Patients with treatment-refractory tumors who received eligibility and testing waivers to participate in a large basket/umbrella oncology trial demonstrated similar rates of clinical benefit and adverse events compared with patients who participated in the trial without waivers, according to recent findings published by van Berge Henegouwen et al in Clinical Cancer Research.
Background
Eligibility requirements for clinical trials help protect patients whose comorbidities may put them at an additional risk of severe harm from adverse treatment-related events and help ensure that analyses are performed on a carefully controlled population—minimizing outliers that could skew the data. However, the patients who will eventually receive the treatments are not homogeneous. As a result, when new therapies become available, they have not always been tested in patients with diverse backgrounds and medical histories.
In a previous study published by Mitchell et al in JCO Oncology Practice in 2015, researchers revealed that 39% of patients treated for renal cell carcinoma in clinical practice wouldn’t have been eligible for the trials that led to the approval of the drugs they received. Additionally, among the patients in the general population who were treated with osimertinib for non–small cell lung cancer, 62% of them wouldn’t have been eligible for the phase II trial.
“It is well known that results in an ‘ideal’ population do not always translate to the real-world population,” explained senior study author Hans Gelderblom, MD, Chair of the Department of Medical Oncology at the Leiden University Medical Center in the Netherlands. “Eligibility criteria are often too strict, and educated exemptions by experienced investigators can help individual patients, especially in a last-resort trial,” he added.
Such exemptions—which allow patients to participate in trials that they would otherwise be ineligible for—can include a lab test slightly outside the eligibility range, a necessary imaging scan completed outside the recommended window, or a tumor that could not be biopsied for safety reasons. Whether these exemptions or, by extension, the broadening of clinical trial eligibility criteria lead to poorer patient outcomes has not yet been comprehensively evaluated.
Study Methods and Results
In the recent study, the researchers examined the effects of protocol waivers on patient outcomes in the Drug Rediscovery Protocol trial—a pancancer basket/umbrella trial matching 1,019 patients who had treatment-refractory tumors with off-label targeted therapies on the basis of their tumors’ genetic profiles between September 2016 and September 2021. They noted that 82 patients received a protocol waiver.
The researchers then grouped the reasons for the waivers into four categories: eligibility criteria exceptions, out-of-window testing, treatment exceptions, and testing exceptions. The most common waivers granted were exceptions to eligibility criteria, frequently because of out-of-range lab tests, whereas the second most common waivers granted were for testing exceptions, often exemptions from a biopsy.
After a follow-up of 16 weeks posttreatment, the researchers discovered that the clinical benefit rate was 40% among the patients who received a protocol waiver compared with 33% among those who didn’t receive a waiver. Similarly, the median overall survival was 11 months among the patients who were granted waivers vs 8 months among those who weren’t granted waivers.
Further, the patients who received waivers experienced similar rates of severe adverse events compared with those who didn’t receive waivers (39% vs 41%, respectively). After evaluating the likelihood that each severe adverse event was caused by a protocol waiver, the researchers reported that the relationship between waivers and severe adverse events was “unlikely” in 86% of the patients and “possible” for 14% of them. The rates of treatment discontinuation as a result of toxicity or disease progression during the first treatment cycle were similar among the patients who did and didn’t receive waivers.
Conclusions
Although the protocol exceptions examined in the trial were minor, they could have broader implications for the design of clinical trial eligibility criteria. The limitations of the study included a broad diversity in cancer types, treatments, and reasons for protocol exemptions among the participants, which, while improving the generalizability of the findings, precluded specific subgroup analyses. Additionally, because the likelihood of clinical benefit was an integral part of physicians’ decision to grant waivers, the researchers suggested that it was possible the patients who received waivers were positively selected for clinical benefit compared with the general study population.
“These findings advocate for a broader and more inclusive design when establishing novel trials, paving the way for a more effective and tailored application of cancer therapies in patients with advanced or refractory disease,” concluded Dr. Gelderblom.
Disclosure: The research in this study was funded by the Stelvio for Life Foundation, the Dutch Cancer Society, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, pharma&, Eisai, Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, and Roche. For full disclosures of the study authors, visit aacrjournals.org.
