Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers

Abstract

Immunotherapy induces durable responses in a subset of patients with cancer. High tumor mutational burden (TMB) may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free survival (PFS), and overall survival (OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥20 mutations/mb) versus low to intermediate TMB was 22/38 (58%) versus 23/113 (20%; P = 0.0001); median PFS, 12.8 months vs. 3.3 months (P ≤ 0.0001); median OS, not reached versus 16.3 months (P = 0.0036). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders versus nonresponders treated with anti-PD-1/PD-L1 monotherapy was 18.0 versus 5.0 mutations/mb (P < 0.0001). Interestingly, anti-CTLA4/anti-PD-1/PD-L1 combinations versus anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%; P = 0.004) and PFS (P = 0.024). Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB. Mol Cancer Ther; 16(11); 2598-608. ©2017 AACR.

©2017 American Association for Cancer Research.

Figures

Figure 1. Forest plots comparing TMB for patients treated with immunotherapy agents: responders vs. non-responders

The mean with standard deviation is represented. Panel A: Patients with all tumors excluding melanoma and NSCLC (N = 63) (P<0.0001). Panel B: Patients with all tumors including melanoma and NSCLC (N = 151) (P = 0.0001). Panel C: Patients with melanoma or NSCLC (N = 88) (P = 0.0003). Abbreviations: CR = complete response, mb = megabase, NSCLC = non small cell lung cancer; PD = progressive disease, PR = partial response, SD = stable disease, TMB = tumor mutational burden

Figure 2. Kaplan Meier curves for PFS and OS (for patients treated with anti-PD-1/PD-L1 monotherapy)

Tick marks represent patients at the time of censoring, and P values were calculated using log-rank (Mantel-Cox) test. For a similar analysis by TMB low vs. intermediate to high, see Supplemental Figure 2. Panel A: PFS for patients with all tumor types excluding melanoma and NSCLC – TMB low to intermediate vs. high [P = 0.0033, HR = 0.35 (95% CI 0.19 to 0.64)]. For TMB low to intermediate, N = 40 with 35 events. For TMB high, N = 15 with 8 events. Panel B: PFS for patients with all tumor types including melanoma and NSCLC – TMB low to intermediate vs. high [P = 0.0005, HR = 0.36 (95% CI 0.23 to 0.58)]. For TMB low to intermediate, N = 80, with 66 events. For TMB high, N = 22 with 12 events. Panel C: PFS for patients with melanoma or NSCLC – TMB low to intermediate vs. high [P = 0.0402, HR = 0.36 (95% CI 0.17 to 0.77)]. For TMB low to intermediate, N = 40 with 31 events. For TMB high, N = 7 with 4 events. Panel D: OS for patients with all tumor types excluding melanoma and NSCLC – TMB low to intermediate vs. high for all tumor types excluding melanoma and NSCLC [P = 0.2836, HR = 0.59 (95% CI 0.25 to 1.40]. For TMB low to intermediate, N = 40 with 20 events. For TMB high, N = 15 with 5 events. Panel E: OS for patients with all tumor types including melanoma and NSCLC – TMB low to intermediate vs. high [P = 0.0557, HR = 0.44 (95% CI 0.23 to 0.87)]. For TMB low to intermediate, N = 80 with 36 events. For TMB high, N = 22 with 6 events. Panel F: OS for patients with melanoma or NSCLC – TMB low to intermediate vs. high [P = 0.0926, HR = 0.21 (95% CI 0.07 to 0.63)]. For TMB low to intermediate, N = 40 with 16 events. For TMB high, N = 7 with 1 events. Abbreviations: CI = confidence interval; HR = hazard ratio; NSCLC = non-small cell lung cancer; OS = overall survival; PD-1 = programmed death receptor-1; PD-L1 = programmed death receptor-ligand 1; PFS = progression free survival; TMB = tumor mutational burden

Figure 3. Linear correlation1 between TMB cutoff for OR2 for CR/PR rates and HR2 for PFS, and OS depending on TMB for patients treated with anti-PD-1/PD-L1 monotherapy (N = 102)

Panel A: OR for CR/PR rate depending on TMB cutoff (R2 = 0.1985, P = 0.0106, Y = 0.07617*X + 7.494). Panel B: HR for PFS depending on TMB cutoff (R2 = 0.1246, P = 0.0487, Y = −0.001184*X + 0.3886). Panel C: HR for OS depending on TMB cutoff (R2 = 0.1985, P = 0.0476, Y = −0.001275*X + 0.5462). 1Linear regression performed using the least squares method. 2Odds Ratio (OR) >1.0 implies higher chance of response. The OR was calculated by comparing RR above and below the cut-off for each value. Hazard Ratio (HR) <1.0 implies less chance of progression or death. The HR was evaluated by comparing OS above and below the cut-off for each value. Abbreviations: CR = complete response, HR = hazard ratio; mb = megabase, NSCLC = non small cell lung cancer; OR = odds ratio; OS = overall survival; PD-1 = programmed death receptor-1; PD-L1 programmed death receptor-ligand 1; PFS = progression free survival; PD = progressive disease; PR = partial response; SD = stable disease; TMB = tumor mutational burden