The Checkmate 026 study is a significant investigation in the field of lung cancer, designed with the goal of shifting the paradigm for how a large number of patients with advanced disease would receive their very first treatment. The trial evaluated a newer class of therapy against the established standard of care. The central question was whether this approach could redefine the frontline treatment strategy for a significant portion of individuals with the most common type of lung cancer.
Trial Design and Objectives
The Checkmate 026 trial focused on patients with previously untreated, advanced non-small cell lung cancer (NSCLC). A requirement for participation was that the patients’ tumors had to show expression of a protein known as programmed death-ligand 1 (PD-L1). For this study, the cutoff for inclusion was set at a level of 5% or greater tumor cell staining for this biomarker. This criterion was based on earlier data suggesting that patients with at least this level of expression might respond well to the new therapy.
The study enrolled 541 eligible patients and randomly assigned them into two distinct treatment groups. One group received the investigational drug, an immunotherapy agent called nivolumab, which is designed to help the body’s own immune system fight cancer cells. The other group was treated with the standard of care at the time, which consisted of a physician’s choice of platinum-based doublet chemotherapy. This traditional treatment works by directly killing rapidly dividing cells.
The primary goal was to determine if nivolumab was superior to chemotherapy at delaying the growth and spread of the cancer. This outcome, known as progression-free survival (PFS), was the trial’s primary endpoint. The hope was that immunotherapy would offer a more effective and potentially less toxic initial treatment for this defined patient population.
Key Findings and Results
The results of Checkmate 026 were surprising to the oncology community. The trial did not meet its primary endpoint, as the data demonstrated that nivolumab did not provide a superior progression-free survival benefit compared to standard chemotherapy for patients whose tumors had at least 5% PD-L1 expression.
Specifically, the median progression-free survival for patients receiving nivolumab was 4.2 months. In contrast, the median PFS for patients in the chemotherapy arm was 5.9 months. The hazard ratio, a statistical measure used to compare the rates of progression, further confirmed the lack of benefit for the immunotherapy group.
The study also failed to show a significant advantage in its main secondary endpoints, including overall survival (OS). The median overall survival was 14.4 months for the nivolumab group versus 13.2 months for the chemotherapy group, a difference that was not statistically significant. The outcome was declared “negative,” as the hypothesis that this immunotherapy strategy would be better than chemotherapy was not proven.
Interpreting the Unexpected Outcome
The trial’s failure to meet its primary goal prompted analysis within the scientific community, leading to a deeper understanding of immunotherapy treatment. A central reason identified for the trial’s outcome was the selection of the PD-L1 biomarker cutoff. The threshold of ≥5% PD-L1 expression was likely too low.
This broad inclusion criterion meant the study enrolled many patients whose tumors did not have high enough levels of the biomarker to derive a substantial benefit from immunotherapy when used as a single agent.
This interpretation is supported by contrasting the trial with a concurrent study, KEYNOTE-024. That trial evaluated a similar immunotherapy drug, pembrolizumab, but used a more stringent patient selection criterion, requiring tumor PD-L1 expression of ≥50%. Unlike Checkmate 026, KEYNOTE-024 was a positive trial, demonstrating a clear survival benefit for immunotherapy over chemotherapy. This different result highlighted that successful first-line immunotherapy was dependent on using a high biomarker cutoff to select the patients most likely to respond.
Another complicating factor in interpreting the overall survival data from Checkmate 026 was patient crossover. Approximately 60% of patients who were initially in the chemotherapy group went on to receive immunotherapy, including nivolumab, as their next treatment after their cancer progressed. This subsequent treatment, known as second-line therapy, can obscure the true survival difference between the initial treatment strategies. The trial’s result was therefore not seen as a failure of the drug itself, but rather a failure of the treatment strategy and patient selection criteria.
The Legacy of Checkmate 026
Despite being a “negative” trial, Checkmate 026 provided a valuable lesson to oncology. Its outcome underscored the importance of using a high PD-L1 expression level as a predictive biomarker. It taught researchers and clinicians that for single-agent immunotherapy to be effective as an initial treatment, it must be targeted to the patients most likely to benefit.
This finding influenced the clinical practice of using a high biomarker cutoff (typically ≥50%) to select patients for this specific therapeutic approach. The results also impacted clinical trial design and drug development strategies. The failure of the broad approach in Checkmate 026 spurred research into alternative strategies for the majority of patients with lower or no PD-L1 expression. This shift was instrumental in the development of combination therapies.
Consequently, a new standard of care emerged for patients with low or negative PD-L1 levels: combining immunotherapy with chemotherapy. This approach has proven effective, extending survival for a broader population of patients with advanced NSCLC. In this way, the lessons from the negative outcome of Checkmate 026 paved the way for a more inclusive standard of care.