Outcomes Following Immune Checkpoint Inhibitor Treatment of Patients With Microsatellite Instability-High Cancers: A Systematic Review and Meta-analysis

Key Points

Question  What are the outcomes in patients with advanced, microsatellite instability-high (MSI-H) cancers following treatment with immune checkpoint inhibitors (ICIs)?

Findings  In patients with MSI-H advanced cancers, even in the pretreated setting, the pooled response rate and disease control rate of ICIs were 41.5% and 62.8%, respectively. The pooled 1- and 2-year OS were 75.6% and 56.5%, respectively.

Meaning  In patients with MSI-H cancer, treatment with ICIs was associated with high activity; MSI status may have a high predictive value for the benefit of immunotherapy.

Importance  The mismatch repair (MMR) pathway plays a crucial role in repairing DNA replication errors in normal and cancer cells. Defects in DNA MMR proteins that determine the microsatellite instability-high (MSI-H) condition lead to the accumulation of mutations and the generation of neoantigens, which may stimulate the antitumor immune response. Clinical trials have demonstrated that MSI-H status is associated with long-term benefit in patients treated with immune checkpoint inhibitors (ICIs).

Objective  To evaluate the activity of ICIs in terms of overall response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) in patients with MSI-H cancers.

Data Sources  Published articles that evaluated ICIs in the treatment of advanced MSI-H tumors from inception to December 2019 were identified by searching the PubMed, EMBASE, and Cochrane Library databases.

Study Selection  Prospective or retrospective studies, published in the English language, providing outcome data with ICIs in patients with MSI-H cancer were selected.

Data Extraction and Synthesis  Author and year of publication, type of studies, diseases included, median follow up, type of ICI, median OS ,and PFS, ORR, DCR and 1-, 2-, and 3-year OS were retrieved. Analysis was performed in December 2019.

Main Outcome and Measures  The primary outcome of interest was ORR. Secondary end points were median PFS, median OS, pooled rate of patients alive at 1, 2 ,and 3 years, and pooled rate of patients that attained disease control rate ([DCR] calculated as the sum of stable disease rate and ORR).

Results  Overall, 939 patients (14 studies) were analyzed mainly in pretreated settings. The pooled ORR was 41.5% (95% CI, 34.9%-48.4%). The pooled DCR was 62.8% (95% CI, 54.5%-70.3%). Pooled median PFS was 4.3 months (95% CI, 3-6.8 months). The pooled median OS was 24 months (95% CI, 20.1-28.5 months). The pooled 1- and 2-year OS were 75.6% (95% CI, 61.8%-85.5%) and 56.5% (95% CI, 46%-66.4%), respectively. Because only 1 study provided 3-year OS data, a formal pooled analysis for 3 years was not possible.

Conclusions and Relevance  In this meta-analysis of patients with pretreated MSI-H cancer, ICIs were associated with high activity independent of tumor type and drug used. Among molecular biomarkers for selection of treatment, MMR proteins may have a predictive value for the activity of immunotherapy.

High level of microsatellite instability (MSI-H) is the genetic feature of a well-defined subgroup of cancers characterized by a deficient mismatch repair (dMMR) system and the resulting inability to correct damage to DNA that primarily derives from single base pair insertions or deletions that may occur during DNA replication by DNA polymerases.

In 2017 the US Food and Drug Administration (FDA) approved Pembrolizumab for use in solid tumors with MSI-H or dMMR.¹

The aim of this study was to evaluate the activity of different available immune checkpoint inhibitors (ICIs) in terms of overall response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) in patients with MSI-H cancers.

The systematic review and meta-analysis was conducted according to the PRISMA guidelines for systematic reviews. Institutional review board approval and written informed consent were not required for this database review. Analysis was performed in December 2019.

A comprehensive search was performed with the following terms: (“microsatellite instability” OR MSI-H or “mismatch-repair deficient”) and (avelumab or pembrolizumab or ipilimumab or nivolumab or atezolizumab or durvalumab). We searched PubMed, the Cochrane Library, and EMBASE for studies eligible for this meta-analysis published from inception up to December 14, 2019. To be eligible, studies needed to have prospectively accrued patients with advanced or metastatic MSI-H/dMMR cancers regardless of line of therapy and to provide data available for ORR and/or survival analysis (OS and/or PFS). Studies were excluded if they enrolled fewer than 10 patients, pediatric participants, patients with hematological diseases, and if they were phase 1 studies.

The primary end point was the percentage of evaluable patients who attained a partial or complete response (ORR). Secondary end points were (a) median PFS; (b) median OS; (c) rate of patients alive at 1, 2, and 3 years; and (d) rate of patients who attained DCR (calculated as the sum of stable disease rate and ORR). Quality assessment of the included studies was performed using the Newcastle-Ottawa Scale for observational or retrospective studies (that represents a score between 0 and 9 related to 3 quality parameters such as selection, comparability, and outcome), and the MINORS score for nonrandomized studies (ie, a score ranged from 0 to 12 calculated through a 12-item list).

The extracted data included the type of study, number of patients, cancer type, performance status, line of treatment, treatment schedule, and clinical outcomes, including ORR, median OS, 1-, 2-, and 3-year OS, median PFS, and DCR. From trials that investigated multiple treatment arms, data were only included from the arms that used ICIs. The outcome data extracted for each arm were analyzed using random-effects models and were reported as weighted measures. Median OS and PFS (where provided) were extracted and a pooled effect size with its 95% CI was calculated. Briefly, the variance of each median time was calculated and thereafter the median times were pooled using inverse variance weighted average values. The response rates and 1-, 2-, and 3-year survival rates reported in the individual studies were aggregated as pooled rates. Heterogeneity among studies was assessed using the χ² test. All analyses were performed using Comprehensive Meta-Analysis statistical software (version 2.2, Biostat).

In total, 14 studies (including an updated version of 1 previously published study) were included^2-15 (Figure) (eTable in the Supplement).

Except the phase 3 first-line trial of Shitara et al¹³ in gastric cancer and the first-line cohort of Lenz et al¹⁰ (CheckMate 142⁷), all studies included pretreated patients with solid tumors. Among the included studies, 2 were prospective or observational studies, 10 were phase 2 studies, 1 was a phase 3 study, and 1 was a pooled analysis of 1 phase 1-2 and 1 phase 2 study. In total, 939 patients were analyzed (range, 11-233).

All studies were available for ORR analysis. The pooled ORR was 41.5% (95% CI, 34.9%-48.4%), and ranged from 0 (Caccese et al,⁸ including high-grade gliomas) to 64.7% (arm including pembrolizumab plus chemotherapy in the phase 3 study of Shitara et al¹³).

Thirteen studies provided data for DCR (only the study by Shitara et al¹³ provided ORR only). The pooled DCR was 62.8% (95% CI, 54.5%-70.3%) and ranged from 33% (Caccese et al,⁸ including high-grade gliomas) to 81% (combination arm of the Checkmate 142 trial⁷).

Median PFS was reported in 7 studies. Pooled median PFS was 4.3 months (95% CI, 3-6.8 months). Median OS was reported in 5 studies. Pooled median OS was 24 months (95% CI, 20.1-28.5 months). The 1-, 2-, and 3-year OS were available in 7, 6, and 1 studies, respectively. The pooled 1- and 2-year OS were 75.6% (95% CI, 61.8%-85.5%) and 56.5% (95% CI, 46%-66.4%), respectively.

The ORR was similar according to histologic analysis with the higher values for gastric cancer (61.2%) and the lowest associated with colorectal cancer (47.1%), endometrial (36.1%), and other tumors (35.5%).

Visual inspection of the funnel plots for ORR (eFigure in the Supplement) revealed no asymmetry, suggesting that publication bias was not an influential factor. Begg and Egger test results were not significant.

Despite the limitation of the nonrandomized design and the short follow-up, the pooled analysis provided evidence that MSI-H tumors, in various disease settings, were associated with benefit from ICIs in different lines of therapy. Taking into consideration that ICIs were mostly offered in advanced lines of therapy, short-term OS (1- and 2-year) rates are encouraging. Although deriving from few studies, median PFS and OS figures were also promising but not definitive yet (4.3 and 24 months, respectively). Finally, many studies have short follow-up and deserve full publication. The possible explanation of the positive outcomes following ICI treatment in MSI-H tumors relies on the possible association with programmed death-ligand 1 (PD-L1) expression and the high mutational burden of these diseases. First, the higher mutational load in MSI-H colorectal cancer can elicit an endogenous immune antitumor response, counterbalanced by the expression of immune inhibitory signals, such as PD-L1, that prevent tumor elimination.¹⁶ Based on these findings, the FDA has released market authorization of pembrolizumab for any solid tumors that have dMMR/MSI-H and that have progressed following prior therapies and who have no further treatment options. In addition, it seems appropriate to implement testing for dMMR/MSI-H patients with any advanced disease who have no more effective systemic therapies available.

Immunotherapy has dramatically changed the therapeutic landscape of multiple tumors. Recently published trials have highlighted the high activity of ICIs in dMMR/MSI-H tumors, and dMMR/MSI-H status has been approved by the FDA as an indication for ICIs use for metastatic cancers, irrespective of the cancer types, likely due to the enhanced immune response related to the presence of increased somatic variations and emergence of neoantigens in these tumors.

Although not currently approved worldwide, according to these findings anti-PD-(L)1 agents represent a potentially important treatment option for dMMR/MSI-H tumors.

Corresponding Author: Fausto Petrelli, MD, Oncology Unit, Medical Sciences Department, ASST Bergamo Ovest, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy (faupe@libero.it).

Accepted for Publication: March 10, 2020.

Published Online: May 14, 2020. doi:10.1001/jamaoncol.2020.1046

Author Contributions: Dr Petrelli had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Petrelli, A. Ghidini.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Petrelli, A. Ghidini.

Critical revision of the manuscript for important intellectual content: Petrelli, M. Ghidini, Tomasello.

Statistical analysis: Petrelli.

Administrative, technical, or material support: A. Ghidini.

Supervision: M. Ghidini, Tomasello.

Conflict of Interest Disclosures: None reported.