Trial-Ineligible Patients With Advanced Solid Tumors More Likely to Receive Immune Checkpoint Inhibitor Monotherapy


Patients with advanced cancers who were ineligible for trials were more likely to receive frontline immune checkpoint inhibitor monotherapy than patients with the same advanced cancers who were eligible for trials.

Patients with advanced solid cancers who did not meet eligibility criteria for clinical trials were more likely to preferentially receive first-line immune-checkpoint inhibitor (ICI) monotherapy when compared with patients who did meet criteria for eligibility, according to results from a retrospective cohort study published in JAMA Oncology.1

The proportion of patients who received ICI monotherapy increased from 0% to 30.2% for patients who were trial ineligible compared with an increase from 0.1% to 19.4% for patients who were trial eligible.

“Despite the lack of evidence and benefits for this vulnerable population, we found that oncologists used immunotherapy at faster rates for trial-ineligible patients,” Ravi B. Parikh, MD, an assistant professor of Medical Ethics & Health Policy and Medicine at Penn, said in a press release.2 “However, health care providers of patients with poor functional status or organ dysfunction should not assume immunotherapies will confer the same benefit as the populations studied in trials.”

The cohort included 34,131 patients of whom 26,904 (78.8%) had advanced non–small cell lung cancer (NSCLC), 3382 (9.9%) had urothelial carcinoma (UCC), 3323 (9.7%) had renall cell carcinoma (RCC), and 522 (1.5%) had hepatocellular carcinoma (HCC). Patients had to be aged 18 years or older and to have undergone first-line systemic therapy between January 1, 2014, and December 31, 2019 to be included in the analysis.

Trial eligibility status was also necessary, with the research team defining ineligibility by common exclusion criteria for phase 3 clinical trials focusing on ICIs such as an ECOG performance score of 2 or higher or the presence of organ dysfunction.

The primary end point for assessing ICI use was the receipt of first-line ICI monotherapy. Overall survival (OS) was the primary outcome for analyzing ICI comparative survival, defined as first-line treatment initiation to death to assess.

Median age was 70 years (IQR, 62-77), most patients were White (69%), and most were women (42%). A total of 27.3% of patients were ineligible for trials, with 71% of those having an ECOG performance score of 2 or greater and 37% with organ dysfunction.

Overall, trial ineligibility was associated with an increased use of ICI monotherapy compared with non-ICI therapy (inverse probability–weighted [IPW]-adjusted odds ratio [aOR], 1.80; 95% CI, 1.70-1.92). Patients with NSCLC (aOR, 1.95; 95% CI, 1.80-2.10) and UCC (aOR, 2.48; 95% CI, 2.11-2.92) had the strongest association of trial ineligibility and ICI monotherapy.

Median follow-up for patients who were trial ineligible was 7.8 months (IQR, 3.4-16.5). Median OS was 9.7 months for patients who underwent ICI monotherapy, 9.3 months for those receiving ICI combination therapy, and 8.8 months for patients receiving non-ICI therapy.

Moreover, data revealed an association between ICI monotherapy and higher mortality during the first 6 months post-treatment for trial-ineligible patients with NSCLC (aHR, 1.13; 95% CI, 1.05-1.23), UCC (aHR, 1.63; 95% CI, 1.36-1.95), and HCC (aHR, 2.53; 95% CI, 1.75-3.65). Mortality was lower for trial-ineligible patients who survived 6 months with NSCLC (aHR, 0.77; 95% CI, 0.72-0.82), UCC (aHR, 0.77; 95% CI, 0.64-0.92), and HCC (aHR, 0.89; 95% CI, 0.46-1.71) when compared with non-ICI therapy.

“While it makes sense to consider novel therapies like immunotherapies for trial-ineligible patients, it is essential to be alert when using ICI, and to be honest with the limitations of current supporting research to date,” Ronac Mamtani, MD, MSCE, assistant professor of Hematology-Oncology at the Abramson Cancer Center at Penn, said in a press release. “Even though ICIs have a better side-effect profile for most patients, positive results in phase 3 trials may not necessarily translate to improved quality of life and survival for all patients.”


  1. Parikh RB, Min EJ, Wileyto EP, et al. Uptake and Survival Outcomes Following Immune Checkpoint Inhibitor Therapy Among Trial-Ineligible Patients With Advanced Solid Cancers. JAMA Oncol. Published online November 4, 2021. doi:10.1001/jamaoncol.2021.4971
  2. Penn Study Finds Solid-Tumor Cancer Patients Ineligible for Clinical Trials Receive Immunotherapy at Greater Rates Despite Lack of Benefits. News release. Penn Medicine. November 9, 2021. Accessed November 15, 2021.
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