c-MET: A Novel Target for Anticancer Therapies

On January 4, 2022, U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation (BTD) to telisotuzumab vedotin (Teliso-V) , an antibody conjugate drug (ADC), for the treatment of patients with advanced/metastatic epidermal growth factor receptor (EGFR) wild type, nonsquamous non-small cell lung cancer (NSCLC) with high levels of c-Met overexpression whose disease has progressed on or after platinum-based therapy.

Telisotuzumab vedotin (ABBV-399), Image Source: https://www.abbvie.com/

Lung cancer is the leading cause of cancer-related deaths worldwide, with NSCLC accounting for approximately 85% of lung cancer. Patients with lung cancer whose disease has progressed after standard of care therapy, including prior platinum, have limited treatment options and a poor prognosis.

Teliso-V is an ADC drug that targets c-Met, a receptor tyrosine kinase (RTK) that is overexpressed in a variety of tumors, including NSCLC. Currently, no cancer therapies have been approved specifically for patients with c-Met overexpressed NSCLC.

This BTD determination is supported by data from LUMINOSITY (M14-239), an ongoing phase 2 study designed to identify c-Met overexpressing NSCLC populations best suited to receive Teliso-V monotherapy in second- or third-line therapy, and then further evaluate efficacy in selected populations. The primary endpoint of the study is the overall response rate (ORR) in patients with ≥12 weeks of follow-up.

Previously published interim analysis showed an ORR of 53.8% in the c-Met high expression group and 25.0% in the c-Met intermediate expression group in patients with EGFR wild-type non-squamous NSCLC. Teliso-V was also evaluated in combination with osimertinib in the ongoing Phase 1 study M14-237 in previously treated patients with c-Met overexpressing NSCLC. In addition, it will be further evaluated as monotherapy in previously treated c-Met overexpressing NSCLC patients in the randomized Phase 3 study TeliMET NSCLC-01 (M18-868).

c-MET: a novel target for anticancer therapy

c-Met is a protein product encoded by the c-Met proto-oncogene, a hepatocyte growth factor receptor with tyrosine kinase activity. c-Met is associated with a variety of oncogene products and regulatory proteins, and is involved in the regulation of cellular information transduction, cytoskeletal rearrangement, and is an important factor in cell proliferation, differentiation, and motility.

It is now believed that c-Met is closely associated with the development and metastasis of many types of cancer. Studies have shown that many tumor patients have c-Met overexpression and gene amplification during their tumorigenesis and metastasis. c-Met has become another important molecular therapeutic target for NSCLC after EGFR and ALK.

➤ Monoclonal antibodies

To date, several companies have ventured into monoclonal antibodies targeting c-Met, such as ARGX-111 from argenx, Emibetuzumab from Lilly, Onartuzumab from Genentech, and HLX55 from Henlius. Unfortunately, the first three drugs have been discontinued from clinical trials due to their poor efficacy.

HLX55 specifically binds to the Sema/PSI domain of human c-MET, and has a dual mechanism of action by blocking the binding of c-MET to its ligand HGF, thereby blocking c-MET activation, and promoting c-MET degradation. Currently, HLX55 has been licensed for clinical trials in Taiwan and China, and clinical trials are in progress.

➤ Bispecific Antibodies

Compared to monoclonal antibodies, bispecific antibodies have been more well researched in c-MET targets. Among them, the fastest progress is Johnson & Johnson/Janssen's bispecific antibody Amivantamab targeting c-Met/EGFR. on May 21, 2021, the FDA accelerated the approval of Amivantamab for patients with metastatic NSCLC with EGFR exon 20 insertion mutation progressing after platinum-based chemotherapy.

➤Polyclonal Antibody

GB263T is the first tri-specific antibody (EGFR/cMET/cMET) developed by GENOR BIOPHARMA. On December 20, 2021, GENOR BIOPHARMA has submitted a clinical trial application to the Bellberry Human Research Ethics Committee (Bellberry HREC) in Australia for GB263T for the treatment of advanced malignancies. It is expected to file IND applications in China and the United States in 2022.

➤ ADCs

c-Met is also one of the targets for ADC drug development. In addition to teliso-V, two other anti-cMet ADCs (TR1801-ADC and SHR-A1403) are currently under investigation for use against solid tumors with promising preclinical activity.

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Reference:
[1] AbbVie Announces U.S. FDA Granted Breakthrough Therapy Designation (BTD) to Telisotuzumab Vedotin (Teliso-V) for Previously Treated Non-Small Cell Lung Cancer https://news.abbvie.com/news/press-releases/abbvie-announces-us-fda-granted-breakthrough-therapy-designation-btd-to-telisotuzumab-vedotin-teliso-v-for-previously-treated-non-small-cell-lung-cancer.htm