Tumor Mutational Burden, Toxicity, and Response of Immune Checkpoint Inhibitors Targeting PD(L)1, CTLA-4, and Combination: A Meta-regression Analysis

Abstract

Purpose: Tumor mutational burden (TMB) has emerged as a potential predictive biomarker for clinical response to ICI therapy, but whether TMB also predicts toxicity remains unknown. We investigated the relationship between TMB, objective response rate (ORR), overall survival (OS), and toxicity for ICI therapy across multiple cancer types.

Experimental design: We searched MEDLINE, PubMed, and ASCO/ESMO/AACR meetings for clinical trials of anti-PD(L)1, CTLA-4, or combination in 29 cancer types. We assessed ICI administered, responses (complete or partial response), median OS, OS HR, and grade 3/4 toxicity. We conducted a systematic review, meta-analysis and meta-regression using tumor level TMB data from Foundation Medicine.

Results: One hundred seventeen clinical trials, which included 12,450 patients treated with ICI therapy were analyzed. Meta-regression analysis revealed that TMB was significantly associated with ORR for anti-PD(L)1, anti-CTLA-4, and combination (P < 0.0001 for all), but not associated with toxicity in all treatment groups. OS data were unavailable for most studies included in our meta-analysis, and the relationship between TMB and OS in this subset was not significant (P = 0.26). In high TMB tumor types (≥10 mut/megabase) the improvement of ORR and increase in grade 3/4 toxicity with combination ICI therapy as compared with PD(L)1 monotherapy were 21.13% and 25.41%, respectively, as compared with 3.73% and 18.78% in low TMB tumor types (<10 mut/megabase).

Conclusions: There is a positive association between TMB and clinical response with anti-PD(L)1, anti-CTLA-4, and combination ICIs, but no association between TMB and toxicity. These results imply a favorable risk/benefit ratio for ICIs in tumors with a higher TMB.

Figure 1:. PRISMA Flowchart

* from experts in the field to locate additional published trials of ICI agents

Figure 2:. Association Between Overall Response Rate and TMB of Single and Dual ICI Therapy

Shown above is the graphical representation of the meta-regression summary of ORR and TMB. This includes the median number of coding somatic mutations per megabase (MB) of DNA in 29 tumor types or subtypes among patients who received inhibitors of PD-1, PD-L1 and CTLA-4, as single or dual agents as described in published studies for which data regarding the objective response rate were available. The number of patients who were evaluated for the objective response rate is shown for each tumor type (size of the shape indicates weight of study as assessed by inverse-variance, color and shape indicate tumor type, see Legend Key). Data on the x axis are shown on a logarithmic scale. 2A: Association between objective response rate and TMB of anti-PD(L)1 monotherapy 2B: Association between objective response rate and TMB of anti-CTLA-4 monotherapy 2C: Association between objective response rate and TMB of anti-PD(L)1 plus anti-CTLA-4 combination therapy

Figure 3:. Association Between Toxicity Rate and TMB of Single and Dual ICI Therapy

Shown above is the graphical representation of the meta-regression summary of grade 3/4 toxicity rate and TMB. This includes the median number of coding somatic mutations per megabase (MB) of DNA in 29 tumor types or subtypes among patients who received inhibitors of PD-1, PD-L1 and CTLA-4, as single or dual agents as described in published studies for which data regarding the toxicity information was available. The number of patients who were evaluated for the toxicity rate is shown for each tumor type (size of the shape indicates weight of study as assessed by inverse-variance, color and shape indicate tumor type, see Legend Key). Data on the x axis are shown on a logarithmic scale. 3A: Association between toxicity rate and TMB of anti-PD(L)1 monotherapy 3B: Association between toxicity rate and TMB of anti-CTLA-4 monotherapy 3C: Association between toxicity rate and TMB of anti-PD(L)1 plus anti-CTLA-4 combination therapy

Figure 4:. Estimated Overall Response and Toxicity Rates from Meta-Regression of Single and Dual ICI therapy

Shown above is the estimated overall response (blue) and toxicity rates (red) from meta-regression for anti-PD(L)1 monotherapy and anti-PD(L)1 plus anti-CLTA-4 combination therapy. TMB is on a logarithmic scale.

Figure 5:. Heatmap and Correlative Analysis of Response and Toxicity: Single and Dual ICI therapy

5A: Response and Toxicity Rates by Treatment Group and Tumor Type: Heatmap Analysis Shown above is the graphical heatmap representation of response and toxicity rates of 19 tumor types for which both toxicity and response data was available for both anti-PD(L)1 monotherapy and anti-PD(L)1 plus anti-CTLA-4 combination ICI therapy. Darker shading represents a higher rate of toxicity and response, whereas lighter shading indicates a lower rate of toxicity and response. eTable 3 in the Supplement shows individual data for each tumor type, including median TMB, ORR and toxicity rates. 5B: Correlative Analysis of Response and Toxicity Rates of Single vs Dual ICI therapy across 19 tumor types. The above figure represents the Spearman’s correlation between response rate (y-axis) and toxicity rate (x-axis) of both anti-PD(L)1 monotherapy (blue line) and anti-PD(L)1 plus anti-CTLA-4 therapy (red line). The circles represent individual tumor types and varying sizes of circle represent the value of TMB, which the size of the circle is proportional to the value of TMB (higher TMB equates to larger circle). Loess smoothing curve with the default span of 0.75 is shown.

Figure 6:. Association Between Survival Hazard Ratio and TMB of anti-PD(L)1 Monotherapy

Shown above is the graphical representation of the meta-regression of survival hazards ratio and TMB. This includes the median number of coding somatic mutations per megabase (MB) of DNA in 8 tumor types or subtypes among patients who received inhibitors of PD(L)1 monotherapy for which data regarding the hazard ratio were available. A plot of hazard ratios versus median TMB was created. The meta-regression summary was graphically displayed on top of it. Inverse-variance weighting was used to vary the size of each point shape. Median TMB is shown on a log scale, but labeled on the original scale.