FDA Grants Breakthrough Therapy Designation to Petosemtamab in HNSCC

Supporting data for the breakthrough therapy designation came from an open-label phase 1/2 trial (NCT03526835), in which investigators are evaluating treatment with petosemtamab as a single agent in those with advanced solid tumors.

The FDA has granted breakthrough therapy designation to petosemtamab (MCLA-158), an investigational IgG1 antibody targeting EGFR, as a treatment for adult patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), according to a press release from the developers, Merus N.V.¹

Specifically, the designation is for the agent’s use in patients with disease progression following prior platinum-containing chemotherapy plus an anti–PD-1 or anti–PD-L1 agent.

Supporting data for the breakthrough therapy designation came from an open-label phase 1/2 trial (NCT03526835), in which investigators are evaluating treatment with petosemtamab as a single agent in those with advanced solid tumors. Additional efficacy, safety, and durability data from the HNSCC cohort of the trial are anticipated for release in the second half of 2024.

According to findings presented at the 2023 American Association for Cancer Research Annual Meeting, the objective response rate (ORR) was 35.7% (n = 15/42) with petosemtamab per investigator assessment.² Investigators observed 1 complete response (CR), 12 partial responses (PRs), and 2 unconfirmed PRs. Additionally, the median duration of response (DOR) was 6.0 months (95% CI, 3.3-not evaluable), and the median progression-free survival (PFS) was 5.0 months (95% CI, 3.2-6.8).

Among all patients who received the recommended phase 2 dose (RP2D) of 1500 mg every 2 weeks, common any-grade and grade 3/4 adverse effects (AEs) included rash (33%, 0%), hypotension (26%, 6%), dyspnea (26%, 4%), nausea (26%, 1%), dermatitis acneiform (24%, 1%), and blood magnesium decreases (19%, 5%). Of note, 6% of patients discontinued study treatment due to infusion-related reactions.

“We are excited and encouraged to receive [breakthrough therapy designation] for petosemtamab, which further validates its potential to become a new standard of care for patients with previously treated HNSCC,” Ashley Pereira, PharmD, senior vice president of Regulatory Affairs at Merus, said in the press release.¹ “We look forward to continued constructive conversations with the FDA as we move forward in our plan to initiate a phase 3 trial in previously treated HNSCC mid-2024 and prepare for a potential phase 3 trial evaluating the combination of petosemtamab and pembrolizumab [Keytruda] in previously untreated patients.”

The investigational low-fucose human full-length IgG1 antibody petosemtamab was designed to make use of 3 mechanisms of action. These mechanisms include EGFR-dependent signaling inhibition, LGR5 binding to facilitate EGFR internalization and cancer cell degradation, and enhanced antibody-dependent cell-mediated cytotoxicity as well as antibody-dependent cellular phagocytosis activity.

Investigators of the open-label, multi-center study assessed treatment with petosemtamab across multiple patient cohorts. Patients who received treatment had advanced or metastatic solid tumors including colorectal cancer, gastric cancer, gastroesophageal junction cancer, non–small cell lung cancer, and HNSCC.³

The trial’s primary end point in the expansion portion was investigator-assessed ORR per RECIST v1.1 criteria. Secondary end points included DOR, PFS, overall survival, and safety and tolerability.

Patients 18 years and older with histologically or cytologically confirmed solid tumors showing evidence of metastatic or locally advanced disease not amenable to standard curative therapy were eligible for enrollment on the trial. Additional eligibility criteria included having measurable disease per RECIST v1.1 guidelines, a minimum life expectancy of 12 weeks, adequate organ function, and an ECOG performance status of 0 or 1.

Those with untreated or symptomatic central nervous system metastases or known leptomeningeal involvement were ineligible for enrollment on the trial.

The FDA previously granted fast track designation to petosemtamab as a treatment for those with recurrent or metastatic HNSCC in August 2023.⁴

References

1. Petosemtamab granted breakthrough therapy designation by the U.S. FDA. News release. Merus N.V. May 13, 2024. Accessed May 15, 2024. https://tinyurl.com/wmhnw8dc
2. Cohen EE, 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 cancer (HNSCC). Cancer Res. 2023;83(suppl 8):CT012. doi:10.1158/1538-7445.AM2023-CT012
3. A study of bispecific antibody MCLA-158 in patients with advanced solid tumors. ClinicalTrials.gov. Accessed May 15, 2024. https://tinyurl.com/2epu6xf4
4. Merus announces financial results for the second quarter 2023 and provides business update. News release. Merus N.V. August 7, 2023. Accessed May 15, 2024. https://tinyurl.com/43a5v7br