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Novel Bispecific Antibody Active in Recurrent/Metastatic Head and Neck Cancer

— Responses in 37% of patients previously treated with anti-PD-1/L1 agents, platinum chemotherapy

Ƶ MedicalToday

ORLANDO -- More than a third of patients with previously treated head and neck cancer responded to a novel bispecific antibody, a preliminary clinical trial showed.

The data showed that 37.2% of patients had objective responses, including one complete response. More than 70% of patients obtained disease control with petosemtamab, which targets EGFR and LGR5, the latter expressed by cancer stem cells (CSCs). The treatment was associated with a median progression-free survival of 5.3 months and median overall survival of 11.5 months.

About a fifth of patients had infusion-related reactions (IRRs), which were severe in a majority of cases, reported Ezra Cohen, MD, of the University of California San Diego Moores Cancer Center, at the American Association for Cancer Research meeting.

"We observed clinically meaningful activity and durable responses in this cohort of patients with advanced and quite refractory head and neck squamous cell carcinoma [HNSCC] who had been previously treated with both immunotherapy and platinum-based chemotherapy," he said. "This validates an earlier clinical report that demonstrated almost the exact same objective response rate. The agent is relatively well tolerated with a manageable safety profile."

Petosemtamab clearly has single-agent activity in recurrent/metastatic HNSCC, and further investigation is warranted, said invited discussant Lillian Siu, MD, of Princess Margaret Cancer Centre in Toronto. However, a number of questions remain to be addressed in ongoing and future studies.

  • Is petosemtamab uniquely different from the anti-EGFR antibody cetuximab (Erbitux)?
  • What does LGR5 contribute?
  • Did the study suggest potential predictive biomarkers for patient selection?
  • How much of the activity observed in the study owed to a "priming" effect of prior immunotherapy?
  • What is the mitigation plan for IRRs?

"I do believe that a randomized trial would be the best way to go to make decisions for a go/no go for this particular compound," said Siu.

EGFR has a well recognized association with malignancy, including HNSCC, Cohen noted in his introduction to the study. In contrast, LGR5 has emerged fairly recently as a potential target for cancer therapy. Expressed primarily on CSCs, LGR5 is upregulated in many tumor types, including HNSCC. Petosemtamab demonstrated substantial antitumor activity against tumor-initiating cells and CSCs expressing LGR5 and in multiple models of head and neck cancer associated with high EGFR expression.

LGR5 is expressed in 50-90% of HNSCCs, and EGFR is overexpressed in up to 90%, said Cohen.

Investigators evaluated petosemtamab in patients with recurrent/metastatic HNSCC that had progressed on anti-PD-1/L1 therapy and platinum-based chemotherapy, or in patients who could not tolerate the drugs. Patients received petosemtamab every 2 weeks in 28-day cycles until progressive disease or toxicity. Follow-up for survival continued for as long as 18 months. The primary objective was investigator-assessed response.

Efficacy assessment was limited to patients who completed at least two treatment cycles and had at least one post-baseline tumor assessment or discontinued early because of progression or who died (N=43). Six patients were excluded because of protocol violations.

Patients had a median age of 63, and cancer of the oropharynx (17 patients, 35%) or oral cavity (15, 31%) accounted for a majority of cases. About 20% of patients were PD-L1 positive, and six of the 17 patients with oropharyngeal cancer were positive for HPV p16. Eight patients had unknown HPV p16 status.

The results showed objective responses in 16 of 43 patients (37.2%), and 31 of 43 (72.1%) had response or stable disease. The median time to response was 1.8 months, and responses had a median duration of 6.0 months. Cohen showed images demonstrating rapid, dramatic responses in several patients.

In a safety analysis that included 80 patients treated with petosemtamab, the most common adverse events (≥20% of patients) were rash, dyspnea, hypotension, nausea, dermatitis acneiform, IRRs, hypomagnesemia, and diarrhea. IRRs were the most common grade 3/4 AEs (10 patients, 13%). No fatal treatment-related AEs occurred.

With regard to the IRRs, Cohen said "they almost exclusively occurred during the first infusion. All of the infusion-related reactions resolved. Six of the 80 patients discontinued because of infusion-related reactions. For all patients who were rechallenged, rechallenge was successful. We developed and learned along the way how to manage and prophylax for infusion-related reactions."

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined Ƶ in 2007.

Disclosures

The study was sponsored by Merus.

Cohen disclosed relationships with Adagene, Astellas, Cidara, Eisai, Genmab, Gilboa, iTeos, Eli Lilly, MSD, Merck, NectinTX, Novartis, Nykode, Pangea Therapeutics, PCI Biotech, Replimune, Roche, Soteria, Tempus, Viracta, Kinnate Biopharma, Primmune Therapeutics, Akamis Bio, and Kura.

Siu disclosed relationships with Merus, Merck, Pfizer, Roche, GSK, Voronoi, Aniva, Tessa, Navire, Relay, Daiichi Sankyo, Coherus, Amgen, Marengo, InteRNA, Medicenna, Tubulis, LTZ Therapeutics, Novartis, Bristol Myers Squibb, Boehringer-Ingelheim, Bayer, AbbVie, Symphogen, Intensity Therapeutics, Mirati, Shattuck Lab, BioNTech, 23andMe, EMD Serono, and Treadwell Therapeutics.

Primary Source

American Association for Cancer Research

Cohen EEW, et al "Clinical activity of MCLA-158 (petosemtamab) an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced head and neck squamous cell cancer (HNSCC)" AACR 2023; Abstract CT012.