Beigene has submitted the IND application for its anti-EGFR×c-MET×c-MET tri-specific antibody BG-T187 in China. This marks the company's first in-house tri-specific antibody entering the clinical stage. In NSCLC, BeiGene has strategically targeted numerous molecular pathways, including PD-1, TIGIT, TIM3, LAG3, OX40, PanKRASi, HPK1, PRMT5i, B7H3 ADC, CEA ADC, and EGFR degrader.
BG-T187
EGFR is a critical biomarker for the diagnosis and treatment of non-small cell lung cancer (NSCLC). Beigene had not previously targeted this pathway, but they have now discovered therapeutic approaches beyond single inhibitors, such as TsAb and degraders.
 |
| Prevalence of EGFRm in NSCLC |
In 2023, Beigene submitted a patent (WO2024153168) covering anti-cMET antibodies, including multispecific antibodies such as the anti-EGFR×c-MET×c-MET tri-specific antibody in the examples. Different types of tri-specific antibodies were developed and evaluated in preclinical models. TE-647 has demonstrated superior anti-tumor activity in animal models with c-MET amplification or EGFR mutations, with particularly strong effects observed in models with c-MET amplification.
| Tri-specific antibodies in patent |
EGFR×c-MET
With the gradual increase in therapies targeting EGFR and c-MET, and the success of Amivantamab in targeting both, drugs aimed at these two targets have started to emerge and enter clinical trials. These include bi-specific antibodies, multi-specific antibodies, and ADCs.
Amivantamab
Amivantamab is the first approved bispecific antibody that targets EGFR and c-MET, developed by Janssen. Following the success in the first-line treatment of NSCLC, the product is forecasted to generate more than $5 billion in peak sales.
Currently, Amivantamab is approved in combination with Lazertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations; in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations; as a single agent for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.
EMB-01
EMB-01, a novel anti-EGFR×cMET bispecific antibody, is discovered by EpimAb. EMB-01 is currently investigating in the phase 1/2 trial in patients with NSCLC and GI cancers as monotherapy or in combination with Osimertinib.
In 2022, EpimAb presented the results of the phase 1 trial in patients with solid tumors. Among 38 response-evaluable NSCLC patients, 2 experienced a partial response (PR) (1 confirmed), while 14 had stable disease as their best response.
MCLA-129
MCLA-129, discovered by Merus, is a bispecific antibody that targets EGFR and c-MET. Merus has exclusively licensed Betta Pharmaceuticals Co. Ltd. to develop and potentially commercialize MCLA-129 in China in 2019.
In 2024, Merus presented results from the phase 1/2 study at the ASCO Annual Meeting. Among 15 evaluable patients with METex14 skipping mutations, the best overall response included 3 partial responses (PRs) and 6 unconfirmed PRs, resulting in an overall response rate (ORR) of 60% (9/15; 90% confidence interval [CI]: 36–81). Overall, 19 out of 22 patients (86%) experienced infusion-related reactions (IRRs), with 4 patients (18%) having Grade ≥3 IRRs. One patient (5%) developed treatment-related Grade 2 interstitial lung disease. Venous thromboembolism was reported in 2 patients: one with possibly treatment-related Grade 3 and the other with non-treatment-related Grade 2.
In 2023, Merus brought the results of the phase 1/2 trial in patients with HNSCC at the ESMO Asia Congress. Among the 20 evaluable patients, 2 (10%) demonstrated partial responses—one confirmed with a duration of over 3.4 months and the other later verified—leading to a disease control rate (DCR) of 60% (95% CI: 36–81).
AZD9592
AZD9592 developed by AstraZeneca is an antibody-drug conjugate (ADC) with a bispecific antibody targeting EGFR and c-MET, conjugated with TOP1 inhibitor, and has a drug-to-antibody ratio (DAR) of 6. It is currently under investigation in the phase 1 study in patients with metastatic NSCLC (mNSCLC) with EGFRm (sensitizing L858R mutation or exon 19 deletions) or EGFR wild-type, or recurrent or metastatic HNSCC. And the combination of AZD9592 and Osimertinib is also evaluated in the Module 2 part of this trial.
| AZD9592 |
FPI-2068
FPI-2068, discovered by Fusion Pharmaceuticals (now an AstraZeneca company), is a targeted alpha therapeutic (TAT), consisting of a humanized EGFR and cMET targeting bispecific antibody (FPI-2053) radiolabeled with actinium-225. As of now, FPI-2068 is in the phase 1 trial in patients with metastatic and/or recurrent solid tumors (HNSCC, NSCLC, mCRC, PDAC).
| FPI-2068 |
HS20117 (PM1080)
HS20117 (PM1080), discovered by Biotheus and partnered by Hansoh, is an asymmetric 1+1 IgG-like bispecific antibody targeting EGFR×c-MET. Currently, HS20117 is in the phase 1b trial in patients with NSCLC and other solid tumors as monotherapy or in combination with Hansoh's 3rd gen EGFR inhibitor Aumolertinib. In May 2024, Hansoh registered a phase 1b/3 trial of HS-20117 in combination with Aumolertinib in patients with EGFRm NSCLC. Biotherus presented the preclinical results of PM1080 at the 2023 AACR Annual Meeting.
GB263T
GB263T, discovered by Genor Biopharma, is a novel anti-EGFR×cMET×cMET tri-specific antibody that is in the phase 1/2 trial in patients with NSCLC and other solid tumors.
In 2024, Genor presented the results from a first-in-human, phase I/II study of GB263T at the ESMO Congress. Among 14 response-evaluable EGFR, NSCLC patients, there were two partial responses (PRs) and six stable diseases (SDs). In those with EGFR-sensitive mutations who progressed after third-generation EGFR-TKI treatment (N=7) at doses of 1260/1680 mg, the confirmed overall response rate (ORR) was 28.6% (2/7), while three patients with cMET alterations demonstrated clinical benefit with 2 PRs and 1 durable SD, the longest treatment duration exceeding 12 months at 840 mg by the data cutoff.
YH013
YH013, developed by Biocytogen and DOMA, is a novel EGFR×MET bispecific antibody-drug conjugate that is still in the preclinical stage. Biocytogen presented the preclinical results at the 2023 AACR Annual Meeting. In multiple patient-derived xenografts of non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC co-expressing EGFR and MET, YH013 exhibited superior and durable efficacy, outperforming benchmark antibodies at a lower dose of 3 mg/kg.
|
| In vivo efficacy |
Comments