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FDA Approvals Surge for Targeted Therapies in Advanced NSCLC

• The FDA has approved 30 new drugs for advanced non-small cell lung cancer (NSCLC) since 2011, primarily tyrosine kinase inhibitors and immune checkpoint inhibitors. • Targeted therapies, particularly small-molecule inhibitors, have shown high overall response rates and durable responses in NSCLC with oncogene driver alterations. • Regulatory agencies prioritize survival or event-free survival endpoints in randomized controlled trials for NSCLC without driver alterations. • Antibody-drug conjugates, potent biologics linked to cytotoxic compounds, are emerging as a significant class of therapeutics in NSCLC treatment.

The landscape of advanced non-small cell lung cancer (NSCLC) treatment has dramatically shifted with the FDA's approval of 30 new drugs since 2011. These approvals predominantly include tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors, marking a significant advancement in therapeutic options for this challenging disease.

Targeted Therapies in Oncogene-Driven NSCLC

NSCLC characterized by oncogene driver alterations has proven particularly amenable to targeted therapies, often involving small-molecule inhibitors. The accelerated approval pathway in the United States has been leveraged in these cases, based on the demonstration of high overall response rates coupled with a lasting duration of response in single-cohort or multicohort trials. Postmarketing trials have subsequently provided confirmatory clinical evidence.

Regulatory Focus on Survival Endpoints

In contrast, for NSCLC without such driver alterations, regulatory agencies in both the United States and the European Union emphasize clinical evidence derived from randomized controlled trials primarily focused on determining survival or event-free survival. This approach reflects the need for robust evidence in the absence of specific oncogenic targets.

Emerging Role of Antibody-Drug Conjugates

Beyond small-molecule inhibitors and immune checkpoint inhibitors, biologics, including monoclonal antibodies (mAbs) inhibiting immune checkpoints like PD-(L)1 or cell surface receptors, and antibody-drug conjugates (ADCs) are gaining prominence. ADCs, which combine the specificity of an antibody with the cytotoxic potency of a chemical drug, represent a promising strategy for delivering targeted therapy to cancer cells.
The differentiation of NSCLC into oncogene- and non-oncogene-addicted subtypes significantly influences drug development strategies, the extent of clinical development programs, access to orphan drug development incentives, and regulatory approval strategies. This tailored approach is essential for optimizing treatment outcomes in this heterogeneous disease.
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Reference News

[1]
Targeted Therapies, Novel Antibodies, and Immunotherapies in Advanced Non–Small Cell ...
aacrjournals.org · Sep 20, 2024

Since 2011, US FDA approved 30 new drugs for advanced NSCLC, mainly tyrosine kinase and immune checkpoint inhibitors. Ta...

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