Clinical trials in oncology strive for perfection: “Perfect” patients, conditions, methods, and endpoints, and thus provide findings that are not always translatable to the real world.
While randomized controlled trials remain the gold standard for evaluating an intervention before integration into clinical practice, several challenges exist in translating clinical trial outcomes to patients treated with identical interventions in the real world. Patients enrolled in randomized controlled trials are selected by meeting stringent criteria and often differ significantly from the heterogenous patient population encountered in routine clinical practice.1 Further, clinical trials are often conducted at tertiary care centers in urban settings.
Based on an analysis of the Investigational New Drugs applications submitted in 2015 to the U.S. Food and Drug Administration, most clinical trials require patients to be Eastern Cooperative Oncology Group performance status 0 or 1 and often exclude elderly patients and patients with significant co-morbidities.2,3,4,5 Vulnerable patient populations such as veterans receiving care within the Veterans Health Administration are often under-represented in clinical trials. This suggests that the efficacy of an intervention determined in clinical trials may be substantially different from its effectiveness in the real world, which is often influenced by suboptimal adherence to treatment, higher incidence of comorbid conditions, competing risks of death, and reduced tolerability to treatments.6
While several real-world data (RWD) analyses have confirmed the efficacy of immune checkpoint inhibitors for treatment of advanced non-small cell lung cancer (NSCLC), others continue to challenge the magnitude of efficacy previously shown in randomized controlled trials.7
In a study comparing real world and clinical trial data of patients with advanced NSCLC treated with first- and second-line immunotherapy, the overall survival for patients treated with first-line pembrolizumab was significantly shorter in the real world. The efficacy-effectiveness gap was 0.45, indicating a median survival 55% shorter in patients treated in clinical practice relative to the median survival from the clinical trial. Similarly, in a systematic real-world review of 35,103 patients with previously treated advanced NSCLC who were treated with second-line immunotherapy, the overall survival benefit was lower in patients with poor performance status (ECOG PS ≥2) as compared to patients with ECOG PS <2.8
For patients with unresectable locally advanced or stage III NSCLC, the PACIFIC trial established 12 months of adjuvant durvalumab after definitive concurrent chemoradiotherapy as the “standard-of-care” treatment.9,10 Updated analyses showed a median overall survival of 47.5 versus 29.1 months in the durvalumab and placebo groups respectively at a median follow up of 34 months.11 However, the effect size of durvalumab in the real world has not been extensively measured.
Furthermore, the PACIFIC trial did not include veterans receiving care within the Veterans Health Administration, a population characterized by significant co-morbidities and tobacco exposure. We sought to examine treatment adherence, toxicity, and oncologic outcomes in veterans with stage III NSCLC treated with concurrent chemoradiotherapy with or without adjuvant durvalumab, and correlate outcomes to those reported in the PACIFIC trial using data from the largest integrated healthcare system in the United States.
We identified a cohort of 1006 veterans with stage III NSCLC who received concurrent chemoradiotherapy and at least one dose of durvalumab between November 2017 to April 2021, and 989 veterans who received concurrent chemoradiotherapy alone prior to the approval of durvalumab between January 2015 and December 2016.12 We found that adjuvant durvalumab significantly prolonged both progression-free survival (median PFS 16.9 mo. vs. 9.6 mo.; HR 0.62 (95% CI, 0.55-0.7), p<0.001) and overall survival (median OS 34.7 mo. vs. 19.2 mo.; HR 0.57 (95% CI, 0.50-0.66); p<0.001) .12 To minimize optimistic selection bias in favor of the durvalumab cohort, we excluded patients in the pre-durvalumab cohort who had disease progression prior to the imputed durvalumab start date (defined as 86 days after date of radiation start, which was the median time from radiation start to durvalumab start in the durvalumab cohort).
To compare the real world and clinical trial survival outcomes of patients who received concurrent chemoradiotherapy and durvalumab, we calculated the efficacy-effectiveness factor and hazard ratio for overall survival, comparing patients who received adjuvant durvalumab on our study to those in PACIFIC. The efficacy-effectiveness factor was 0.73, indicating that median survival was 27% shorter in patients treated in VA clinical practice relative to the median survival time registered in the clinical trial receiving identical treatment (HR 1.24 (95% CI, 1.03-1.48), p=0.02).
Furthermore, patients in our study received a shorter median duration of durvalumab therapy as compared to patients in the PACIFIC trial (median duration of durvalumab therapy 215 days vs. 310 days). VA patients also had a higher rate of durvalumab discontinuation due to toxicity (n=212; 21.1%) compared to PACIFIC (n=73; 10.2%).
Our findings are buttressed by other real-world studies of immune checkpoint inhibitor use where overall survival in clinical practice tends to be shorter than that reported in clinical trials.13,14,15,16,17,18 We posit that in our study, several real-world factors including older age, more comorbidities, and greater incidence of immunotherapy related toxicities, including pneumonitis, might have contributed to a lower efficacy-effectiveness gap. Further investigations are warranted to identify factors that lead to higher rates of durvalumab discontinuation, shorter overall survival, and higher rates of toxicity in vulnerable populations with stage III NSCLC.
Registry, case series, and cohort studies have intrinsic downsides, chief among them the lack of a randomized control group. Additionally, the quality of observational research can be limited by limited cohort sizes and a variety of measured and unmeasured bias including immortal time bias, ascertainment bias, and others. However, these clinical research approaches still offer valuable insights into treatment practices and in answering clinically relevant questions.
For example, we identified that timing of adjuvant durvalumab up to 120 days following the completion of chemoradiotherapy in a real world cohort of patients with stage III NSCLC was not associated with progression-free or overall survival detriment, suggesting that the start of durvalumab may be extended without significant concern for compromise in oncologic outcomes. In the actual PACIFIC trial, treatment with Durvalumab was mandated to begin within 42 days of completion of chemo-radiation.19 Real-world data may also be used to further define or validate molecular predictive or prognosis biomarkers in larger cohorts.
As another example, we found that patients with tumor PD-L1 expression of <1% had limited benefit from adjuvant durvalumab.20 Further, real-world data may be used to define safety events, particularly long-term adverse events.
In summary, real-world evidence may be useful to better define effectiveness of treatments in patients who may have been excluded from clinical trials, to collect long term safety data in large cohorts, and to study interventions in more heterogenous patient populations. Therefore, RWD studies, particularly those involving large numbers of patients, can serve as a complement to randomized controlled clinical trials to inform clinical practice.
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