Journal for ImmunoTherapy of Cancer (Jan 2023)

Durable responders in advanced NSCLC with elevated TMB and treated with 1L immune checkpoint inhibitor: a real-world outcomes analysis

  • David P Carbone,
  • David Spigel,
  • Jeffrey S Ross,
  • Karthikeyan Murugesan,
  • Gerald Li,
  • Richard S P Huang,
  • Ryon P Graf,
  • Geoffrey R Oxnard,
  • Alexa Schrock,
  • Liangliang Zhang,
  • Khaled Tolba,
  • Jacob Sands

DOI
https://doi.org/10.1136/jitc-2022-005801
Journal volume & issue
Vol. 11, no. 1

Abstract

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Background For patients with advanced non-small cell lung carcinoma (NSCLC), immune checkpoint inhibitor (ICPI) and chemotherapy (chemo) ICPI represent two distinct first-line standard-of-care regimens without clear and established biomarkers to inform the optimal choice for individual patients. Here, we examined the complementary roles of tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) immunohistochemistry (IHC) to inform first-line therapy using a large real-world (rw) data set.Materials and methods The study included patients with NSCLC from an rw de-identified clinico-genomic database. All patients underwent genomic testing using Foundation Medicine’s tissue comprehensive genomic profiling assay and PD-L1 IHC assay scored for tumor cell staining (TS).Results Of 2165 patients included in the analysis, 150 exhibited durable benefit from first-line ICPI regimens (these patients were enriched for PD-L1 TS ≥50, non-squamous histology, and TMB ≥20 mutations/megabase (muts/Mb)). Comparing low TMB (<10 muts/Mb), high TMB (10–19 muts/Mb), and very high TMB (≥20 muts/Mb) receiving ICPI alone, we observed a stepwise increase in median rwPFS (real world-progression free survival) (6.5, 7.5, 17.2 months) and rwOS (real world-overall survival) (10.1, 11.8, 26.9 months) as TMB increased. In the low PD-L1 (TS <50%) cohort, TMB <20 muts/Mb showed a more favorable rwPFS (HR: 0.56 (95% CI: 0.40 to 0.79)) and rwOS (HR 0.74 (95% CI: 0.58 to 0.96)) on chemoICPI when compared with ICPI alone while the point estimate in rwPFS favored monoICPI in the TMB ≥20 muts/Mb cohort, the CI is wide and does not reach statistical significance (HR: 1.68 (95% CI: 0.52 to 5.48)).Conclusion This study provides evidence that higher TMB cut-offs, such as 20 muts/Mb, can identify patients with prolonged benefit from ICPI. TMB ≥20 muts/Mb is a potential biomarker that may identify patients in whom an ICPI without chemo could be considered, even in the setting of lower PD-L1 levels. Prospective validation of these findings could increase access to chemo-sparing regimens for the first-line treatment of advanced NSCLC.