Petosemtamab

Shows activity

Also known as:

MCLA-158

Cancer types include:

cervical cancer colon cancer esophageal cancer head and neck cancer rectal cancer

HealthScout AI Analysis

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Overview

Petosemtamab (MCLA-158) is an investigational, ADCC‑enhanced, full‑length bispecific IgG1 antibody that targets EGFR and LGR5. It is being developed primarily for recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC), with ongoing phase 2 and phase 3 development; the FDA has granted Breakthrough Therapy designation for post–PD‑1/platinium r/m HNSCC (May 2024) and for the first‑line combination with pembrolizumab in PD‑L1–positive disease (February 2025). (aacrjournals.org)

Mechanism of action

Dual targeting of EGFR and LGR5 on tumor cells; binding blocks EGFR ligand engagement and, when both targets are present, promotes LGR5‑mediated internalization and degradation of EGFR. The Fc region is engineered for enhanced innate immune effector functions (ADCC/ADCP). (pubmed.ncbi.nlm.nih.gov)

Efficacy

Monotherapy (phase 1/2, expansion cohort, previously treated r/m HNSCC): Among 43 evaluable patients, overall response rate (ORR) was 37.2% with median duration of response (DOR) 6.0 months (data cutoff Feb 1, 2023; AACR 2023). (aacrjournals.org)
First‑line combination with pembrolizumab (phase 2 expansion, PD‑L1 CPS ≥1 r/m HNSCC):
Early ASCO 2024 readout (n=24 evaluable): investigator‑assessed ORR 67%. (merus.gcs-web.com)
Updated 2025 interim analysis (data cutoff Feb 27, 2025; n=43 evaluable): confirmed ORR 63% (6 CR, 21 PR); median PFS 9.0 months (95% CI 5.2–12.9); 12‑month overall survival rate 79%; median DOR and OS not reached. Responses were observed across PD‑L1 levels (CPS 1–19: 47%; CPS ≥20: 73%). (ir.merus.nl)
Study design and initial safety run‑in details were presented at ASCO 2024 (NCT03526835). (ascopubs.org)

Note: Phase 3 trials in first‑line PD‑L1+ and in post‑PD‑1 settings have been initiated/planned by the sponsor based on these data. For current recruitment/status, see the study record for NCT03526835 and sponsor updates. (fdaaa.trialstracker.net)

Safety

Monotherapy (AACR 2023, n=78 at RP2D across escalation/expansion): most frequent adverse events (all grades/grade 3–4) included rash (33%/0%), hypotension (26%/6%), dyspnea (26%/4%), nausea (26%/1%), acneiform dermatitis (24%/1%), hypomagnesemia (19%/5%); infusion‑related reactions (IRRs) in 74%/21% (mostly first infusion; 6% discontinued due to IRR). One unrelated grade 5 GI bleed in an esophageal cancer patient. (aacrjournals.org)
First‑line combination with pembrolizumab (ASCO 2024 safety run‑in): no grade 4–5 AEs observed at early cutoff; most AEs were grade 1–2 (e.g., acneiform dermatitis 31%, asthenia 27%, rash 27%); IRRs in 27% (grade 3 in 3.8%, first infusion, resolved). (ascopubs.org)
Updated 2025 interim combination data (n=45 treated): grade ≥3 treatment‑emergent AEs in 60% and grade ≥3 treatment‑related AEs in 44%; IRRs in 38% (grade 3 in 7%), mainly first infusion; no significant overlapping toxicities with pembrolizumab reported. (ir.merus.nl)

Active trials using Petosemtamab

Found 3 active trials using this drug:

A Phase 3 Randomized, Open-label Study to Evaluate the Efficacy and Safety of Petosemtamab Plus Pembrolizumab vs Pembrolizumab in First-line Treatment of Recurrent or Metastatic PD-L1+ Head and Neck Squamous Cell Carcinoma

Sponsor: Merus N.V. (industry) Phase: 3 Start date: Sept. 25, 2024

HealthScout AI summary: Adults with PD-L1 CPS ≥1 recurrent or metastatic HNSCC (oral cavity, oropharynx, hypopharynx, larynx) without prior systemic therapy for incurable disease are randomized to petosemtamab plus pembrolizumab vs pembrolizumab alone. Petosemtamab (MCLA-158) is a bispecific IgG1 targeting EGFR and LGR5 that blocks EGFR signaling and promotes EGFR internalization in LGR5+ tumor cells with Fc-mediated ADCC/ADCP.

ClinicalTrials.gov ID: NCT06525220

A Phase 3 Open-label, Randomized Controlled Study to Evaluate the Efficacy and Safety of Petosemtamab Compared With Investigator's Choice Monotherapy Treatment in Previously Treated Patients With Incurable, Metastatic/Recurrent Head and Neck Squamous Cell Carcinoma

Sponsor: Merus N.V. (industry) Phase: 3 Start date: June 25, 2024

HealthScout AI summary: Adults with metastatic or recurrent, non-curable HNSCC (oral cavity, oropharynx, hypopharynx, larynx) who progressed after anti–PD-1 and platinum therapy (ECOG 0–1, measurable disease) are randomized to petosemtamab (MCLA-158), a bispecific EGFR/LGR5 antibody that blocks EGFR signaling and promotes LGR5-mediated EGFR degradation with Fc effector activity, versus investigator’s choice single-agent therapy. Key endpoints are ORR and OS; excludes nasopharyngeal primaries and active CNS disease.

ClinicalTrials.gov ID: NCT06496178

Phase 1/2 Dose Escalation and Cohort Expansion Study Evaluating MCLA-158 (Petosemtamab) as Single Agent or in Combination in Advanced Solid Tumors

Sponsor: Merus N.V. (industry) Phase: 1/2 Start date: May 2, 2018

HealthScout AI summary: Adults with EGFR‑dependent advanced solid tumors—primarily mCRC (RAS/RAF WT, MSS; anti‑EGFR–naive for chemo combos or 3L+ without HER2 amp/oncogenic EGFR ECD mutations) and previously included HNSCC—receive petosemtamab, a bispecific anti‑EGFR/LGR5 IgG1 antibody given Q2W as monotherapy or combined with FOLFOX/FOLFIRI (and previously pembrolizumab in HNSCC). Suitable for ECOG 0–1 patients without uncontrolled CNS disease; aims to exploit EGFR blockade and LGR5‑targeted EGFR degradation with Fc effector function.

ClinicalTrials.gov ID: NCT03526835