Plasma Tumor Mutation Burden and Response to Pembrolizumab-Letter.

Abstract

Recent studies reported negative predictors for immune checkpoint inhibitors (ICI) in non–small cell lung cancer (NSCLC), including STK11, KEAP1, and PTEN (1–3). Aggarwal and colleagues' study showed that patients with NSCLC with high blood-based tumor mutation burden (bTMB) and absence of STK11/KEAP1/PTEN mutation had prolonged overall survival (OS) treated with ICI (1). Low allele frequency–adjusted bTMB (LAF-bTMB) outperformed bTMB as a predictor in NSCLC treated with ICIs (4). To explore whether STK11/KEAP1/PTEN mutation was prognostic or predictive and whether the combination of STK11/KEAP1/PTEN mutation and LAF-bTMB could optimize therapeutic regimen, we analyzed the clinical and gene mutation data from POPLAR and OAK trial that compared second/third-line atezolizumab with docetaxel in metastatic NSCLC (5). STK11/KEAP1/PTEN mutation was defined as at least one nonsynonymous mutation in STK11, KEAP1, or PTEN with allele frequency exceeding 0.005. The calculation of LAF-bTMB was described previously (4).There were 19.2% (164/853) patients carrying STK11/KEAP1/PTEN mutations. In subgroups with or without STK11/KEAP1/PTEN mutation, patients treated with atezolizumab had prolonged OS than docetaxel and the Pinteraction was not significant [median OS, 7.3 months vs. 6.2 months; HR, 0.66; 95% confidence interval (CI), 0.47–0.93; P = 0.02 for mutation subgroup; median OS, 14.5 months vs. 9.6 months; HR, 0.65; 95% CI, 0.54–0.78; P < 0.001 for wild-type subgroup; Pinteraction = 0.84), which indicated that STK11/KEAP1/PTEN mutation was prognostic but not predictive in NSCLC. In patients without STK11/KEAP1/PTEN mutation, OS in atezolizumab arm was longer than docetaxel arm, regardless of LAF-bTMB level (median OS, 12.6 months vs. 10.5 months; HR, 0.71; 95% CI, 0.58–0.86; P = 0.0005 for LAF-bTMB < 12; median OS, 20.1 months vs. 7.0 months; HR, 0.44; 95% CI, 0.28–0.70; P = 0.0003 for LAF-bTMB ≥ 12; Pinteraction = 0.04). In patients with STK11/KEAP1/PTEN mutation, atezolizumab was associated with prolonged OS only in patients with LAF-bTMB ≥ 12 (median OS, 15.9 months vs. 6.3 months; HR, 0.38; 95% CI, 0.20–0.71; P = 0.002) and did not bring OS benefit in patients with LAF-bTMB < 12 (median OS, 5.7 months vs. 5.4 months; HR, 0.87; 95% CI, 0.58–1.31; P = 0.51; Pinteraction = 0.05).STK11/KEAP1/PTEN mutation was negative prognostic but not predictive biomarker in NSCLC treated with ICI. In patients with STK11/KEAP1/PTEN mutation, ICI could bring survival benefit only in patients with LAF-bTMB ≥ 12. Among patients with LAF-bTMB ≥ 12 in atezolizumab arm, median OS were comparable between patients with and without STK11/KEAP1/PTEN mutation which suggested that LAF-bTMB high might reverse the negative prognostic effect of STK11/KEAP1/PTEN mutation.See the Response, p. 1581No disclosures were reported.