The Role of Antibody-Drug Conjugates in mNSCLC

ADCs represent an innovative therapeutic modality that marries the specificity of monoclonal antibodies with the cytotoxic effects of chemotherapy agents. This dual approach offers a promising avenue for treating mNSCLC, particularly in the 2L setting where options have been historically constrained. However, the complexity of ADCs necessitates the identification of reliable biomarkers that can predict patient response and optimize treatment outcomes.

Methodology and Scope of Our Research

Our research team conducted a systematic review leveraging the LARVOL CLIN database, which encompasses over 100,000 clinical trials. The focus was on identifying trials that compare ADCs with non-ADC therapies in 2L+mNSCLC. Additionally, we utilized LARVOL VERI, a precision oncology database, to validate predictive biomarkers of response that were assessed in these trials.

Key Findings from the Clinical Trials

The analysis centered on four pivotal Phase 2/3 trials that have provided outcome data comparing ADCs to conventional treatments in the 2L+mNSCLC setting:

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• DESTINY-Lung01 and DESTINY-Lung02: These trials were instrumental in the approval of trastuzumab deruxtecan (T-DXd), an ADC targeting HER2. T-DXd has demonstrated efficacy, particularly in HER2-mutated NSCLC. However, the correlation between HER2 overexpression and response to T-DXd remains an area requiring further investigation.

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• TROPION-LUNG02: This Phase 1b trial evaluated datopotamab deruxtecan (Dato-DXd), a TROP2-targeted ADC, in combination with pembrolizumab. Notably, Dato-DXd demonstrated efficacy regardless of PD-L1 expression, indicating its potential utility across a broad spectrum of patients.

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• HERTHENA-LUNG01: Patritumab deruxtecan (HER3-DXd), targeting HER3, was evaluated in EGFR-mutated NSCLC. The data suggest that HER3-DXd efficacy is independent of wild-type HER3 heterodimerization, providing a new therapeutic option for patients with specific genetic profiles.

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Clinical Implications and Future Directions

The findings from these trials suggest that Dato-DXd and HER3-DXd could be the first non-HER2-targeting ADCs approved for 2L+ mNSCLC, targeting TROP2 and HER3, respectively. While HER2-targeting T-DXd remains a valuable option, particularly in HER2-mutated NSCLC, the need for precise biomarker-driven treatment strategies is evident.

These results underscore the importance of ongoing research to identify and validate predictive biomarkers that can enhance patient selection and optimize therapeutic outcomes. The continued exploration of these biomarkers will be crucial in refining the use of ADCs and ensuring they are deployed in the most clinically effective manner.

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As LARVOL’s team presents these findings at WCLC 2024, we anticipate that this research will contribute to a deeper understanding of the role of ADCs in mNSCLC and help shape future treatment protocols. The advances in ADCs, supported by robust biomarker research, hold the potential to significantly improve the management of mNSCLC in the 2L+ setting.

We look forward to ongoing discussions and collaborations that will further these goals and improve outcomes for patients with mNSCLC.