Immunotherapy Use Increased in Patients Ineligible for Cancer Trials, Highlighting the Need for More Research in Vulnerable Populations


The use of immunotherapy in patients with advanced cancers and decreased fitness levels or organ function increased from 2014 to 2019, although trials for this treatment typically exclude this population.

Patients with advanced cancers who were not eligible for clinical trials were nearly twice as likely to receive first-line immune checkpoint inhibitors compared with those who participated in trials, although this treatment had no overall survival benefit and could cause early harm, according to recent study results.

Findings from this study, which were published in JAMA Oncology, suggest that patients with poor physical status or organ dysfunction should have careful discussions with their cancer teams about the potential risks and benefits of immune checkpoint inhibitors if they are considering it as a treatment option.

“Immunotherapies are used at a disproportionately higher amount in traditionally trial-ineligible patients compared to trial-eligible patients, but their effectiveness in trial-ineligible is not analogous to what's seen in clinical trials,” said Dr. Ravi B. Parikh, an assistant professor in the Departments of Medical Ethics and Health Policy and of Medicine at the University of Pennsylvania in Philadelphia, in an interview with CURE®. “In fact, it didn't really look like there was a benefit of these novel immunotherapies at all compared to traditional chemotherapy in this population, while there was a benefit in published phase III trials.”

Parikh added that results from this study are “the strongest evidence to date that quantifies the uptake and effectiveness of these drugs in this vulnerable patient population. I think the key message is we need better and more trials in patients traditionally excluded from clinical trials so that we can adequately counsel our patients.”

Ineligibility in Clinical Trials

Approximately 30% of all patients in oncology clinics are ineligible for clinical trial participation due to their fitness level or organ function, Parikh explained, yet decisions on novel cancer therapies for these patients are often generalized from clinical trials.

“Essentially, we're making decisions in somewhat of an evidence-free zone for that large segment of our patient population,” he told CURE®. “It's really important because we need to be able to adequately counsel those patients, particularly with regard to the expected benefit of therapies, or whether other courses of care would be more appropriate. We wanted to shed some light not only on how often immunotherapies were being used in this understudied population but also just how effective they were.”

To do so, Parikh and his colleagues analyzed data from 34,131 patients (median age, 70 years; 42% women), of whom 27.3% were trial ineligible. All patients were treated with first-line systemic therapy from 2014 to 2019 for newly diagnosed metastatic or recurrent non-targetable non-small cell lung, renal cell, urothelial cell or hepatocellular carcinoma. Patients were considered ineligible for clinical trials if they had a low physical performance status or the presence of liver or kidney dysfunction.

From 2014 to 2019, the use of immune checkpoint inhibitors in patients ineligible for clinical trials increased from 0% to 30.2%, whereas use in trial-eligible patients increased from 0.1% to 19.4%. Through this, trial ineligibility in the study was linked with increased use of immune checkpoint inhibitor monotherapy.

“Probably the most stark finding from our research is how rapidly treatments like immunotherapy have been (taken up), particularly in groups that haven't been studied,” Parikh said. “This presents a potential value crisis in oncology care because novel therapies are expensive and are not going to stop in oncology care. We need to really have a value focus in mind with when it comes to using these novel drugs in traditionally trial-ineligible patients because oncology care is on the cusp of bankrupting the health care system.”

At 12 months, there was no difference among trial-ineligible patients regarding overall survival in those who received immune checkpoint inhibitor monotherapy (7.8 months), immune checkpoint inhibitor combination therapy (7.7 months) and non-immune checkpoint inhibitor therapy (8.1 months). This persisted at 36 months (15 months versus 13.9 months versus 14.4 months, respectively).

Immune checkpoint inhibitor monotherapy was more likely to cause early harm within six months compared with non-immune checkpoint inhibitor therapy. Despite this, these patients had a late benefit if they survived at six months.

“Prior to our study, no study had looked at rates of immunotherapy use, arguably the fastest growing and most promising therapeutic category in oncology care over the past five to 10 years, among trial-ineligible patients across cancers,” Parikh said. “ Similarly, no clinical trial has assessed their effectiveness since clinical trials traditionally exclude this population systematically.”

‘What About for Me?’

Parikh explained that both patients and oncologists want more evidence in this area to help make more informed decisions.

“As a patient, … I would want the evidence to be out there for myself because my No. 1 goal as a patient — and as an oncologist too — is to make sure a treatment has the best chance of working, that we're not either using an ineffective therapy or throwing therapies at a patient where it wouldn't be expected to be a benefit. We should be demanding more both as patients and as clinicians.”

Given the available evidence in this area, or lack thereof, Parikh advised that patients should focus on themselves especially when talking with their cancer team about treatment decisions.

“(If I were a patient), the key question that I would ask my oncologist is, ‘we’ve heard about how effective these treatments are in a healthier population. But what about for me? Given my type of cancer, its extensiveness, and my baseline health status, what can I expect about this treatment’s effectiveness?’ That’s important to know: simply saying that this clinical trial has shown that novel therapies are effective isn't enough when you dig down into the details and see who’s really participated in that clinical trial? And does that patient that was included in a trial look like me? I think the No. 1 question I'd ask my oncologist, based off the studies, how do I think about treatment effectiveness, for me, in particular, rather than just the average patient included in the clinical trial?”

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