ADC Targets And Representative Drugs For Non-Small Cell Lung Cancer (NSCLC)

Technological advances have re-established ADC as a viable treatment strategy for advanced solid tumors. ADCs targeting several tumor targets have shown great potential in the treatment of refractory NSCLC, including HER2, HER3, TROP2, CEACAM5, and MET. On August 11, 2022, the FDA accelerated approval of Enhertu (trastuzumab deruxtecan, T‑DXd), a HER2 ADC drug jointly developed by Astrazeneca and Daiichi Sankyo, for patients with unresectable or metastatic NSCLC with HER2 mutations. It is the first drug approved by the FDA for the treatment of HER2-mutated NSCLC, which confirms that ADC drugs have great potential for NSCLC. This article briefly introduces five potential ADC targets and representative drugs for NSCLC.

HER2

HER2 gene amplification, gene mutation and protein overexpression have been found in NSCLC. HER2 is overexpressed in nearly 20% of NSCLCS, and HER2 mutations are found in 2-4% of NSCLCS. Activating mutations in the HER2 gene promote internalization of the HER2 receptor, providing mechanistic possibilities for exploring ADC therapy in this NSCLC subtype.

Ado‑Trastuzumab Emtansine (T‑DM1)

T-DM1 is a HER2-targeting ADC with a DAR of 3.5, consisting of the HER2 monoclonal antibody trastuzumab linked to the microtubule inhibitor Emtansine (DM1) through a non-cleavable linker. T-DM1 has been approved by the FDA for the treatment of advanced HER2-positive breast cancer. Early trials have also shown efficacy in HER2-mutated and amplified NSCLC. In a single-center phase II trial in the NSCLC cohort of 49 patients with HER2-mutated or amplified NSCLC who received T-DM1 3.6 mg/kg q3w, ORR was 31% and mPFS was 5 months. Treatment was well tolerated with only one grade 3 (G3) treatment-related adverse event. Based on these data, T-DM1 was classified as class 2A by the NCCN for the treatment of patients with advanced HER2 mutant NSCLC. T-DM1 is not effective in NSCLC patients with HER2 overexpression. In several clinical trials, trials were stopped early because of limited efficacy.

Trastuzumab Deruxtecan ‑ DXd (T)

T-DXd is an ADC drug that combines the HER2 mab trastuzumab with the topoisomerase inhibitor DXd through an enzymeable peptide adaptor with a DAR of 8. It has a significant bystander effect on adjacent cells, providing mechanistic feasibility for its application in NSCLC tumors with heterogeneous HER2 expression.

T-DXd was evaluated in patients with HER2-expressing or HER2-mutated refractory advanced solid tumors in a single-arm Phase I dose-escalation and dose-expansion trial. The trial included 18 patients with NSCLC. The results showed that 10 patients achieved partial response (ORR 55.6%), mPFS was 11.3 months, and median duration of response (mDOR) was 10.7 months. Among patients with HER2-mutated NSCLC, ORR was 72.7% (8/11), mPFS was 11.3 months, and mDOR was 9.9 months.

On this basis, the Destination-Long01 phase II trial evaluated the efficacy of T-DXd 6.4 mg/kg q3w in advanced, refractory HER2 mutated NSCLC. This study included patients with HER2 overexpression (cohort 1, HER2 IHC 3+ or 2+) or with HER2-activating mutations (cohort 2). The efficacy of T-DXd in patients with HER2-mutated NSCLC(cohort 2) was impressive. In 91 patients, ORR was 55%, mDOR, mPFS, and OS were 9.3, 8.2, and 17.8 months, respectively. ≥G3 TRAE occurred in 46% of patients, with neutropenia (19%), anemia (10%), nausea (9%), and fatigue (7%) being the most common, and drug-related interstitial lung disease (ILD) occurred in another 24 patients (26%) : G3 in 4 patients (17%) and death in 2 (8%) (G5). T-DXd activity was also seen in NSCLC patients with HER2 overexpression (cohort 1), but the efficacy was limited. Among 49 patients, ORR was only 24.5%, mDOR 6.0 months, mPFS 5.4 months, mOS 11.3 months. Toxicity was similar to cohort 2, with ≥G3 TRAE observed in 55% of patients, with neutropenia (20%) being the most common. The incidence of drug-related ILD was 16.3%, including 3 deaths.

T-DXd received accelerated FDA approval based on the excellent data from the DESTINY-Lung02 phase II trial. In 52 patients with HER2+, unresectable, and/or metastatic NSCLC, the ORR was as high as 58%.

HER3

HER3 is an important molecule for HER2 heterodimerization and activation of PI3K/AKT signaling pathway. HER3 is expressed in a variety of solid tumors, including 83% of NSCLC. Given the high expression of HER3 in NSCLC and its potential role in mediating EGFR tyrosine kinase inhibitor (TKI) resistance, HER3 has become an attractive ADC target in NSCLC.

Patritumab Deruxtecan

Patritumab deruxtecan (HER3-DXd) is linked to DXd by a cleavable tetrapeptide linker, which is also the HER3 monoclonal antibody Patritumab, with a DAR of 8.

HER3-DXd was evaluated in a phase I study involving patients with advanced NSCLC who activated EGFR mutations after TKI and chemotherapy progression (cohort 1) and patients who did not activate EGFR after anti-PD (L)1 immune checkpoint blockade (cohort 2). In cohort 1, 81 patients were enrolled regardless of HER3 expression and the dose of HER3-DXD was increased from 3.2 mg/kg to 6.4 mg/kg q3w. In this population, 47% of patients experienced ≥G3 TRAE, with thrombocytopenia (26%), neutropenia (15%), and fatigue (10%) being the most prevalent. Four patients (5%) developed ILD due to treatment, of which only one was G3. 5.6 mg/kg was chosen as the recommended dilation dose (RDE). The effect was significant in 57 patients treated with RDE. ORR was 39%, mDOR 6.9 months and mPFS 8.2 months. Antitumor efficacy was observed in patients with a range of EGFR resistance mechanisms, including EGFR C797S mutation, MET amplification, HER2 mutation, BRAF fusion, and PIK3CA mutation. All patients who could be evaluated had HER3 expression, and the median HER3 expression score was higher in patients who responded than in patients with disease progression. Based on these findings, HER3-DXd was granted breakthrough therapy designation by the FDA in December 2021.

TROP2

TROP2 is a glycoprotein transmembrane calcium signal transduction protein, which is expressed in a variety of epithelial tumors including lung cancer. In NSCLC, the expression of TROP2 in lung adenocarcinoma and lung squamous cell carcinoma was 100% and 92% respectively, and the overexpression of TROP2 protein was 64% and 75% respectively. Several ADCs targeting trop-2 are currently undergoing clinical trials.

Sacituzumab Govitecan

Sacituzumab govitecan (SG) is an ADC drug composed of humanized anti-TROP2 monoclonal antibody Sacituzumab linked to topoisomerase-I inhibitor SN-38 through an acid-cleavable linker with a DAR of 7.6.

The first clinical trial to explore the safety and efficacy of SG was the Phase I/II dose escalation and expanded IMMU-132-01 basket trial. The study included 495 patients without selection for TROP2 expression, with treatment doses ranging from 8 to 18 mg/kg on days 1 and 8 of the 21-day cycle. In this cohort, ≥G3 TRAE occurred in 59.6% of patients, with neutropenia (42.4%), anemia (10.3%), diarrhea (7.9%), fatigue (6.3%), and febrile neutropenia (5.2%) being the most common. Based on these data, a dose of 10 mg/kg was selected for dose expansion.

In the SCLC cohort (n=62), patients received 8, 10, 12, or 18 mg/kg SG on days 1 and 8 of the 21-day cycle, respectively. ORR was 17.7%, mPFS was 3.7 months, mDOR was 5.7 months and OS was 7.1 months. In the NSCLC cohort, 54 patients received 8, 10, or 12 mg/kg SG on days 1 and 8 of a 21-day cycle. ORR was 16.7%, mPFS 4.4 months, mDOR 6.0 months, OS 7.3 months. Both squamous cell carcinoma and adenocarcinoma respond. 92% of patients had moderate or high TROP2 expression on IHC staining, precluding its utility as a predictive biomarker. Based on these data, the Phase III trial EVOKE-01 is evaluating SG 10 mg/kg versus docetaxel 75 mg/m2 in patients with advanced EGFR/ALK wild-type NSCLC after anti-PD (L)-1 immunotherapy and platinum-based chemotherapy.

Technological advances have revived ADC as an effective anticancer drug for solid tumors, including lung cancer. Although several ADC drugs are promising to be approved for NSCLC patients, many challenges remain, such as optimal drug sequencing, novel combination strategies, and management of unique toxicities such as ILD. However, the future of ADC drugs is bright. In the future, more ADC breakthroughs will further improve the treatment situation of NSCLC and greatly improve the survival benefit of NSCLC patients.

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Article source: https://article-realm.com/article/Finance/30015-ADC-Targets-And-Representative-Drugs-For-Non-Small-Cell-Lung-Cancer-NSCLC.html