MCLA-129 and the cost of arriving fourth in MET

What was tried

Merus opened NCT04868877 on 28 April 2021 as a Phase 1/2 dose escalation and expansion study of MCLA-129, a human bispecific antibody directed at EGFR and c-MET. The molecule now carries the nonproprietary name pamvatamig and the ChEMBL identifier CHEMBL5314862. The design was open label and non-randomized, with parallel assignment. Part One enrolled patients with non-small cell lung cancer, gastric or gastroesophageal junction cancer, head and neck squamous cell carcinoma, or esophageal squamous cell carcinoma who had progressed on or were intolerant to prior standard first-line treatment. Part Two split into seven cohorts, most defined by molecular alteration or prior therapy: NSCLC carrying an EGFR exon 20 insertion, NSCLC carrying a MET exon 14 skipping mutation, first-line EGFR-mutant disease dosed alongside osimertinib, osimertinib-resistant disease dosed alongside either osimertinib or chemotherapy, osimertinib- and platinum-resistant disease dosed alongside chemotherapy, and a basket of selected solid tumors with or without an EGFR or MET alteration. The co-primary objectives were the maximum tolerated dose or recommended Phase 2 dose across the first 28 days of treatment, and clinical activity measured as objective response rate. Actual enrollment reached 194 participants. The record moved to terminated status with a last update posted on 26 October 2026 and a completion date of 1 October 2026. No results have been posted to ClinicalTrials.gov.

The biological hypothesis

MET is one of the better supported targets in lung cancer. The Open Targets Platform scores the MET association with non-small cell lung carcinoma at 0.724 overall, built from a literature datatype score of 0.995, a clinical datatype score of 0.986, an affected pathway score of 0.679 and a somatic mutation score of 0.451. MET amplification and MET exon 14 skipping are established oncogenic drivers, and MET activation is a recognized bypass route when EGFR is inhibited. The bispecific logic follows from that: block the driver and its principal escape hatch with one molecule, so resistance has one fewer route to take. Open Targets flags MET as tractable to both small molecules and antibodies, and lists a single safety liability entry for the target, drawn from ToxCast. Nothing in the target biology predicted this outcome.

What actually happened

The trial ran for roughly five and a half years and accrued 194 participants, then stopped without posting results. The sponsor's stated reason reads: "The Sponsor terminated the trial early for strategic business reasons. This isn't related to any safety/efficacy/clinical activity/benefit-risk concern with petosemtamab. Ongoing participants will have access to treatment outside of this trial." The sentence names petosemtamab, a different Merus bispecific directed at EGFR and LGR5, rather than the asset under study. Whether that is a drafting artifact or a deliberate pointer to where the sponsor's attention went, the direction of travel is the same.

While NCT04868877 was running, the MET field filled in. Open Targets lists 38 distinct MET-directed drugs and clinical candidates, of which 8 are approved and 6 sit in Phase 3. The approved set includes amivantamab, an EGFR and MET bispecific antibody, along with capmatinib, tepotinib, savolitinib and crizotinib. A second EGFR and MET bispecific entering Phase 2 cohorts in 2024 and 2025 was no longer testing a novel mechanism. It was competing for the same biomarker-selected patients against agents that already had labels.

Failure mechanism, best guess

This was portfolio triage, not a biological refutation. The archetype is strategic reprioritization. The sponsor disclaimed safety, efficacy and benefit-risk concerns, and no posted data contradict that. What changed was the value of the asset rather than its performance.

The limit on this reading is that no efficacy data were released. Absent posted response rates, there is no way to separate an asset that worked and was outcompeted from one that worked modestly and was quietly shelved. Both are consistent with the public record. What can be said without inference is that a Phase 1/2 asset competing in a space holding 8 approved agents faces a commercial bar set by those agents, not by chemotherapy, and that bar rose during the trial rather than after it.

How to prevent this next time

No endpoint-level data were posted for this trial, so no Bayesian update, power calculation or subgroup analysis is possible here. The available levers are the qualitative ones, and they are the right ones for this failure mode.

Run a competitive clock analysis at program start, not at readout. The relevant question is not whether the mechanism is differentiated today but whether it will be differentiated on the date the pivotal trial reads out, given what is already in Phase 3. Apply a base rate correction for crowded target classes: a target carrying 38 programs and 8 approvals is one where the marginal entrant needs a specific advantage, stated in advance, in a defined population. The biomarker enrichment in this trial was sound, with cohorts built around EGFR exon 20 insertions and MET exon 14 skipping, so that lever was already pulled. The gap was upstream of trial design.

The single highest leverage change would have been to fix, before Part Two opened, the response rate and duration that MCLA-129 would need in EGFR exon 20 insertion and MET exon 14 disease to beat the agents already approved in those exact populations, and to treat failure to clear that bar at interim as a stopping rule rather than as a business decision taken later.

What this means for similar programs

The Mechanism Risk Score for MET computes to 31 on this run, in the yellow band. The components are informative: phase burden 5.13, archetype severity 2.00, recency 4.25, genetic deficit 4.14 and saturation 14.99 out of a possible 15. Almost half the score comes from crowding alone, and the genetic component is small precisely because the target is well validated. That is the signature of a commercially risky target rather than a biologically risky one, and it is a different problem requiring a different fix. Teams entering MET should assume the clinical comparator is an approved MET-directed agent and budget for a head-to-head argument.

Open questions

Were objective response data generated in the EGFR exon 20 insertion and MET exon 14 skipping cohorts, and will Merus publish them? Did the osimertinib combination arms show any signal that would inform sequencing in osimertinib-resistant disease? Does the reference to petosemtamab in the termination record reflect a shared safety database across the Merus bispecific portfolio, or is it a clerical error? Will the disposition of pamvatamig change under Merus's announced acquisition by Genmab, and will the 194 participants' data reach the literature either way?

Sources

1. • ClinicalTrials.gov, NCT04868877, "Phase 1/2 Dose Escalation and Expansion Study Evaluating MCLA-129, a Human Anti-EGFR and Anti-c-MET Bispecific Antibody, in Patients With Advanced NSCLC and Other Solid Tumors", record retrieved 27 October 2026. https://clinicaltrials.gov/study/NCT04868877 - Open Targets Platform v4 GraphQL API, MET (ENSG00000105976) and non-small cell lung carcinoma (MONDO_0005233), association scores, tractability, safety liabilities and drug-and-clinical-candidate counts, retrieved 27 October 2026. https://platform.opentargets.org/target/ENSG00000105976 - ChEMBL, pamvatamig (MCLA-129), CHEMBL5314862, retrieved 27 October 2026. https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL5314862/ - Genmab A/S, "Genmab to Acquire Merus, Expanding Late-Stage Pipeline and Accelerating into a Wholly Owned Model", 29 September 2025. https://ir.genmab.com/news-releases/news-release-details/genmab-acquire-merus-expanding-late-stage-pipeline-and/ - Camidge DR et al. Phase I Study of 2- or 3-Week Dosing of Telisotuzumab Vedotin, an Antibody-Drug Conjugate Targeting c-Met. Clin Cancer Res.

2. - Exploiting MET dysregulation in EGFR-addicted non-small-cell lung carcinoma. Transl Lung Cancer Res.

3. - MET: a new promising biomarker in non-small-cell lung carcinoma. Pharmacogenomics.

4. - openFDA drug event endpoint, queried 27 October 2026 for MCLA-129 and pamvatamig: no matching reports.