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Antibody- drug conjugates in treatment of non-small cell lung cancer

Even though both targeted and immunotherapy-based therapies have been established as frontline standard-of- care for patients with advanced non- small cell lung cancer (NSCLC), adverse events, resistance, and disease progression remain unavoidable in most cases. In this scenario, chemotherapy is a remaining salvage option, but it has a narrow therapeutic index. By harnessing the powers of both cytotoxic chemotherapy and targeted therapy, antibody- drug conjugates (ADCs) are unique in offering the potential to deliver highly potent cytotoxic agents to cancer cells which express a pre-defined cell surface target. These drugs have shown promising efficacy with limited toxicities compared to conventional treatment in many advanced solid tumors and have become a viable treatment option in NSCLC as well. Structure and mechanism of action of ADCs The basic components of an ADC are an antigen-specific monoclonal antibody (MoA) and a potent cytotoxic drug (the payload) connected via a chemical linker. Monoclonal antibody is targeted against a specific unique antigen with minimal cross reactivity and immunogenicity with normal tissue, and strong antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Cytotoxic drug is DNA damaging or microtubule disturbing agent. Antibody- drug conjugates with low drug to antibody ratio (DAR) may not offer the desired clinical effect while ADCs with high DAR can result in increased plasma concentration and off-target toxicity. The linker links the MoA with the payload. Ideally, the linker must be stable in the systemic circulation and efficiently cleaved inside the tumor cell to release the payload. The action of ADCs with cleavable linkers starts with circulating ADCs binding to the target antigen, internalization of ADC-antigen complex, then lysosomal fusion with the endosome resulting in the cytotoxic drug release. In addition to ADCs direct anti-tumor effects on antigen-positive tumor cells, the ADCs with cleavable linker also have the capacity to kill adjacent antigen-negative tumor cells, (bystander effect). Antigenic targets and ADC pharmacologic agents in NSCLC Human epidermal growth factor receptor 2 (HER2) is coded by ERBB2 gene whose alterations (gene mutations, amplifications and HER2 protein overexpression) have been identified as oncogenic drivers and potential therapeutic targets in 2-4% of NSCLC. Ado-trastuzumab ematansine (T-DM1) is a novel ADC that consists of anti-HER2 MoA trastuzumab linked to the microtubule inhibitor ematansine (DM1) via non-cleavable linker with DAR of 3.5. In the study of Li et al. T-DM1 showed an objective response rate (ORR) of 51% with a median PFS of 5 months in 49 patients with HER2-amplified or mutant metastatic NSCLC. Consistent responses were observed across HER2 status, with ORR of approximately 50%. Treatment was well tolerated. Trastuzumab Deruxtecan (T-DXd) is a novel ADC that consists of trastuzumab conjugated to topoisomerase I inhibitor deruxtecan via a cleavable linker with DAR of 8. These characteristics allow for greater bystander effect and more anti-tumor activity despite low HER2 antigen density. A phase II trial (DESTINY- Lung01) evaluated the efficacy of T-DXd in advanced NSCLC in HER2 mutated and HER2 overexpressed cohort. Out of 91 patients in HER2 mutated cohort, the ORR was 54.9%, and median PFS and OS were 8.2 and 17.8 months, respectively. There were 46% patients with adverse events grade ≥ 3, and 26.4% cases of any- grade interstitional lung disease (ILD). In HER2-overexpressed cohort, out of 49 patients 24.5% had ORR, which did not differ in various HER2 expression status. The median PFS was 5.4 months.Grade ≥ 3 AEs were reported in 73.5% patients, and 16.3% developed drug related ILD. There are multiple ongoing clinical trials on T-DXd in advanced NSCLC. Human epidermal growth factor receptor 3 (HER3) or ERBB3, a member of HER receptor family, is expressed in various cancers. Moreover, resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in lung cancer can be induced via MET amplification via HER3 activation of downstream signaling pathway. Patritumab Deruxtecan (HER3-DXd) is a novel ADC that consists of anti-HER3 MoA patritumab linked to the topoisomerase I inhibitor DXd via a cleavable linker with DAR of 8. Tumors with EGFRmutation are associated with higher expression of HER3 compared with EGFR wild-type NSCLC. Results of a phase I trial with HER3-DXd in patients with EGFR TKI- resistant NSCLC showed 39% ORR and 72% DCR and the activity of HER3-DXd across the spectrum of EGFR TKI resistance mechanisms including EGFR C797S, MET or HER2 amplification, and BRAF fusion. Grade ≥ 3 treatment related AEs occurred in 64% of patients ; the rate of ILD was acceptable. Based on these promising results, FDA has given HER3-DXd breakthrough therapy designation and there are multiple ongoing clinical trials on HER3-DXd use especially in EGFR-mutant NSCLC. Trophoblast cell-surface antigen (Trop-2) is a cell surface glycoprotein expressed in many epithelial cancer cells including lung cancer. Sacituzumab govitecan (SG) is a novel ADC that consists of anti-Trop-2 MoA sacituzumab linked to the topoisomerase I inhibitor SN-38 via a cleavable linker with DAR of 7.6. In a phase I trial, 44 patients with refractory Trop-2 positive NSCLC achieved the ORR of 16.7%. The median DOR, PFS and OS were 6, 4.4 and 7.3 months, respectively. The most common reported grade ≥ 3 AEs was neutropenia (42.4%), and it is considered dose- limiting. Datopotamab Deruxtecan (Dato-DXd)) is a novel ADC composed of anti-Trop-2 MoA datopotamab linked to topoisomerase I inhibitor deruxtecan via cleavable linker with DAR of 4. TROPION-PanTumor01 is an ongoing trial enrolling patients with Trop-2-expressing, advanced or refractory solid tumors. Data of 175 patients with NSCLC who received Dato-DXd showed ORR of 21-25%, depending on dose. The toxicity, including ILD, was dose- limiting, so dato-DXd at a dose of 6 mg/kg was selected in ongoing clinical trials. Mesenchymal-to-epithelial transition (MET) receptor, or hepatocyte growth factor (HGF) receptor, is a transmembrane tyrosine kinase receptor encoded by MET proto-oncogene. In NSCLC, activating mutations in MET, including MET exon-14 skipping mutations, occur in about 3%. Amplification of MET occurs in 3% to 4% of treatment- naive NSCLC patients and in up to 20% in patients with acquired resistance to EGFR TKI. Due to increased prevalence of MET alterations and being involved in treatment resistance in NSCLC, MET represents a promising target for ADCs in NSCLC. Telisotuzumab vedotin (Teliso-V) is a novel ADC that consists of anti-MET MoA ABT-700 linked to the microtubule inhibitor monomethyl auristatin E via a cleavable linker with DAR of 3.1. A phase II trial with Teliso-V was discontinued owing to toxicity and lack of efficacy. Teliso-V has been studied in patients with EGFR-mutant TKI-refractory NSCLC. In a phase Ib trial, 29 patients with MET-positive EGFR-mutant TKI- refractory NSCLC were enrolled. Patients were treated with oral erlotinib and intravenous teliso-V. Results were promising with an ORR of 34.5% and acceptable toxicity. Future perspectives of ADCs in NSCLC Antibody- drug conjugates are among the fastest growing drug classes in NSCLC. The development of next-generation ADCs with site-specific linker technology, enhanced mAb selectivity, and more effective cytotoxic payloads is presently underway, as are clinical trials with promising combinations of ADCs with agents such as tyrosine- kinase inhibitors or immune- checkpoint inhibitors as a strategy to overcome mechanisms of resistance to ADC treatment.

non-small cell lung cancer ; antibody-drug conjugates ; targeted therapy ; immunotherapy ; chemotherapy

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