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Published on: February 8, 2018
Tumor Mutational Burden, Toxicity, and Response of Immune Checkpoint Inhibitors Targeting PD(L)1, CTLA-4, and
Arsen Osipov1, Su Jin Lim1, Aleksandra Popovic1
1Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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.
Insights
Tumor mutational burden (TMB) predicts response to immunotherapy (ICI) but not toxicity. Higher TMB in tumors suggests a favorable risk/benefit ratio for ICI treatments, enhancing objective response rates.
Area of Science:
- Oncology
- Immunotherapy
- Biomarkers
Background:
- Tumor mutational burden (TMB) is a potential biomarker for predicting response to immune checkpoint inhibitor (ICI) therapy.
- The association between TMB and ICI-related toxicity is not well understood.
Purpose of the Study:
- To investigate the relationship between TMB, objective response rate (ORR), overall survival (OS), and toxicity in patients receiving ICI therapy.
- To determine if TMB can predict toxicity associated with ICI treatment across various cancer types.
Main Methods:
- Systematic review and meta-analysis of 117 clinical trials involving 12,450 patients treated with anti-PD(L)1, anti-CTLA-4, or combination ICIs.
- Meta-regression analysis using tumor-level TMB data to assess associations with ORR, OS, and grade 3/4 toxicity.
Main Results:
- TMB was significantly associated with ORR for all ICI types (P < 0.0001).
- No significant association was found between TMB and toxicity across treatment groups.
- In high TMB tumors (≥10 mut/megabase), combination ICI therapy showed a 21.13% improvement in ORR compared to PD(L)1 monotherapy, with a 25.41% increase in grade 3/4 toxicity.
Conclusions:
- A positive association exists between TMB and clinical response to various ICIs.
- TMB is not associated with ICI-related toxicity, suggesting a favorable risk/benefit profile for higher TMB tumors.
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