In a systematic review and meta-analysis of phase III trials of immune checkpoint inhibitor treatment in patients with advanced gastroesophageal cancer reported in JAMA Oncology, Harry H. Yoon, MD, MS, and colleagues found that PD-L1 expression was the strongest predictor of overall survival benefit in patients with squamous cell carcinoma and the second-strongest predictor—after microsatellite instability (MSI)-high status—in those with adenocarcinoma.
As state by the investigators, “Approval by the U.S. Food and Drug Administration of immune checkpoint inhibition for advanced gastroesophageal cancer irrespective of PD-L1 status has generated controversy. Exploratory analyses from individual trials indicate a lack of meaningful benefit from immune checkpoint inhibition in patients with absent or low PD-L1 expression; however, analysis of a single variable while ignoring others may not consider the instability inherent in exploratory analyses.”
Study Details
The study included 17 studies comparing PD-1 or PD-L1 inhibitors with standard of care in a total of 11,166 patients, including 5,067 with squamous cell carcinoma and 6,099 with adenocarcinoma. The prespecified outcome of interest was overall survival. In addition to PD-L1 expression, 13 additional variables identified as predictive within studies were analyzed. The mean hazard ratio for immune checkpoint inhibitors vs standard of care was calculated, and predictive values were generated by calculating the ratio of mean hazard ratios between two levels of each variable.
Tissue-based PD-L1 expression, more than any variable other than MSI-H, identified varying degrees of benefit from immune checkpoint inhibitor–containing therapy vs standard of care among patients with advanced gastroesophageal cancer in 17 randomized clinical trials.— Harry H. Yoon, MD, MS, and colleagues
Tweet this quote
Key Findings
Among patients with squamous cell carcinoma, PD-L1 tumor proportion score (TPS) was the strongest predictor of immune checkpoint inhibitor benefit. In five trials (six comparisons) using TPS, high TPS was defined as TPS > 1 in all but one (TPS ≥ 10), with the TPS-high group consisting of 1,489 patients and TPS-low group consisting of 1,799. Hazard ratios vs standard of care were 0.60 (95% confidence interval [CI] = 0.53–0.68) for high TPS and 0.84 (95% CI = 0.75–0.95) for low TPS, yielding a predictive value of 41.0% favoring high TPS. The predictive values for all other variables except combined positive score (CPS) were ≤ 16%.
CPS was the second-strongest predictor in squamous cell carcinoma. In six trials (seven comparisons) using CPS, high CPS was defined as ≥ 10 in all except one (CPS ≥ 1), with the CPS-high group consisting of 1,943 patients and the CPS-low group consisting of 1,499. Hazard ratios were 0.62 (95% CI = 0.54–0.69) for high CPS and 0.82 (95% CI = 0.72–0.94) for low CPS, yielding a predictive value of 34.3% favoring high CPS.
In adenocarcinoma, MSI-high status was the strongest predictor of benefit of immune checkpoint inhibitors vs standard of care, with a predictive value of 135.8%. Hazard ratios were 0.35 (95% CI = 0.22–0.55) for MSI-high (4 trials; n = 153) and 0.82 (95% CI = 0.74–0.91) for MSI-low (3 trials; n = 1,957). CPS was the second-strongest predictor. Among six trials (seven comparisons), high CPS was defined as ≥ 10, ≥ 5, and ≥ 1 in two trials each, with 2,352 patients having high CPS and 1,543 having low CPS. Hazard ratios were 0.73 (95% CI = 0.66–0.81) for high CPS and 0.95 (95% CI = 0.84–1.07) for low CPS, yielding a predictive value of 29.4% for high CPS. For all other variables, predictive values were ≤ 12.9%.
Head-to-head analyses of trials containing both levels of a variable or having similar design generally yielded consistent results.
The investigators concluded, “Tissue-based PD-L1 expression, more than any variable other than MSI-H, identified varying degrees of benefit from immune checkpoint inhibitor–containing therapy vs standard of care among patients with advanced gastroesophageal cancer in 17 randomized clinical trials.”
Dr. Yoon, of the Mayo Clinic, Rochester, is the corresponding author for the JAMA Oncology article.
Disclosure: For full disclosures of the study authors, visit jamanetwork.com.
