The study, by Ravi B. Parikh, MD, an assistant professor of medical ethics and health policy and medicine at the University of Pennsylvania, Philadelphia, is an analysis of patient data from 280 U.S.-based community oncology practices. It included 34,131 patients who received first-line systemic therapy with immune checkpoint inhibitors (ICIs), or other treatment, between January 2014 and December 2019 for newly diagnosed metastatic or recurrent non–small cell lung cancer (NSCLC), urothelial cell cancer (UCC), renal cell cancer (RCC), or hepatocellular carcinoma (HCC). Researchers examined survival outcomes between patients who were eligible to participate in clinical trials with those who were deemed ineligible but may have still received ICIs.
For patients with poor performance status or organ dysfunction, participating in randomized clinical trials for immune checkpoint inhibitors is largely out of reach because of advanced disease, but it is not unusual for these patients to be accepted into clinical trials, a decision sometimes referred to as “desperation oncology,” the authors wrote.
In this study of 34,131 patients, 9,318 were considered ineligible to participate in ICI clinical trials because of advanced disease or organ dysfunction, yet up to 30% of these patients were treated with ICIs by their physician outside of a clinical trial. Dr. Parikh and colleagues found no overall survival differences between patients deemed ineligible for clinical trials, but were ultimately treated with ICI monotherapy, ICI combination therapy, or other treatments at 12 and 36 months. In fact, ICI monotherapy appeared to be harmful within 6 months of starting treatment.
“Clinicians who care for patients with poor performance status or organ dysfunction should be cautious about ICI use and carefully weigh expected survival gains against the potential for early mortality and adverse effects,” the authors wrote. They found the efficacy of ICI treatment alone, or in combination with other treatment, can be worse among trial-ineligible patients than patients who met the criteria for clinical trials.
No survival benefit was found for trial-ineligible patients who were treated with ICI monotherapy or combination therapy. Overall survival rates were similar at 12 and 36 months for both treatment groups. The overall median survival was less than 10 months, but 40% of trial ineligible patients treated with ICIs died within 6 months.
The use of ICIs for patients with poor performance status was found to be associated with lower hospice enrollment, more inpatient deaths, and more treatment during the last month of life. “It is critical to ensure that vulnerable, trial-ineligible patients are not exposed to non–evidence-based therapies that could cause harm and contradict patient goals,” the authors wrote.
The harms of treating unfit patients
The use of immune checkpoint inhibitor monotherapy in trial-ineligible patients is concerning, the authors said, because for patients with UCC and NSCLC, the standard of care is platinum-based chemotherapy. For patients with HCC and RCC, the standard of care is oral anti–vascular endothelial growth factor therapy. Immune checkpoint inhibitors may be prescribed in these cases to avoid side effects associated with other therapies, despite the lack of evidence showing that ICIs are effective in these cases.
“Individuals with poor performance status and/or organ dysfunction are vulnerable to receiving treatments that may not benefit them or cause disproportionately high side effects,” Dr. Parikh said in an interview. “Immunotherapy causes fewer side effects overall and is an attractive option, but there is no good phase 3 evidence that immunotherapy has benefits in this population.
“Physicians are preferentially using immunotherapy for unfit patients despite the fact that these individuals are usually excluded from clinical trials. Trial-ineligible patients – despite making up 30% of the cancer population – are different from patients studied in clinical trials. They are generally sicker, older and more prone to treatment adverse effects (including death), However, excluding these groups means that we don’t have good data on what treatments could benefit this vulnerable group. Thus, we are usually left to extrapolating results from healthier patients to unhealthy patients which risks giving them the wrong treatment,” he said.
Phase 3 trials needed for patients with poor performance
This retrospective study included 34,131 patients (median age, 70 years; 42% women) of which 27.3% had poor performance status and/or organ dysfunction and were classed as trial ineligible. The researchers assessed the use and overall survival outcomes following first-line ICI and non-ICI therapy that was initiated from January 2014 through December 2019.
Over the course of the study, the proportion of patients receiving ICI monotherapy increased from 0%-30.2% among trial-ineligible patients and from 0.1%-19.4% among eligible patients. However, among trial-ineligible patients, there were no overall survival differences between treatment with ICI monotherapy, ICI combination therapy and non-ICI therapy at 12 and 36 months.
Among trial-ineligible patients, ICI use was linked to a 14%-19% greater risk of death during the first 6 months after ICI initiation, but a 20% lower risk of death among those who survived 6 months after ICI initiation. Further, ICI combination therapy was associated with potential early harm among trial-ineligible patients.
“Phase 3 trials are sorely needed in patients with poor performance status or organ dysfunction so that we can adequately counsel patients who are unfit about expectations with novel cancer therapies,” Dr. Parikh said.
The cohort only included patients who received systemic therapy, which is a limitation of the study, so conclusions cannot be made about the efficacy of systemic therapy versus no systemic therapy in trial-ineligible patients.
Dr. Parikh reported nonfinancial support from Flatiron Health, grants from Humana, personal fees and equity from GNS Healthcare and Onc.AI, along with personal fees from the Cancer Study Group and Nanology outside the submitted work.