TMB Predicts Efficacy of Immune Checkpoint Inhibitors in MSI-H mCRC

Microsatellite instability (MSI) is a recognized biomarker of response to immune checkpoint inhibitors (ICIs) in metastatic colorectal cancer (mCRC). However, not all MSI-H patients respond to ICIs, indicating a need for additional biomarkers. In many cancers, tumor mutation burden (TMB) has been shown to be associated with response to immunotherapy, regardless of MSI status or PD-L1 expression. Cancers that have more somatic mutations and higher neoantigen burden are more immunogenic and responsive to immunotherapy. A study recently published in Annals of Oncology evaluated the predictive value of TMB in patients with MSI-H mCRC treated with a ICIs. A hybrid capture-based next-generation sequencing (NGS) assay (Foundation Medicine) was used for assessment of genomic characteristics, MSI, and TMB. TMB was determined on 0.8 to 1.1 Mbp of sequenced DNA and reported as mutations/Mb.

Among 22 patients with MSI-H mCRC who were treated with ICIs (19 patients received pembrolizumab), 13 were identified as having high TMB and 9 as having low TMB. High TMB was significantly associated with improved objective response rate (ORR). The median TMB among patients achieving an ORR was 54 mutations/Mb, while those who did not respond had a median TMB of 29 mutations/mB (P<.001). All 13 patients with high TMB responded to treatment, while ORR was observed only in 3 of 9 patients with low TMB (33%). There was also a significant association between high TMB and improved progression-free survival (PFS; P<.001). With a median follow-up of 18 months, the median PFS has not yet been reached among patients with a high TMB, while the median PFS was 2 months among patients with a low TMB. Furthermore, there was also a significant improvement in overall survival (OS) among patients with high TMB compared to patients with low TMB (P  = .003). Of note, TMB remained independent predictive factor of PFS and OS in multivariate analysis.

In this analysis, the optimal cut-point for TMB as a predictive marker was identified between 37 and 41 mutations/Mb. To test this, TMB status was evaluated in a Foundation Medicine database that included 18,140 patients with mCRC, of whom 821 (4.5%) had MSI-H disease. The median TMB among patients with MSI-H mCRC was 46.1 mutations/Mb, while microsatellite stable patients had a median TMB of 3.5 mutations/Mb. The authors highlighted that, among patients with MSI-H, the optimal TMB cut-point of their study corresponded to approximately the 35th percentile (37.4 mutations/Mb) of patients with MSI-H mCRC in the database, indicating that patients with TMB below 35th percentile are less likely to respond to PD-1 or PD-L1 inhibitors.

The investigators concluded that this is the first study that suggests TMB is an independent predictor of response to ICIs among patients with MSI-H mCRC and, if validated in prospective trials, TMB score may help guide treatment selection and sequencing of therapy in these patients.

Ann Oncol. 2019 April 30. [Epub ahead of print.]
TMB-predictive-for-immunotherapy in MSI-CRC

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