Certain Tumor Microenvironment Factors Associated With Durable Clinical Benefit From Immune Checkpoint Inhibitor Therapy for Extensive Stage SCLC

A recent study found that programmed death-ligand 1 (PD-L1) expression, CD8⁺ tumor-infiltrating lymphocyte (TIL) density, and high-frameshift neoantigen load were associated with durable clinical benefit in patients with extensive stage small-cell lung cancer (ES-SCLC) being treated with immune checkpoint inhibitor (ICI) therapy plus platinum-based chemotherapy.

“Phase 3 trials have revealed a substantial survival advantage for the addition of antibodies to [PD-L1] to first-line chemotherapy for [ES-SCLC], although the benefit of this new treatment strategy is restricted to a small subset of patients, in part because of a limited understanding of both the disease and the key determinants of a response to immunotherapy,” wrote Hiroaki Kanemura, MD, Kindai University, Osaka, Japan, and colleagues.

The retrospective study investigated potential immunologic determinants of response or resistance to immunotherapy to identify which patients are most likely to benefit most from immune checkpoint inhibitor therapy.

Tumors from a total of 135 patients with ES-SCLC who were receiving either chemotherapy alone (n = 710) or in addition to an ICI (n = 64) were identified as either inflamed or noninflamed based on PD-L1 expression and CD8⁺ TIL density. Whole genomic sequencing was used to determine predicted neoantigen loads of patients for whom immune-related gene expression profiling data was available (n=89).

Among patients receiving ICI and chemotherapy, median progression-free survival (PFS) was 10.8 months for patients with inflamed (n=7) tumors and 5.1 months for those with noninflamed (n=56) tumors (log-rank test P = .002; hazard ratio [HR] 0.26). Among those patients with immune-related gene expression profiling data available, inflamed tumors had a T cell-inflamed GEP score of −0.18 vs −0.58 for noninflamed tumors (P < .001). In the ICI and chemo group, the 12-month PFS rate was 16.1% in patients with tumors with a high frameshift neoantigen load (n = 26) vs 0% for patients with tumors with a low frameshift neoantigen load (n = 18). A durable clinical benefit in patients receiving ICI therapy with inflamed tumors and a high-frameshift neoantigen load.

Dr Kanemura et al concluded, “Our study thus provides insight into the pathologic, transcriptomic, and genetic immune profiles of SCLC.  Further investigation of inflamed and noninflamed tumors should inform personalized treatment strategies and identify treatment resistance mechanisms in SCLC.”

Source:                                        

Kanemura H, Hayashi H, Tomida S, et al. The tumor immune microenvironment and frameshift neoantigen load determine response to PD-L1 blockade in extensive-stage SCLC. JTO Clin Res Rep. 2022;3(8):100373. doi:10.1016/j.jtocrr.2022.100373