Trial-ineligible patients more likely to receive immunotherapy despite lack of benefit
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Trial-ineligible patients with advanced cancer appeared nearly twice as likely as trial-eligible patients to receive immunotherapy, despite no evidence of a survival benefit compared with chemotherapy for this population.
The findings of the retrospective cohort study, published in JAMA Oncology, suggest positive results for immune checkpoint inhibitors (ICIs) in phase 3 trials may not translate to the real world, especially in populations traditionally excluded from trials, according to researchers.
“Patients with poor performance status or organ dysfunction are vulnerable to treatment that is not consistent with their goals, and oncologists should counsel these patients appropriately about the uncertainty of immunotherapy's benefit,” Ravi B. Parikh, MD, MPP, assistant professor of medical ethics and health policy and medicine at Perelman School of Medicine at University of Pennsylvania, told Healio.
Parikh and colleagues set out to study how commonly oncologists used immunotherapy in trial-ineligible populations and whether survival benefits seen in phase 3 trials of immunotherapy would translate to this vulnerable population.
“Thirty percent of patients in my practice would be traditionally ineligible for phase 3 trials of immunotherapy due to being ‘unfit,’ ie, being inactive or having lower-than-normal function in their kidneys or liver,” Parikh said. “I'm often tempted to use immunotherapy for these patients rather than chemotherapy because immunotherapy is less toxic. However, this is truly an ‘evidence-free zone,’ because clinical trials exclude these patients, and I had very little idea of how well they would work.”
The analysis included 34,131 adults (median age, 70 years; 69% white; 42% women; 27.3% trial ineligible) who initiated first-line systemic therapy between 2014 and 2019 for newly diagnosed metastatic or recurrent nontargetable non-small cell lung, urothelial cell, renal cell or hepatocellular carcinoma.
Parikh and colleagues assessed the association between trial ineligibility and ICI monotherapy uptake. Next, they analyzed comparative survival outcomes following ICI and non-ICI among trial-ineligible patients. Researchers reported 12-month and 36-month restricted mean survival times (RMSTs) and time-varying HRs of less than 6 months and 6 months or greater.
Results showed the proportion of patients receiving ICI monotherapy increased from 0% to 30.2% among trial-ineligible patients and 0.1% to 19.4% among trial-eligible patients during the 6-year study period.
Additionally, they reported no OS differences among trial-ineligible patients who received ICI monotherapy, ICI combination therapy or non-ICI therapy at 12 months (RMST, 7.8 months vs. 7.7 months vs. 8.1 months) or 36 months (RMST, 15 months vs. 13.9 months vs. 14.4 months). ICI monotherapy, when compared with non-ICI therapy, showed evidence of early harm (inverse probability weighting-adjusted HR within 6 months = 1.2; 95% CI, 1.1-1.2) but late benefit (adjusted HR among patients who survived 6 months = 0.8; 95% CI, 0.7-0.8).
“I suspected that oncologists would use immunotherapy at higher rates for trial-ineligible patients than trial-eligible patients, but I was surprised at how commonly this was occurring — particularly in lung and bladder cancers,” Parikh told Healio. “Such drift in the indication of novel therapies like immunotherapy is more common than I thought.”
Parikh and colleagues wrote that the findings must be validated in prospective phase 3 studies. Meanwhile, clinicians caring 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,” they wrote.
Parikh added that clinical trials should eliminate their traditional exclusions regarding performance status and organ dysfunction.
“Rather, randomized clinical trials should ensure that unfit patients are well-represented in clinical trials of immunotherapy and other novel therapies, so that we can counsel this vulnerable patient population appropriately,” Parikh told Healio.
For more information:
Ravi B. Parikh, MD, MPP, can be reached at University of Pennsylvania, 423 Guardian Drive, Blockley 1102, Philadelphia, PA 19104; email: ravi.parikh@pennmedicine.upenn.edu.
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