A Call to Optimize First-Line NSCLC Treatment Strategies

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Nearly 1 in 5 patients with NSCLC and targetable mutations never received second‑line therapy, highlighting the urgency of optimizing first‑line treatments.

A study presented at the 2025 ASCO Annual Meeting showed that a subset of patients with non-small cell lung cancer (NSCLC) did not receive second-line treatment due to death or hospice transitions, highlighting the importance of optimizing first-line treatment selection.

For patients with advanced NSCLC and actionable genomic alterations, the advent of targeted therapy has reshaped treatment paradigms and significantly improved outcomes. Yet, despite advances, a notable proportion of patients never receive second‑line therapy, according to Shuchi Pandey, MD, and colleagues.

“Several studies suggest that up to 30% of patients with NSCLC do not receive second-line systemic therapy. Characterizing the patterns of second-line treatment in patients with NSCLC and targetable mutations may help identify barriers to treatment and improve patient outcomes,” the researchers said.

Researchers conducted the retrospective study at MedStar Georgetown University Hospital. The investigators analyzed 197 patients with metastatic NSCLC and targetable mutations treated after January 1, 2018.

The cohort represented the breadth of actionable genomic alterations seen in clinical practice: 41% harbored classical EGFR mutations, 13% had ALK fusions, and smaller subsets possessed EGFR exon 20 insertions (6%), atypical or compound EGFR mutations (5%), KRAS G12C mutations (11%), ROS1 fusions (6%), HER2 mutations (7%), RET fusions (5%), MET exon 14 skipping mutations (2%), BRAF V600E mutations (6%), or NRG1 fusions (1%).

Overall, 24% of the cohort remained on first-line therapy at the time of data collection. Of the 150 patients who discontinued first-line therapy, 121 (81%) subsequently received second-line therapy.

The second‑line treatments varied, including targeted therapy (38%), chemotherapy with or without prior targeted therapy (25%), clinical trial treatments (24%), chemoimmunotherapy (8%), immunotherapy alone (2%), and other treatments (2%). The median interval between second‑ and third‑line treatments was roughly six months.

A total of 29 patients (19%) never progressed to second‑line therapy. Of these, 27 (93%) died or transitioned to hospice due to disease progression or complications related to their illness, while two (7%) were lost to follow‑up. Patients who did not receive second‑line therapy were older (median age, 69 vs 62; P<0.01).

“While most patients receive second-line treatment, a subset do not. This is primarily due to death or transition to hospice, which are mostly due to disease progression or cancer-related complications,” Dr. Pandey and colleagues said. “The findings emphasize the importance of optimizing first-line treatment strategies and the need to address barriers to second-line treatment.”