Andrea Arfè1, Geoffrey Fell2, Brian Alexander3, Mark M Awad4, Scott J Rodig5, Lorenzo Trippa2, Jonathan D Schoenfeld6. 1. Harvard-MIT Center for Regulatory Science, Harvard Medical School, Boston, MA. 2. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA. 3. Foundation Medicine, Cambridge, MA. 4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. 5. Department of Pathology, Dana-Farber Cancer Institute, Boston, MA. 6. Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA.
Abstract
PURPOSE: Programmed cell death receptor ligand 1 (PD-L1) expression is the most studied biomarker to predict the efficacy of immune checkpoint inhibitors (ICIs), but its clinical significance is controversial. We estimated the distribution of PD-L1 expression scores (ie, tumor proportion score or combined proportion score) and the relationship between PD-L1 levels and ICIs' impact on overall survival (OS). METHODS: We reconstructed, pooled, and analyzed individual-level data on 7,617 patients with cancer from 14 randomized clinical trials. The effects of ICIs were quantified using differences in 24-month restricted mean survival times (ΔRMSTs; ie, the increase in life expectancy truncated at 2 years associated with ICI therapy). In a simulation study, we compared standard randomized clinical trial designs with a trial design that leverages meta-analytic results like ours. RESULTS: Approximately 93% of patients had a PD-L1 expression ≤ 5% (66% of patients) or > 50% (27% of patients). OS improves with ICIs regardless of PD-L1 expression level, which predicts the benefits' magnitude. For patients with non-small-cell lung cancer (NSCLC), ΔRMSTs ranged from 1.4 months (95% probability interval [PI], 0.7 to 2.2 months) for PD-L1 expression ≤ 1% to 4.1 months (95% PI, 3.2 to 5.2 months) for PD-L1 expression > 80%. For patients with non-NSCLC tumors, ΔRMSTs ranged from 0.8 months (95% PI, -0.1 to 1.7 months) to 2.3 months (95% PI, 1.3 to 4.4 months), again for PD-L1 expression levels of ≤ 1% and > 80%, respectively. Simulations suggested that designs tailored to meta-analytic results can detect the effects of ICIs in PD-L1 subgroups with higher probability (> 15%) than standard designs. CONCLUSION: The practice of dichotomizing the range of PD-L1 expression scores is inadequate for patient stratification. Meta-analytic estimates of the distribution of PD-L1 scores and subgroup-specific treatment effects can improve the designs of future trials of ICIs.
PURPOSE: Programmed cell death receptor ligand 1 (PD-L1) expression is the most studied biomarker to predict the efficacy of immune checkpoint inhibitors (ICIs), but its clinical significance is controversial. We estimated the distribution of PD-L1 expression scores (ie, tumor proportion score or combined proportion score) and the relationship between PD-L1 levels and ICIs' impact on overall survival (OS). METHODS: We reconstructed, pooled, and analyzed individual-level data on 7,617 patients with cancer from 14 randomized clinical trials. The effects of ICIs were quantified using differences in 24-month restricted mean survival times (ΔRMSTs; ie, the increase in life expectancy truncated at 2 years associated with ICI therapy). In a simulation study, we compared standard randomized clinical trial designs with a trial design that leverages meta-analytic results like ours. RESULTS: Approximately 93% of patients had a PD-L1 expression ≤ 5% (66% of patients) or > 50% (27% of patients). OS improves with ICIs regardless of PD-L1 expression level, which predicts the benefits' magnitude. For patients with non-small-cell lung cancer (NSCLC), ΔRMSTs ranged from 1.4 months (95% probability interval [PI], 0.7 to 2.2 months) for PD-L1 expression ≤ 1% to 4.1 months (95% PI, 3.2 to 5.2 months) for PD-L1 expression > 80%. For patients with non-NSCLC tumors, ΔRMSTs ranged from 0.8 months (95% PI, -0.1 to 1.7 months) to 2.3 months (95% PI, 1.3 to 4.4 months), again for PD-L1 expression levels of ≤ 1% and > 80%, respectively. Simulations suggested that designs tailored to meta-analytic results can detect the effects of ICIs in PD-L1 subgroups with higher probability (> 15%) than standard designs. CONCLUSION: The practice of dichotomizing the range of PD-L1 expression scores is inadequate for patient stratification. Meta-analytic estimates of the distribution of PD-L1 scores and subgroup-specific treatment effects can improve the designs of future trials of ICIs.