High tumor mutational burden predicts favorable response to anti-PD-(L)1 therapy in patients with solid tumor: a real-world pan-tumor analysis

Abstract

BackgroundTumor mutation burden (TMB) is an important biomarker to predict response to anti-PD-L1 treatment across cancer types. TruSight Oncology 500 (TSO500) is currently used globally as a routine assay for TMB.MethodsBetween 2019 and 2021, 1744 patients with cancer received TSO500 assay as part of a real-world clinical practice at the Samsung Medical Center, and 426 received anti-PD-(L)1 treatment. Correlations between TMB and clinical outcomes of anti-PD-(L)1 were analyzed. Digital spatial profiling (DSP) was used to investigate the tumor immune environment’s influence on the treatment response to anti-PD-(L)1 in high TMB (TMB-H) patients (n=8).ResultsThe incidence of TMB-H (≥10 mutations (mt)/megabase (Mb)) was 14.7% (n=257). Among TMB-H patients, the most common cancer type was colorectal cancer (n=108, 42.0%), followed by gastric cancer (GC; n=49, 19.1%), bladder cancer (n=21, 8.2%), cholangiocarcinoma (n=21, 8.2%), non-small cell lung cancer (n=17, 6.6%), melanoma (n=8, 3.1%), gallbladder cancer (GBC; n=7, 2.7%), and others (n=26, 10.1%). The response rate to anti-PD-(L)1 therapy was substantially higher in GC (71.4% vs 25.8%), GBC (50.0% vs 12.5%), head and neck cancer (50.0% vs 11.1%), and melanoma (71.4% vs 50.7%) among TMB-H patients when compared with low TMB (TMB-L) (<10 mt/Mb) patients with statistical significance. Additional analysis of patients with TMB ≥16 mt/Mb demonstrated prolonged survival after anti-PD-(L)1 therapy compared with patients with TMB-L (not reached vs 418 days, p=0.03). The benefit of TMB ≥16 mt/Mb was greater when combined with microsatellite status and PD-L1 expression profiles. Among the TMB-H patients, those who responded to anti-PD-L1 therapy had numerous active immune cells that infiltrated the tumor regions during the DSP analysis. Natural killer cells (p=0.04), cytotoxic T cells (p<0.01), memory T cells (p<0.01), naïve memory T cells (p<0.01), and proteins related to T-cell proliferation (p<0.01) were observed in a responder group compared with a non-responder group. In contrast, exhausted T-cell and M2 macrophage counts were increased in the non-responder group.ConclusionsThe overall incidence of TMB status was analyzed by the TSO500 assay, and TMB-H was observed in 14.7% of the pan-cancer population. In a real-world setting, TMB-H identified by a target sequencing panel seemed to predict response to anti-PD-(L)1 therapy, especially in patients with a higher proportion of immune cells enriched in the tumor region.

Current Standards, Multidisciplinary Approaches, and Future Directions in the Management of Extrahepatic Cholangiocarcinoma

“…Similarly, a linear correlation has been observed in a wide range of solid tumors between TMB and response to ICI such that as TMB increases, response to ICI increases [130]. High TMB (TMB-H; ≥10 mt/MB) has been reported in up to 8.2% of CCA [131]. In BTC, TMB-H (>20 mt/MB) often coexists with TP53 (58%) and DNA damage repair mutations such as BRCA1/2 and dMMR (78%) [132].…”

“…In BTC, TMB-H (>20 mt/MB) often coexists with TP53 (58%) and DNA damage repair mutations such as BRCA1/2 and dMMR (78%) [132]. In TMB-H CCA patients who received ICI, ORR were significantly improved (25% vs 13.5%; p = 0.048) [131]. In the Checkmate-848 phase II trial [98], including over 40 TMB-H (≥10mt/MB) solid tumor types, dual ICI with ipilimumab + nivolumab (ipi + nivo) produced an ORR of 35.3% (95% CI 24.1, 47.8%), mPFS of 4.1 months (95% CI 2.…”

Molecular profiling of a bladder cancer with very high tumour mutational burden

“…2A ). The concurrent high values of TMB, along with elevated expressions of PD-L1, PD-L2, and PD1, offer clinical evidence for supporting the development of tailored therapies based on immune checkpoint inhibitors [ 25 ]. Currently, immunotherapy is a suitable initial treatment for individuals with advanced bladder carcinoma who cannot be treated with chemotherapy using platinum, independently of their immune-checkpoints expression profile [ 26 ].…”

Neoadjuvant radiotherapy in ER+, HER2+, and triple-negative -specific breast cancer based humanized tumor mice enhances anti-PD-L1 treatment efficacy

“…A therapeutic strategy to reactivate immune cells is the application of antibodies targeting these immune checkpoints. Atezolizumab (anti-PD-L1), as well as pembrolizumab and nivolumab (anti-PD-1) demonstrate therapeutic efficiency in treating malignancies characterized by a high mutational burden ( 23 ). An anti-PD-(L)1 treatment (in combination with chemotherapy) has been also approved for the treatment of TNBC; however, the success rates are relatively low ( 24 ).…”