High tumor mutation burden predicts better efficacy of immunotherapy: a pooled analysis of 103078 cancer patients

Abstract

The relation between tumor mutation burden (TMB) and outcome of cancer patients receiving immunotherapy has been reported. This study aimed to evaluate the prognostic role of TMB in cancer patients receiving immunotherapy. Databases including Embase, PubMed, and the Cochrane library were systematically searched to identify potentially eligible studies until Sep 2018 without language limitation. Studies assessing high versus low TMB in predicting survival of various cancer patients were selected. The pooled analyses were conducted using hazard ratio (HR) of high versus low TMB for overall survival (OS) and progression-free survival (PFS), and the odds ratio (OR) for overall response rate (ORR). The primary endpoint was OS. Secondary outcomes were PFS and ORR. A total of 45 studies consisting of 103078 cancer patients were included. The combined results showed that high TMB was associated with better OS (HR = 0.40; 95% confidence interval (CI):0.30-0.53; p< .00001), PFS (HR = 0.37; 95% CI: 0.26-0.53; p< .00001) and ORR (OR = 4.62; 95%CI: 2.90-7.34; p< .0001) when treated with immunotherapy. In studying patients with high TMB, these patients had improved OS (HR = 0.69; 95%CI: 0.47-1.03; p= .07) when comparing immunotherapy to chemotherapy. Subgroup analyses suggested that the prognostic role of TMB was independent of cancer types and TMB detection methods (all p< .05). Our findings suggest that high TMB is associated with better survival in cancer patients receiving immunotherapy. For cancer patients with high TMB, immunotherapy could be considered.

Keywords: Tumor mutation burden; cancer; immunotherapy; prognosis; survival.

Figure 1.

Combined analysis of HR of high versus low tumor mutation burden for OS in various cancer patients treated with or without immunotherapy, and immunotherapy versus chemotherapy in cancer patients with high tumor mutation burden. (a): Above, pooled HR for patients treated with immunotherapy. High tumor mutation burden is in favor of improved OS (n = 620, p< .01); Below, Pooled HR for patients without immunotherapy. High tumor mutation burden is associated with increased risk of death in these patients (n = 3286, p= .14). (b): Evaluating effects of immunotherapy versus chemotherapy on OS in cancer patients with high tumor mutation burden. OS was improved for patients from the immunotherapy group, compared to those in the chemotherapy group (n = 1462, p= .07).

Figure 2.

Subgroup analyses of factors that may affect the pooled HR for OS. (a): Subgroup analysis of OS in term of cancer types. The prognostic role of tumor mutation burden was independent of cancer types (n = 196 for melanoma, n = 240 for NSCLC, n = 1484 for multiple cancers. overall p< .01). (b): Subgroup analysis of OS with regard to detection methods of tumor mutation burden. The prognostic role of tumor mutation burden was independent of detection methods (p< .01).

Figure 3.

Combined analysis of HR of high versus low tumor mutation burden for PFS in various cancer patients treated with or without immunotherapy, and immunotherapy versus chemotherapy in cancer patients with high tumor mutation burden. (a): pooled HR of high versus low tumor mutation burden for patients treated with immunotherapy or not. High tumor mutation burden is in favor of improved OS (n = 440 for immunotherapy, p< .01), but associated with worse outcomes for patients treated without immunotherapy (n = 3480 for non-immunotherapy, p= .01). (b): Evaluating the effects of immunotherapy versus chemotherapy on PFS in cancer patients with high tumor mutation burden. PFS was significantly prolonged in patients receiving immunotherapy, compared to those with chemotherapy (n = 2078, p< .01).

Figure 4.

Subgroup analyses of PFS with regard to cancer types, and tumor mutation burden detection methods. (a): Subgroup analysis of OS in term of cancer types. The prognostic role of tumor mutation burden was similar in enrolled cancer types (n = 65 for melanoma, n = 2442 for NSCLC, n = 261 for multiple cancers. overall p< .01). (b): Subgroup analysis of PFS using different detection methods of tumor mutation burden. The prognostic role of tumor mutation burden was not significantly affected by detection methods (p< .05).

Figure 5.

Meta-analysis of overall response rate in immunotherapy treated patients with high versus low tumor mutation burden, and publication bias assessment. (a): Meta-analysis of overall response rate in cancer patients with high versus low tumor mutation burden after immunotherapy (N = 1108, p< .01). (b): Funnel plot of OS from included studies. (c): Funnel plot of PFS from included studies.