Found 1 Presentation For Request "40P"
40P - Interplay between Mutational Profile and TMB on overall survival: A Posthoc Analysis of 1,662 Metastatic Patients Treated with Immune Checkpoint Inhibitors.
- Camila B. Xavier (Sao Paulo, Brazil)
- Camila B. Xavier (Sao Paulo, Brazil)
- Carlos Diego H. Lopes (Sao Paulo, Brazil)
- Beatriz M. Awni (Sao Paulo, Brazil)
- Eduardo F. De Campos (Sao Paulo, Brazil)
- João Pedro D. Alves (São Paulo, Brazil)
- Denis L. Jardim (Sao Paulo, Brazil)
Abstract
Background
Tumor mutational burden (TMB) ≥10mut/Mb received FDA agnostic approval for pembrolizumab use. A more integrative view of this biomarker is needed to select candidates to immune checkpoint inhibitors (ICI).
Methods
We performed a posthoc analysis using clinical data from an advanced cancer patients cohort treated with ICI and submitted to genomic profiling by MSK-IMPACT platform available as public domain on the cbioportal database. Validation analysis was performed to correlate predefined percentiles used at the original publication with cutoffs used for regulatory approval. Kaplan-Meier (KM) method, multivariate log-rank p values, and Cox regression hazard ratios (HR) for overall survival (OS) were calculated for all patients with TMB ≥20, ≥10, or <10mut/Mb cutoffs. For a ≥10mut/Mb cutoff, KM method was performed, and log-rank P values with confidence interval (CI) of 95% were reported for each gene tested (N=464). Holm-Bonferroni alfa error adjustment was performed. For all genes exhibiting a possible correlation with survival considering a less rigorous alfa-error level (p<0.05), a Cox multivariable analysis was also performed.
Results
A total of 1,662 patients were included. With a maximum follow-up of 80 months, median OS was 42 months for both TMB ≥20 and ≥10 mut/Mb, and 15 months for TMB <10mut/Mb (multivariate log-rank p<0.005). HR for death was 0.44 (95%CI 0.34-0.56; p<0.005) and 0.57 (95%CI 0.49-0.67; p<0.005) for TMB ≥20 and ≥10mut/Mb respectively. From a ≥10mut/Mb cutoff, after log-rank test followed by Holm-Bonferroni alfa-error adjustment (p<0.0009), four genes negatively impacted survival when mutated: CCND3, TIMM8B, CDKN2B and STK11 (median OS of 1, 1, 1, and 7 months). From that same TMB cutoff, a Cox multivariate analysis stratified by median TMB revealed that mutations in STK11 (HR 2.95; p<0.0007) and TP53 (HR 1.89; p<0.0032) were associated with a higher risk of death. Otherwise, mutations in TERT (HR 0.54; p<0.0044) and NOTCH3 (HR 0.23; p<0.0355) were protective.
Conclusions
This analysis confirmed the 10mut/Mb TMB cutoff as a positive predictive biomarker to ICI treatment. For TMB ≥10mut/mB, the mutational profile can contribute to define outcomes to ICIs.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
D.L.F. Jardim: Financial Interests, Personal, Invited Speaker: Roche, Janssen, Astellas, MSD, Bristol Myers Squibb, Libbs; Financial Interests, Personal, Advisory Role: Janssen, Bristol Myers Squibb, Libbs. All other authors have declared no conflicts of interest.