for first-line treatment [of HNSCC.”

EGFR and Wnt represent oncogenic and mitogenic drivers in several cancers, including HNSCC, and LG25 is a receptor of Wnt signaling that is often upregulated. The Biclonics bispecific antibody petosemtamab targets both EGFR and LG25. Specifically, the agent inhibits EGF ligand binding and downstream signaling and leads to the degradation of EGFR through the internationalization of LGR5, Fayette explained. Host immune cells are engaged through enhanced antibody-dependent cellular cytotoxicity. Petosemtamab has previously been found to have preclinical and clinical antitumor activity in HNSCC, he noted.

Investigators hypothesized that pairing an EGFR antibody with a PD-1 inhibitor like pembrolizumab in HNSCC could potentially boost efficacy without the cost of added toxicity. When evaluated as a monotherapy in the second-line setting, the bispecific antibody elicited an ORR of 37.2% (95% CI, 23.0%-53.3%) and led to a median overall survival of 11.5 months (95% CI, 7.2-20.6) in patients with HNSCC.2 These data, which were shared during the 2023 AACR Annual Meeting, served as the rationale to perform the current phase 2 study.

The study enrolled patients with recurrent or metastatic HNSCC and PD-L1 positivity requiring first-line treatment.1 Patients were required to have an ECOG performance status of 0 or 1 and measurable disease. Participants were administered 1500 mg of intravenous (IV) petosemtamab every 2 weeks as part of a 28-day cycle, combined with 400 mg of IV pembrolizumab every 6 weeks. Treatment continued until disease progression or unacceptable toxicity. Tumor assessments were conducted every 8 weeks, and the survival follow-up period was 3 years.

The primary objective of the study is to examine ORR by investigator assessment and RECIST 1.1 criteria, as well as safety and tolerability. Secondary objectives included duration of response and progression-free survival by investigator and central review; OS; pharmacokinetics; immunogenicity; and biomarker analysis.

The study enrolled 45 patients. However, the efficacy-evaluable population comprised 24 patients who received treatment as of the data cutoff date of March 6, 2024, and who had the opportunity to undergo at least 4 months of follow-up. They must have received at least 2 cycles of treatment, and had at least 1 post-baseline tumor assessment performed, or they must have discontinued early because of progressive disease or death. Nineteen patients enrolled after the cutoff date and 2 were excluded due to withdrawn consent before first tumor assessment and due to toxicity with less than 2 cycles of treatment received.

The median patient age in the total 45 patients, who comprised the safety set, was 64 years (range, 23-80). Most patients were male (78%) and had an ECOG performance status of 1 (64%). Main tumor locations included the oral cavity (38%), oropharynx (31%), larynx (16%), hypopharynx (11%), and other (4%). In terms of PD-L1 status, all patients had PD-L1 positivity, with 42% having a CPS of 1 to 19 and 56% having a CPS of 20 or higher.

In terms of p16 (HPV) status by local testing in the 14 patients with an oropharynx tumor, 57% had p16 positivity, 36% had negativity, and 7% had unknown status. With regard to immunohistochemistry H-score, 13% had a score ranging from 0 to less than 100, 16% had a score ranging from 100 to less than 200, and 62% had score ranging from 200 to 300.

At the time of data cutoff, 71% of patients were still receiving treatment. Of the 29% of patients who discontinued, 20% did so due to disease progression, 4% because of withdrawn consent, 2% due to death that was not related to study treatment, and 2% because of a related adverse effect (AE). The median duration of exposure to the bispecific antibody was 3.32 months (range, 0.5-10.3).

“In the waterfall plot, you can see that a great majority of patients had early response and a long duration of response,” Fayette noted. Fourteen of 16 responders were still on therapy at the time of data cutoff.

Regarding safety, treatment-emergent AEs occurred in all patients but most of the effects were grade 1 or 2 in severity, according to Fayette. Grade 3 or higher TEAEs were reported in 40% of patients and 24% of these effects were related to study treatment. Treatment-related TEAEs led to study discontinuation in 2 patients and both effects were grade 1/2. No significant overlapping toxicities were observed.

The most common TEAEs occurring in more than 15% of patients, irrespective of causality, included acneiform dermatitis (all grade, 44%; grade 3-5, 2%), rash (40%; 0%), asthenia (36%; 7%), skin fissures (33%; 0%), constipation (27%; 0%), folliculitis (27%; 0%), nausea (27%; 2%), decreased blood magnesium (22%; 2%), diarrhea (22%; 2%), dry skin (22%; 0%), pruritus (22%; 0%), stomatitis (22%; 2%), cough (16%; 0%), fatigue (16%; 2%), IRR (16%; 2%), paronychia (16%; 0%), and tumor pain (16%; 2%).

Thirty-eight percent of patients experienced IRRs; 7% of these effects were grade 3 and no grade 4 or 5 effects were reported. Most of these effects occurred during the first infusion and resolved. Fayette noted that rechallenge after an IRR was successful in all patients and no patients discontinued due to an IRR that was grade 3 to 5 in severity. Investigators managed IRRs with premedication and prolonged infusion.

Clinical development with petosemtamab in HNSCC and colorectal cancer (CRC) is ongoing, Fayette concluded. He cited the agent’s examination in combination with pembrolizumab as a frontline treatment in patients with HNSCC as part of a phase 3 registration trial that is planned to being at the end of 2024; as a single agent in the second- and third-line treatment of patients with HNSCC as part of another phase 3 registration trial slated to begin mid-2024; and in combination with chemotherapy in the second-line treatment of patients with CRC.

Disclosures: Dr Fayette disclosed receiving honoraria from Bristol Myers Squibb, Hookipa Pharma, Merck Serono, Merck Sharp & Dohme, and Roche; he also serves in a consulting or advisory role for Bristol Myers Squibb, Elevar Therapeutics, Hookipa Pharma, ITeos Therapeutics, Merck Serono, Merck Sharp & Dohme, and Seagen; research funding was provided by AstraZeneca (Inst) and Bristol Myers Squibb (Inst); and travel expenses were covered by Bristol Myers Squibb and Merck Sharp & Dohme.


  1. 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
  2. Cohen EEW, Fayette J, Daste A, et al. Clinical activity of MCLA-158 (petosemtamab), an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced head and neck squamous cell carcinoma (HNSCC). Clin Cancer Res. 2023;83(suppl 8):CT012. doi:10.1158/1538-7445.AM2023-CT012
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