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Background <p>The majority of patients with metastatic non-small cell lung cancer (NSCLC) lack actionable genomic alterations (driver, AGA). While platinum-based chemotherapy represented the standard of care for many years, the introduction of immune checkpoint inhibition has led to sustained improvements in survival. In parallel, the treatment landscape has become increasingly more complex.</p> Objective <p>The aim of this review is to provide a&#xa0;structured overview of current systemic treatment options for metastatic NSCLC without driver alterations, to critically appraise the underlying evidence and to classify practically relevant clinical decisions.</p> Material and methods <p>A&#xa0;narrative review of randomized phase&#xa0;III trials, selected meta-analyses as well as regulatory approvals and guideline-based recommendations is presented. The focus is placed on first-line treatment strategies, predictive biomarkers, treatment sequencing and unresolved clinical questions.</p> Results <p>Immune checkpoint inhibitors nowadays constitute the backbone of first-line treatment either as monotherapy in patients with high programmed cell death&#xa0;1 ligand&#xa0;1 (PD-L1) expression (≥ 50%) or in combination with chemotherapy or dual immune checkpoint blockade irrespective of PD-L1 status. Despite consistent survival benefits, treatment responses remain heterogeneous and robust predictive biomarkers beyond PD-L1 are lacking. After failure of immunotherapy-based first-line regimens, established treatment options are limited; however, novel drug classes such as bispecific antibodies and antibody-drug conjugates could perspectively expand the future therapeutic spectrum.</p> Conclusion <p>The optimal management requires an individualized assessment of tumor biology, the clinical situation and treatment goals. Key unresolved issues include the optimal first-line strategy in cases of high PD-L1 expression, the value of combined immune strategies, management of long-term responders and the development of effective strategies after failure of immunotherapy.</p>

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Metastasiertes NSCLC ohne Treiberalterationen

  • 期刊论文

  • 发表日期：

    2026年3月6日

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  • Nikolaj Frost,
  • Martin Reck

摘要

Background

The majority of patients with metastatic non-small cell lung cancer (NSCLC) lack actionable genomic alterations (driver, AGA). While platinum-based chemotherapy represented the standard of care for many years, the introduction of immune checkpoint inhibition has led to sustained improvements in survival. In parallel, the treatment landscape has become increasingly more complex.

Objective

The aim of this review is to provide a structured overview of current systemic treatment options for metastatic NSCLC without driver alterations, to critically appraise the underlying evidence and to classify practically relevant clinical decisions.

Material and methods

A narrative review of randomized phase III trials, selected meta-analyses as well as regulatory approvals and guideline-based recommendations is presented. The focus is placed on first-line treatment strategies, predictive biomarkers, treatment sequencing and unresolved clinical questions.

Results

Immune checkpoint inhibitors nowadays constitute the backbone of first-line treatment either as monotherapy in patients with high programmed cell death 1 ligand 1 (PD-L1) expression (≥ 50%) or in combination with chemotherapy or dual immune checkpoint blockade irrespective of PD-L1 status. Despite consistent survival benefits, treatment responses remain heterogeneous and robust predictive biomarkers beyond PD-L1 are lacking. After failure of immunotherapy-based first-line regimens, established treatment options are limited; however, novel drug classes such as bispecific antibodies and antibody-drug conjugates could perspectively expand the future therapeutic spectrum.

Conclusion

The optimal management requires an individualized assessment of tumor biology, the clinical situation and treatment goals. Key unresolved issues include the optimal first-line strategy in cases of high PD-L1 expression, the value of combined immune strategies, management of long-term responders and the development of effective strategies after failure of immunotherapy.