Tumor Mutational Burden and Efficacy of Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis
<p>Flow of the literature search.</p> "> Figure 2
<p>Meta-analysis of immune checkpoint inhibitor therapy and overall survival, high TMB group versus low TMB group.</p> "> Figure 3
<p>Meta-analysis of immune checkpoint inhibitor therapy and progression-free survival, high TMB group versus low TMB group.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Identification of Studies and Study Characteristics
2.2. High TMB Group Versus Low TMB Group
2.3. ICI Arm Versus Chemotherapy Arm, within High TMB Group or Low TMB Group
3. Discussion
4. Materials and Methods
4.1. Literature Search Strategy and Eligibility Criteria
4.2. Data Extraction
4.3. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Appendix A
Title | 1 | Identify the Report as a Systematic Review, Meta-Analysis, or Both | 0 |
ABSTRACT | |||
Structured summary | 2 | Provide a structured summary including, as applicable: Background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. | 0 |
INTRODUCTION | |||
Rationale | 3 | Describe the rationale for the review in the context of what is already known. | 1 |
Objectives | 4 | Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). | 1 |
METHODS | |||
Protocol and registration | 5 | Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. | N/A |
Eligibility criteria | 6 | Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. | 11–12 |
Information sources | 7 | Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. | 11 |
Search | 8 | Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. | Appendix B |
Study selection | 9 | State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). | 11–12 |
Data collection process | 10 | Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. | 12 |
Data items | 11 | List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. | 12 |
Risk of bias in individual studies | 12 | Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. | N/A |
Summary measures | 13 | State the principal summary measures (e.g., risk ratio, difference in means). | 12 |
Synthesis of results | 14 | Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis. | 12 |
Risk of bias across studies | 15 | Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). | 12 |
Additional analyses | 16 | Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified. | 12 |
RESULTS | |||
Study selection | 17 | Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. | 2, Figure 1 |
Study characteristics | 18 | For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. | 2, Table 1 and Table 2 |
Risk of bias within studies | 19 | Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). | N/A |
Results of individual studies | 20 | For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. | Figure 2 and Figure 3, Figures S3–S6 |
Synthesis of results | 21 | Present results of each meta-analysis done, including confidence intervals and measures of consistency. | 2, Table 1 and Table 2, Table S1 |
Risk of bias across studies | 22 | Present results of any assessment of risk of bias across studies (see Item 15). | 2, Table S1, Figures S1, S2, S7–S10 |
Additional analysis | 23 | Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). | Table 3 |
DISCUSSION | |||
Summary of evidence | 24 | Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). | 9–11 |
Limitations | 25 | Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). | 11 |
Conclusions | 26 | Provide a general interpretation of the results in the context of other evidence, and implications for future research. | 12 |
FUNDING | |||
Funding | 27 | Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. | 13(none) |
Appendix B
Full Search Strategy in PubMed
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Study | Type of Study | Malignancy | Type of Immunotherapy | Sample Source | Detection Method | TMB Cutoff | Median TMB (range) | Number of Patients (High/Low TMB) | Outcome |
---|---|---|---|---|---|---|---|---|---|
Balar et al. 2017 [44] | Retrospective analysis of clinical trial | Urothelial carcinoma | Atezolizumab | Tumor | FoundationOne | ≥16/MB | 8.1 (0.9–62.2) | 97 (NR) | OS |
Chae et al. 2018 [28] | Retrospective cohort | NSCLC | PD-1/PD-L1 inhibitor | Tumor | FoundationOne | ≥15/MB | 8 (1–55) | 34 (NR) | OS, PFS |
Chae et al. 2019a [41] | Retrospective cohort | NSCLC | Immune checkpoint inhibitors | Blood | Guardant360 | NR (median) | NR | 20 (10/10) | OS, PFS |
Chae et al. 2019b [41] | Retrospective cohort | NSCLC | Immune checkpoint inhibitors | Blood | Guardant360 | NR (median) | NR | 12 (6/6) | OS, PFS |
Cristescu et al. 2018a [30] | Retrospective analysis of clinical trial | Pan-tumor | Pembrolizumab | Tumor | WES | >102.5 | NR | 119 (37/82) | PFS |
Cristescu et al. 2018b [30] | Retrospective analysis of clinical trial | Melanoma | Pembrolizumab | Tumor | WES | >191.5 | NR | 89 (59/30) | PFS |
Cristescu et al. 2018c [30] | Retrospective analysis of clinical trial | HNSCC | Pembrolizumab | Tumor | WES | >86 | NR | 107 (54/53) | PFS |
Fang et al. 2019 [39] | Retrospective analysis of clinical trial | NSCLC | PD-1/PD-L1 inhibitor | Tumor | WES | ≥157 (top tertile) | 87 (4–1528) | 73 (25/48) | PFS |
Goodman et al. 2017 [27] | Retrospective cohort | Various | Various | Tumor | FoundationOne | ≥20/MB | 6 (1–347) | 151 (38/113) | OS, PFS |
Hamid et al. 2019 [37] | Retrospective analysis of clinical trial | Melanoma | Atezolizumab | Tumor | FoundationOne | ≥16/MB | NR | 23 (12/11) | OS, PFS |
Hellmann et al. 2018 [23] | Retrospective analysis of clinical trial | NSCLC | Nivolumab plus ipilimumab | Tumor | WES | >158 (median) | 158 | 75 (37/38) | PFS |
Hugo et al. 2016 [31] | Retrospective cohort | Melanoma | Pembrolizumab or nivolumab | Tumor | WES | ≥577 (bottom tertile) | 489 (73–3985) | 37 (13/24) | OS |
Johnson et al. 2016 [29] | Retrospective cohort | Melanoma | PD-1/PD-L1 inhibitor | Tumor | FoundationOne | >23.1/MB | NR | 65 (27/38) | OS, PFS |
Khagi et al. 2017 [43] | Retrospective cohort | Various | Various | Blood | Guardant360 | >3 total ctDNR alterations | 2 (0–20) | 69 (20/49) | OS, PFS |
Le et al. 2015 [5] | Clinical trial | Various | Pembrolizumab | Tumor | WES | NR | NR | 15 (NR) | OS, PFS |
Ricciuti et al. 2019 [40] | Retrospective cohort | Small-cell lung cancer | Immune checkpoint inhibitors | Tumor | NGS (OncoPanel) | >9.7/MB (median) | 9.8 (1.2–31.2) | 52 (26/26) | OS, PFS |
Rizvi et al. 2015a [22] | Retrospective cohort | NSCLC | Pembrolizumab | Tumor | WES | >209 (median) | NR | 18 (9/9) | PFS |
Rizvi et al. 2015b [22] | Retrospective cohort | NSCLC | Pembrolizumab | Tumor | WES | >200 (median) | NR | 16 (8/8) | PFS |
Rizvi et al. 2018 [26] | Retrospective cohort | NSCLC | Immune checkpoint inhibitors | Tumor | WES | >324 | 171 (1–1147) | 49 (12/37) | PFS |
Roszik et al. 2016 [34] | Retrospective cohort | Melanoma | Ipilimumab | Tumor | NGS | >100 | NR | 76 (57/19) | OS |
Samstein et al. 2019 [32] | Retrospective cohort | Various | Immune checkpoint inhibitors | Tumor | NGS (MSK-IMPACT) | 90th percentile of each histology | NR | 1662 (NR) | OS |
Snyder, et al. 2014a [20] | Retrospective cohort | Melanoma | Ipilimumab or tremelimumab | Tumor | WES | >100 | NR | 25 (10/15) | OS |
Snyder et al. 2014b [20] | Retrospective cohort | Melanoma | Ipilimumab or tremelimumab | Tumor | WES | >100 | NR | 39 (17/22) | OS |
Van Allen et al. 2015 [21] | Retrospective cohort | Melanoma | Ipilimumab | Tumor | WES | ≥202 (median) | 197 (7–5854) | 110 (55/55) | OS, PFS |
Wang et al. 2019 [38] | Retrospective analysis of clinical trial | Gastric cancer | Toripalimab | Tumor | WES | ≥12/MB | NR | 54 (12/42) | OS, PFS |
Yusko et al. 2019a [35] | Retrospective analysis of clinical trial | Melanoma | Nivolumab or ipilimumab | Tumor | WES | NR | 171 | 30 (NR) | OS |
Yusko et al. 2019b [35] | Retrospective analysis of clinical trial | Melanoma | Nivolumab or ipilimumab | Tumor | WES | NR | 159 | 38 (NR) | OS |
Study | Type of Study | Malignancy | Immunotherapy versus Chemotherapy Comparison | Sample Source | Detection Method | TMB Cutoff | Number of Patients with High/Low TMB | Outcome |
---|---|---|---|---|---|---|---|---|
Carbone et al. 2017 [33] | Retrospective analysis of RCT | NSCLC | Nivolumab versus platinum-based chemotherapy | Tumor | WES | ≥243 (top tertile) | 107/205 | OS, PFS |
Gandara et al. 2018a [42] | Retrospective analysis of RCT | NSCLC | Atezolizumab versus docetaxel | Blood | FoundationOne | ≥16/MB | 63/148 | OS, PFS |
Gandara et al. 2018b [42] | Retrospective analysis of RCT | NSCLC | Atezolizumab versus docetaxel | Blood | FoundationOne | ≥16/MB | 158/425 | OS, PFS |
Hellmann et al. 2019 * [45] | RCT | NSCLC | Nivolumab plus ipilimumab versus platinum doublet chemotherapy | Tumor | FoundationOne | ≥10/MB | 299/380 | OS |
Hellmann et al. 2018a * [25] | RCT | NSCLC | Nivolumab plus ipilimumab versus platinum doublet chemotherapy | Tumor | FoundationOne | ≥10/MB | 299/380 | PFS |
Hellmann et al. 2018b [25] | RCT | NSCLC | Nivolumab versus platinum doublet chemotherapy | Tumor | FoundationOne | ≥13/MB | 150/78 | PFS |
Powles et al. 2018 [36] | RCT | Urothelial carcinoma | Atezolizumab versus platinum-based chemotherapy | Blood | FoundationOne | ≥9.65/MB (median) | 274/270 | OS |
Subgroup | Overall Survival | Progression-Free Survival | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Number of Study Estimates | HR (95% CI) | p-Value * | I2 (%) | I2 among Subgroups (%) | Number of Study Estimates | HR (95% CI) | p-Value * | I2 (%) | I2 among Subgroups (%) | |
All studies | 19 | 0.53 (0.42 to 0.67) | <0.001 | 0 | 19 | 0.52 (0.40 to 0.67) | <0.001 | 0 | ||
Subgroup analysis | ||||||||||
Treatment | 0 | - | ||||||||
PD-1/PD-L1 inhibitors | 7 | 0.43 (0.29 to 0.64) | <0.001 | 0 | 11 | 0.51 (0.35 to 0.73) | <0.001 | 0 | ||
CTLA-4 inhibitors | 4 | 0.57 (0.30 to 1.09) | 0.087 | 0 | ||||||
PD-1 inhibitors versus PD-L1 inhibitors | 44 | - | ||||||||
PD-1 inhibitors | 3 | 0.62 (0.33 to 1.17) | 0.14 | 0 | 7 | 0.54 (0.36 to 0.81) | 0.003 | 0 | ||
PD-L1 inhibitors | 2 | 0.35 (0.21 to 0.61) | <0.001 | 0 | ||||||
Cancer type | 0 | 0 | ||||||||
Melanoma | 9 | 0.66 (0.43 to 1.01) | 0.056 | 0 | 4 | 0.47 (0.21 to 1.05) | 0.066 | 32 | ||
NSCLC | 3 | 1.80 (0.21 to 15.60) | 0.59 | 19 | 8 | 0.53 (0.30 to 0.93) | 0.028 | 0 | ||
Sample source | 0 | 0 | ||||||||
Tumor tissue | 16 | 0.52 (0.41 to 0.66) | <0.001 | 0 | 16 | 0.50 (0.38 to 0.66) | <0.001 | 0 | ||
Blood | 3 | 1.22 (0.21 to 7.21) | 0.83 | 39 | 3 | 0.84 (0.26 to 2.70) | 0.77 | 18 | ||
Detection method | 77 | 0 | ||||||||
WES | 8 | 0.73 (0.50 to 1.06) | 0.094 | 0 | 11 | 0.56 (0.41 to 0.77) | <0.001 | 0 | ||
NGS | 11 | 0.44 (0.33 to 0.59) | <0.001 | 0 | 8 | 0.44 (0.26 to 0.73) | 0.001 | 6 | ||
Data source | 0 | 0 | ||||||||
Clinical trials | 6 | 0.57 (0.35 to 0.92) | 0.020 | 32 | 8 | 0.52 (0.36 to 0.75) | <0.001 | 0 | ||
Cohorts | 13 | 0.50 (0.37 to 0.68) | <0.001 | 0 | 11 | 0.51 (0.35 to 0.76) | <0.001 | 1 | ||
Number of participants | 0 | 0 | ||||||||
≥100 participants | 3 | 0.53 (0.37 to 0.75) | <0.001 | 0 | 4 | 0.56 (0.37 to 0.85) | 0.007 | 7 | ||
<100 participants | 16 | 0.53 (0.39 to 0.72) | <0.001 | 0 | 15 | 0.49 (0.34 to 0.69) | <0.001 | 0 |
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Kim, J.Y.; Kronbichler, A.; Eisenhut, M.; Hong, S.H.; van der Vliet, H.J.; Kang, J.; Shin, J.I.; Gamerith, G. Tumor Mutational Burden and Efficacy of Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis. Cancers 2019, 11, 1798. https://doi.org/10.3390/cancers11111798
Kim JY, Kronbichler A, Eisenhut M, Hong SH, van der Vliet HJ, Kang J, Shin JI, Gamerith G. Tumor Mutational Burden and Efficacy of Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis. Cancers. 2019; 11(11):1798. https://doi.org/10.3390/cancers11111798
Chicago/Turabian StyleKim, Jong Yeob, Andreas Kronbichler, Michael Eisenhut, Sung Hwi Hong, Hans J. van der Vliet, Jeonghyun Kang, Jae Il Shin, and Gabriele Gamerith. 2019. "Tumor Mutational Burden and Efficacy of Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis" Cancers 11, no. 11: 1798. https://doi.org/10.3390/cancers11111798