Antibody-Drug Conjugates in Lung Cancer: The Tip of the Iceberg

Antibody-Drug Conjugates in Lung Cancer: The Tip of the Iceberg

Antibody-drug conjugates (ADCs) represent a novel class of therapeutics that selectively target tumor cells and deliver concentrated cytotoxic payloads, showing significant antitumor activity in lung cancer. This analysis covers the latest evidence, key targets, and strategic implications for BD teams, investors, and analysts.

Key Takeaways

• ADCs are an emerging class of antitumor agents that selectively target tumor cells and deliver concentrated cytotoxic payloads, with significant activity in lung cancer.
• Key targets in lung cancer include HER2, HER3, TROP2, MET, CEACAM5, and DLL3, with non–small cell lung cancer (NSCLC) representing 85% of all lung cancer cases.
• The field is rapidly evolving with multiple ADCs in clinical development and regulatory review, making early identification of promising candidates critical for BD teams and investors.

What Is Driving the Development of ADCs in Lung Cancer?

Antibody-drug conjugates are a novel class of therapeutics structurally composed by an antibody directed to a tumor epitope connected via a linker to a cytotoxic payload. They act like a 'smart chemotherapy' that aims to deliver the drug compound directly to cancer cells, reducing harm to healthy tissue. A comprehensive review by Riudavets and Planchard, published in Cancer Research and Treatment (2024 Nov 28;57(2):293–311), describes the pharmacology and design of ADCs and summarizes results from studies evaluating ADCs in lung cancer directed to targets including HER2, HER3, TROP2, MET, CEACAM5, and DLL3. Lung cancer remains the leading cause of cancer-related mortality worldwide, with NSCLC accounting for 85% of cases, underscoring the urgent need for novel therapies.

The review, authored by Mariona Riudavets of Hôpital Cochin APHP Centre in Paris and David Planchard of Gustave Roussy Cancer Campus in Villejuif, France, was received July 26, 2024 and accepted November 27, 2024. It is published under a Creative Commons Non-Commercial License by the Korean Cancer Association. The work covers the available evidence and future perspectives on ADCs for lung cancer treatment, including a comprehensive discussion on structure-activity relationships and clinical trial results.

What Targets Are Driving ADC Development in NSCLC?

The key targets being pursued in lung cancer include HER2, HER3, TROP2, MET, CEACAM5, and DLL3. Each represents a distinct biological pathway and patient population. TROP2-targeting ADCs, for example, have shown activity in both squamous and non-squamous NSCLC, while HER2-directed ADCs are being evaluated in patients with HER2 mutations or amplifications. MET-targeting ADCs aim to address MET exon 14 skipping mutations and MET amplification, which are known resistance mechanisms to other therapies. CEACAM5 is a target enriched in adenocarcinomas, and DLL3 is a target specific to small cell lung cancer, offering a path forward in a historically difficult-to-treat subtype.

For BD teams, the expanding ADC pipeline presents both opportunities and competitive pressures. Differentiation will depend on payload potency, linker stability, and target specificity. The tip-of-the-iceberg metaphor suggests that current approved ADCs represent only a fraction of what is in development, making early identification of promising candidates critical.

How Should Pharma Teams and Investors Evaluate ADC Opportunities?

For BD teams, the expanding ADC pipeline in lung cancer presents both opportunities and competitive pressures. Key targets such as HER2, HER3, TROP2, MET, CEACAM5, and DLL3 are being actively pursued, and differentiation will depend on payload potency, linker stability, and target specificity. Investors should monitor FDA regulatory decisions and pivotal trial readouts, as approvals could reshape the treatment landscape. Analysts should assess the commercial potential of ADCs versus existing standards of care, particularly in biomarker-defined NSCLC subsets.

The tip-of-the-iceberg metaphor suggests that current approved ADCs represent only a fraction of what is in development. The review by Riudavets and Planchard reinforces this view, noting that the field is moving rapidly beyond the first-generation agents. For investors, the key question is which targets and payload technologies will translate into durable clinical benefit and commercial success. The FDA has been actively reviewing ADC applications across multiple tumor types, and the pipeline of ongoing studies evaluating ADCs in lung cancer provides a rich landscape for dealmaking and portfolio planning.

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