Trials for advanced renal cell carcinoma often use restrictive eligibility criteria
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Many contemporary clinical trials for metastatic renal cell carcinoma incorporate restrictive eligibility criteria, according to study results.
“For instance, HIV positivity, as well as hepatitis B and C positivity, were commonly cited exclusion criteria despite limited evidence that these criteria significantly impact clinical outcomes,” Daniela V. Castro, MS, clinical research associate in medical oncology at City of Hope, said during a presentation at International Kidney Cancer Symposium: North America. “Broadening eligibility criteria will ensure that resulting trial data will be more representative of real-world patient populations.”
In 2021, ASCO and Friends of Cancer Research issued a joint statement that emphasized the need to broaden eligibility criteria to increase patient accrual, expand access to investigational therapies and improve the generalizability of study results.
“[Although] eligibility criteria intend to define a specific study population and prioritize patient safety, these criteria often are based on antiquated standards and may not be reflective of real-world practice,” Castro said.
Castro and colleagues aimed to characterize the inclusion and exclusion criteria of metastatic renal cell carcinoma conducted during the past decade.
Researchers used ClinicalTrials.gov to identify phase 1 to phase 3 studies that evaluated adults who received systemic interventions. They excluded trials that evaluated localized treatment or prognostic tools, as well as those that included multiple cancer types or lacked sufficient study information.
Investigators stratified eligibility criteria into three categories — exclusion, for trials that used rigid language and explicitly excluded patients; conditional inclusion, for trials that cited conditions under which patients could be considered for enrollment; or not reported, for trials that did not cite certain eligibility criteria.
The analysis included 112 trials that evaluated combination therapy (42.9%), targeted therapy (39.3%), immunotherapy (16.1%) or chemotherapy (1.8%). The majority (86.6%) were phase 1, phase 1/phase 2, or phase 2.
More than one-third (35.7%) of trials had been completed, whereas 28.6% were active but not recruiting and 33% were still recruiting. Most trial participants had clear cell renal cell carcinoma (57.1%) and ECOG performance status of 0 or 1 (65.8%).
The most common exclusion criteria observed in the analyzed trials included HIV positivity (74.1%), hepatitis B/C positivity (53.6%), brain metastases (33%) and concurrent malignancies, defined as any additional primary tumor or malignancy within the prior 5 years (8%).
The most common conditional inclusion criteria included concurrent malignancies (72.3%), brain metastases (47.3%), hepatitis B/C positivity (27.7%) and HIV positivity (7.1%).
Trials that evaluated chemotherapy (100%), immunotherapy (94.4%) and combination therapy (87.5%) more often included HIV positivity as an exclusion criterion than trials designed to assess targeted therapy (50%). Only 2.1% of trials that assessed combination therapy and 15.9% of those that assessed targeted therapy established HIV positivity as a conditional inclusion criterion.
Trials that evaluated immunotherapy (77.8%) and combination therapy (64.6%) classified hepatitis B/C positivity as an exclusion criterion more often than trials that assessed chemotherapy (50%) or targeted therapy (31.8%). Half of trials that assessed chemotherapy used hepatitis B/C positivity as a conditional inclusion criterion, compared with 34.1% of those that assessed targeted therapy, 25% of those that evaluated combination therapy and 16.7% of trials that assessed immunotherapy.
The percentage of trials that used brain metastases as an exclusion criterion appeared more consistent by evaluated treatment modality (chemotherapy, 50%; targeted therapy, 36.4%; combination therapy, 33.3%; and immunotherapy, 22.2%). Half of trials that evaluated chemotherapy, combination therapy and immunotherapy established brain metastases as a conditional inclusion criterion, as did 43.2% of trials for targeted therapy.
The majority of trials established concurrent malignancies as a conditional inclusion criterion (chemotherapy, 100%; immunotherapy, 83.3%; combination therapy, 77.1%; and targeted therapy, 61.4%).
Researchers acknowledged study limitations, including the fact eligibility criteria are inconsistently reported.
“As with other types of disparities research, barriers of enrollment — including eligibility criteria — need to be re-evaluated in future studies in order to avoid excluding patients from clinical trials unless there is articulated concern for patient safety or toxicity as supported by evidence in current literature.”
Perspective
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Moshe Ornstein, MD, MA
Simply put, the eligibility criteria for metastatic renal cell carcinoma clinical trials are overly restrictive. This is the clear and provocative conclusion of this abstract.With their analysis, the authors highlight a significant limitation in the current clinical trial landscape in renal cell carcinoma. Indeed, these data indicate two specific concerns. The first is that using inclusion/exclusion criteria that may be clinically insignificant makes trials more challenging to conduct because many patients are unnecessarily excluded. This slows trial accrual, limits innovation, and delays novel therapeutics from changing the treatment landscape.
The second issue these data highlight is that the clinical trials being conducted in metastatic renal cell carcinoma are not reflective of the patient population seen in real-world oncology clinics. In clinical practice, it is not unusual to see patients with brain metastases, additional malignancies that occurred within the previous 5 years, and other common inclusion/criteria used in renal cell carcinoma clinical trials. In other words, do our clinical trials truly represent the real-world patients? Can the results of the trials be accurately extrapolated to those patients?
It is important to note, however, that these restrictive criteria are not limited to renal cell carcinoma trials. These are common trial inclusion/exclusion criteria in other cancers, as well. Moreover, one must recognize the rationale for such criteria, which is that pharmaceutical companies, cooperative groups and clinical investigators want the clinical trial patient population to be as refined as possible to ensure that other comorbidities do not negatively impact trial results. They want trials to reflect the activity of therapy and not be influenced by other patient factors.
However, despite these rationale, the data presented serve to challenge the research community to be more liberal in their inclusion/exclusion criteria and create clinical trials that are more reflective of the real-world patient population.
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Castro DV, et al. Abstract 3. Presented at: International Kidney Cancer Symposium: North America; Nov. 4-5, 2022; Austin, Texas.
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