CLINICAL TRIALS INVESTIGATING the effectiveness of new drugs exclude many of the sickest patients, but some patients who would not be eligible for trials are treated with these new therapies when they are available in the clinic. This phenomenon was explored in a recent study in JAMA Oncology showing that some new immunotherapy treatments may not help less fit patients live longer. The researchers emphasized the need for physicians to look to “real-world” findings, in addition to trial results, to get a more realistic picture of how to treat these individuals.

“Patients often ask, will this drug work for me? And the truth is, we don’t know,” says Ronac Mamtani, a co-author on the study and an oncologist specializing in bladder cancer at Penn Medicine’s Abramson Cancer Center in Philadelphia. “The only way to answer this question is to use data from patients outside of clinical trials, which became our focus.”

The team of researchers looked at 34,131 patients treated in 280 community oncology practices. Patients had a median age of 70, and 27% were considered ineligible to participate in clinical trials, according to common exclusion criteria—performance status of grade 2 or higher, signifying diminished capabilities, or organ dysfunction. These patients were first treated between January 2014 and December 2019 for newly diagnosed metastatic or recurrent solid tumors. Of interest to the researchers was the use and effect of treatment with immune checkpoint inhibitors (ICI), a type of immunotherapy that interferes with molecules that tumors deploy to neutralize immune system defenses. Participants were placed into one of three groups based on whether they were treated with a single ICI drug, a combination of drugs including one or more ICIs, or a drug other than an ICI.

The study showed that trial-ineligible patients were nearly twice as likely as healthier patients to receive immunotherapy in the clinic, yet no survival difference was seen among trial-ineligible patients who received the different types of treatment. The study concluded that phase III trials showing success with ICIs may not translate to the clinic, where patients tend to be older, sicker and have more organ dysfunction than clinical trial participants.

Why use these drugs at all with less fit patients? In general, ICI therapy is associated with improved survival for patients with the solid-tumor cancers treated in the study: advanced non-small cell lung cancer, urothelial cell carcinoma, renal cell carcinoma and hepatocellular carcinoma, a type of liver cancer. In addition, ICIs have fewer toxic side effects than chemotherapy.

“Many oncologists are reluctant to use chemotherapy in unfit patients. Immunotherapy seems like a novel, less toxic therapy, and so many of us use it,” even with sicker patients, says oncologist Ravi Parikh, an assistant professor of medical ethics and health policy and medicine at the University of Pennsylvania and a study co-author. “However, we often use ICIs without specific knowledge of how effective they will be in this sicker population.”

Medical oncologist Bradley McGregor, clinical director for the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, says that retrospective research like this study, which he did not participate in, is important because it gives clinicians real-world data about how very sick patients fare when given new treatments. This information helps clinicians form a real-world understanding of what saves lives, what improves a patient’s condition, and what doesn’t.

“Immunotherapy is amazing when it works,” says McGregor, a specialist in genitourinary cancers, but its role in treatment varies depending on the disease. “In bladder cancer, we’re looking to try chemotherapy and then add immunotherapy. In renal-cell cancer, immunotherapy is the gold standard. It really comes down to taking a look at the data we have for that cancer,” McGregor says.

Physicians aren’t the only ones attracted to immunotherapy. Even very sick patients may want to try what seems like a miracle drug. In some cases, “I really worry that while we may hit that home run with immunotherapy, it’s more likely that we won’t,” McGregor says. “It really comes down to having a discussion with the patient about what are the goals of therapy.” One option may be maintaining “the best quality of life for as long as possible,” even if it means moving the patient to palliative care, he says.

Efforts are underway to broaden eligibility criteria for potential clinical trial subjects in hopes of speeding up the trial process and aligning trial results more accurately with real-world outcomes. That doesn’t necessarily mean that truly unfit patients will be included in clinical trials, says McGregor. “You reach a point where the risks of any therapy outweigh the potential benefits,” he says.

“It is a bit of a Catch-22,” Mamtani says. “On one hand, we need to broaden eligibility criteria. On the other, we need to remind ourselves that the purpose of inclusion and exclusion criteria is to protect the safety of trial patients.” 

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