Histologic Subtype May Inform Immunotherapy Strategy in mNSCLC Without Targetable Mutations

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Analyses suggest squamous and nonsquamous tumors differ in immunobiology and may respond differently to the addition of LAG-3 inhibitors to PD-1–based therapy.

Emerging data from a molecular analysis of treatment-naive patients with metastatic non-small cell lung cancer (mNSCLC) suggest that histologic subtype (ie, squamous versus nonsquamous) may meaningfully influence response to immune checkpoint inhibitors, even in the absence of targetable genomic alterations. Researchers presented the findings at the 2025 ASCO Annual Meeting.

Not One-Size-Fits-All

Current first-line treatment strategies for mNSCLC without actionable driver mutations use PD-1 inhibitors combined with platinum-doublet chemotherapy (PDCT), without distinction between squamous and nonsquamous histologies. However, results from recent studies, such as the RELATIVITY-104 study, have raised questions about this one-size-fits-all approach.

“There is growing recognition of differences between squamous and nonsquamous lung cancer that may impact response to treatment,” said Hossein Borghaei, DO, MS, and colleagues. “There is an unmet need to understand differences in tumor biology…to inform on mechanisms underlying differences in clinical activity of anti-PD-1 + PDCT, alone or in combination with a LAG-3 inhibitor.”

The analysis relied on data from patients enrolled in the phase 3 CheckMate 227 study. Researchers used immunohistochemistry to assess PD-L1 and LAG-3 expression, and the FoundationOne panel to assess somatic mutations, copy number alterations, and rearrangements.

“Selected analyses were conducted only in primary tumors to avoid confounding by differences in metastatic tissue site,” the researchers noted.

Tumor Histologies Show Differences

Nonsquamous tumors showed higher expression of immune-related pathways, including those involved in antigen presentation and T-cell signaling. In contrast, squamous tumors exhibited gene signatures associated with rapid cell proliferation and oncogenic signaling, particularly involving the TP53 and PIK3CA genes.

PD-L1 expression also behaved differently by subtype, according to the findings. In nonsquamous tumors, higher PD-L1 levels correlated with greater immune cell infiltration. This correlation was absent in squamous tumors.

In addition, expression of canonical LAG-3 ligands (ie, MHC-II and FGL-1) was higher in nonsquamous tumors, particularly in those with PD-L1 greater than or equal to 1%, which may explain the enhanced clinical benefit observed in this subgroup when LAG-3 inhibition is added to standard PD-1–based therapy.

The findings suggest that in first-line, advanced NSCLC, adding a LAG-3 inhibitor would yield the greatest benefit in patients with nonsquamous versus squamous tumors, particularly those with PD-L1 expression.

“These data provide a supporting mechanistic rationale for the use of tumor histology in addition to PD-L1 expression to identify patients who would benefit from the addition of a LAG-3 inhibitor to PD-1 inhibitor + PDCT,” Dr. Borghaei and colleagues concluded.