A broader set of clinical trial eligibility criteria proposed by the American Society of Clinical Oncology and Friends of Cancer Research would nearly double the number of patients with advanced non-small cell lung cancer available for enrollment.
R. Donald Harvey, PharmD, BCOP
A broader set of clinical trial eligibility criteria proposed by the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research would nearly double the number of patients with advanced non-small cell lung cancer (aNSCLC) available for enrollment, according to findings presented at the 2019 ASCO Annual Meeting.
The study used enrollment criteria proposed in 2017 to consider 10,500 patients whose records were drawn from ASCO’s CancerLinQ Discovery database. They found that 98.5% of patients would be accepted for aNSCLC trials under the expanded criteria versus 52.3% under traditional criteria. This means that just 1.5% of the patients considered would be rejected for clinical trial participation.
The findings are significant due to the difficulty of accruing patients for clinical trials, investigators said in a release. They said that newer types of drugs have milder adverse event profiles, suggesting that the older standards are unnecessarily strict. In November last year, the National Cancer Institute (NCI) implemented revisions in its clinical trial protocol template to broaden eligibility for clinical trials, based largely on the suggested revisions by ASCO and Friends of Cancer Research. Investigators said more time is needed to determine whether these broader criteria are being widely adopted, but urge all clinical trial sponsors to adopt these criteria.
The expanded criteria employed in this retrospective, observational study allowed for the inclusion of patients with brain metastases, prior or concurrent cancer diagnoses, and creatinine clearance levels ≥30 mL/min compared to the traditionally accepted level of ≥60 mL/min. Patients with limited kidney function would also have been eligible for enrollment under the expanded criteria.
Results demonstrated that under traditional clinical trial enrollment criteria, 5005 patients (47.7%) of the 10,500-patient population would not have been eligible for trial enrollment, compared with only 154 patients (1.5%) who would have been excluded under the expanded criteria. No patients were excluded by brain metastases and prior or concurrent disease under the broadened criteria.
In a subanalysis, investigators concluded that expanded criteria would have permitted higher enrollment of the following: women (44% vs 40%), patients with stage IV disease diagnosis (60% vs 55%), patients who never smoked (16% vs 13%), and patients with nonsquamous types of lung cancer (47% vs 45%).1 The expanded eligibility would also raise the mean age of older patients (67.5 years vs 66.1 years) and increase the number of eligible patients ≥75 years (22.23% vs 16.09%).
Of the 10,500 patients, under traditional criteria 21.5% (2254) would have been excluded for recorded creatinine clearance >60 mL/min, 21.2% (2226) for brain metastases, and 14.4% (1509) for prior or concurrent malignancies.
ASCO’s CancerLinQ Discovery database collects and analyzes real-world data using electronic health record (EHR) data from practices across the United States.
In delivering the results, lead study author R. Donald Harvey, PharmD, BCOP, and director of the Winship Cancer Institute of Emory University’s Phase I Clinical Trials Section in Atlanta, Georgia, noted that traditional eligibility criteria for clinical trials placed unnecessary limitations on trial participants.
“It [is] increasingly difficult to conduct clinical trials necessary to demonstrate safety and efficacy of new therapies,” he said. “Changes to eligibility criteria are particularly important as we step further into the era of targeted therapies, including immunotherapies, that have different safety profiles than highly toxic chemotherapies.” The study authors noted that broader exclusion criteria should be based on compelling scientific rationale.
Harvey et al chose to conduct their study in NSCLC due to the population of more advanced patients and the higher existence of comorbidities, as well as the number of trials available to this patient population. Harvey noted that information about drug-specific and population-specific outcomes in NSCLC are needed so that eligibility criteria can be expanded safely, adding that investigators did not examine other criteria such as lowering the eligibility age, the HIV status of patients, and organ function.
The investigators are now developing other models to analyze differences between people who have undergone treatment for their disease and remained stable compared with those with concurrent brain metastases.
“It is important to point out that we looked at only 3 exclusion criteria of what are, oftentimes, dozens of criteria,” said ASCO Chief Medical Officer Richard L. Schilsky, MD, who serves as an author of the study. “There are still many other reasons patients could be excluded, but this study demonstrated the real value of very carefully thinking through what the inclusion and exclusion criteria are.”
Changes in clinical trial eligibility would not only expand the options available for the treatment of patients with cancer but also provide study data more reflective of real-world populations and lead to more equitable outcomes.
“Only about 3% of patients with cancer in the United States currently enroll in a clinical trial, and restrictive eligibility criteria established in an era before advances we have made in supportive care is one reason for this low number,” said ASCO expert David L. Graham, MD, physician administrator at Levine Cancer Institute in Charlotte, North Carolina. “This study makes the case for universal adoption of broader clinical trial eligibility criteria, such as those proposed by ASCO and Friends of Cancer Research, so that more patients with lung cancer and others have the opportunity to safely participate in potentially lifesaving research.”
Drug developers have expressed concerns about the expanded criteria. “The main concern that we’ve heard is that including a more heterogenous population runs the risk of obscuring the data they are looking for, [by] introducing more adverse events,” Harvey said. “We’ve also heard that the FDA is willing to work with companies to mitigate concerns.” Harvey noted that the goal of the broadened criteria is to make these drugs more applicable to treat patients that physicians are seeing in the clinic.
In 2017, ASCO and Friends of Cancer Research teamed up to draft revisions that affect potential clinical trial participants with preexisting conditions and recommended expanding eligibility to 5 categories of patient: those with brain metastases, prior and current malignancies, HIV and hepatitis infection, organ dysfunction, and those under the age of 18 years. The goal of their draft guidance was to improve trial accrual, ensure optimal patient access, and maximize information learned during trials.
“By expanding its clinical trial eligibility requirements, NCI is helping to ensure that participants in clinical trials better reflect the patients who will eventually receive cancer therapies once they’re applied in routine clinical care,” ASCO President Monica M. Bertagnolli, MD, FACS, said in a previous statement. “These requirements balance patient safety with the need to make sure that clinical trial results are generalizable to the broader patient population.”2
Harvey noted that the NCI's National Clinical Trials Network (NCTN) is updating templates for broadened eligibility and the ASCO Targeted Agent and Profiling Utilization Registry (TAPUR) Study has already begun implementing these criteria. Additionally, in March 2019, the FDA issued 4 draft guidance documents concerning minimum age for pediatric patients, HIV status, organ dysfunction, and brain metastases for public comment.