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Uptake and Survival Outcomes Following Immune Checkpoint Inhibitor Therapy Among Trial-Ineligible Patients With
Ravi B Parikh1,2,3,4,5,6, Eun Jeong Min7, E Paul Wileyto8
1Department of Medical Ethics and Health Policy, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Importance:
Immune checkpoint inhibitors (ICIs) are part of standard of care for patients with many advanced solid tumors. Patients with poor performance status or organ dysfunction are traditionally ineligible to partake in pivotal randomized clinical trials of ICIs.
Objective:
To assess ICI use and survival outcomes among patients with advanced cancers who are traditionally trial ineligible based on poor performance status or organ dysfunction.
Design, Setting, And Participants:
This retrospective cohort study was conducted in 280 predominantly community oncology practices in the US and included 34 131 patients (9318 [27.3%] trial ineligible) who initiated first-line systemic therapy from January 2014 through December 2019 for newly diagnosed metastatic or recurrent nontargetable non-small cell lung, urothelial cell, renal cell, or hepatocellular carcinoma. Data analysis was performed from December 1, 2019, to June 1, 2021.
Exposures:
Trial ineligibility (Eastern Cooperative Oncology Group performance status ≥2 or the presence of kidney or liver dysfunction); first-line systemic therapy.
Main Outcomes And Measures:
The association between trial ineligibility and ICI monotherapy uptake was assessed using inverse probability-weighted (IPW) logistic regressions. The comparative survival outcomes following ICI and non-ICI therapy among trial-ineligible patients were assessed using treatment IPW survival analyses. Because we observed nonproportional hazards, we reported 12-month and 36-month restricted mean survival times (RMSTs) and time-varying hazard ratios (HRs) of less than 6 months and 6 months or greater.
Results:
Among the overall cohort (n = 34 131), the median (IQR) age was 70 (62-77) years; 23 586 (69%) were White individuals, and 14 478 (42%) were women. Over the study period, 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. Trial ineligibility was associated with increased ICI monotherapy use (IPW-adjusted odds ratio compared with non-ICI therapy, 1.8; 95% CI, 1.7-1.9). Among trial-ineligible patients, there were no overall survival differences between ICI monotherapy, ICI combination therapy, and non-ICI therapy at 12 months (RMST, 7.8 vs 7.7 vs 8.1 months) or 36 months (RMST, 15.0 vs 13.9 vs 14.4 months). Compared with non-ICI therapy, ICI monotherapy showed evidence of early harm (IPW-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).
Conclusions And Relevance:
In this cohort study, compared with trial-eligible patients, trial-ineligible patients with advanced cancers preferentially received first-line ICI therapy. A survival difference was not detected between ICI and non-ICI therapies among trial-ineligible patients. Positive results for ICI in phase 3 trials may not translate to this vulnerable population.
Insights
Trial-ineligible patients with advanced cancers increasingly receive immune checkpoint inhibitors (ICIs). However, ICI use did not improve survival in this group, suggesting phase 3 trial results may not apply to vulnerable populations.
Area of Science:
- Oncology
- Immunotherapy
- Clinical Trials
Background:
- Immune checkpoint inhibitors (ICIs) are standard care for advanced solid tumors.
- Patients with poor performance status or organ dysfunction are often excluded from clinical trials.
Purpose of the Study:
- To evaluate the use and survival outcomes of ICIs in advanced cancer patients who are traditionally ineligible for clinical trials.
- To compare ICI therapy with non-ICI therapy in this vulnerable patient population.
Main Methods:
- Retrospective cohort study of 34,131 patients across 280 US community oncology practices (2014-2019).
- Identified trial-ineligible patients based on performance status (ECOG ≥2) or organ dysfunction.
- Used inverse probability weighting (IPW) to assess ICI monotherapy uptake and survival outcomes.
Main Results:
- Trial-ineligible patients showed increased first-line ICI monotherapy use (30.2% vs 19.4% in trial-eligible).
- No significant overall survival difference was detected between ICI (mono/combo) and non-ICI therapies in trial-ineligible patients at 12 or 36 months.
- ICI monotherapy demonstrated early harm (HR 1.2 within 6 months) but late benefit (HR 0.8 after 6 months) compared to non-ICI therapy.
Conclusions:
- Trial-ineligible patients with advanced cancers are increasingly receiving first-line ICI therapy.
- ICI therapy did not show a survival benefit compared to non-ICI therapies in this population.
- Findings suggest that the efficacy of ICIs observed in phase 3 trials may not translate to trial-ineligible patients.
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