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Lung cancer is the second most common cancer in the world and the leading cause of cancer-related mortality. Immune checkpoint inhibitors (ICIs), as monotherapy or in combination with platinum-based chemotherapy, have emerged as the standard of care first-line treatment option for patients with advanced non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGAs). Despite significant improvements in patient outcomes with these regimens, primary or acquired resistance is common and most patients develop disease progression, resulting in poor survival. We review the current treatments commonly used for NSCLC without AGAs in the first-line and subsequent settings and describe the unmet needs for these patients in the second-line setting, including a lack of standard definitions for primary and required resistance, and few effective treatment options for patients who develop progression of their disease on first-line therapy. We describe key mechanisms of resistance to ICIs and emerging therapies that are being investigated for patients who develop progression on ICIs and platinum-based chemotherapy. Emerging agents in development have a variety of different mechanisms of action and will likely change standard of care for second-line therapy and beyond for patients with NSCLC without AGAs in the future.

Emerging agents for the treatment of advanced or metastatic NSCLC without actionable genomic alterations with progression on first-line therapy