Bauernfeind, Jennah J

Abstract Everolimus 10 mg daily is the standard dose for advanced neuroendocrine tumors (NETs), but adverse events frequently necessitate dose reduction. As a result, oncologists often adopt a dose‐escalation strategy starting at 5 mg and increasing the dose as tolerated. In this multicenter study, we evaluated the effect of reduced dose (RD) and standard dose (SD) everolimus on survival, progression, and toxicity in patients with advanced NETs. We conducted a multicenter retrospective cohort study of patients with advanced NETs treated with everolimus at Mayo Clinic and University Hospitals (Cleveland, OH). Patients were grouped by starting dose (5 mg vs. 10 mg). Primary endpoints were overall survival (OS), real‐world progression‐free survival (rwPFS), and adverse events. Multivariable Cox models, inverse probability of treatment weighting (IPTW), and time‐varying dose sensitivity analysis were used to account for confounding and dose crossover. Among 170 patients (48 started on 5 mg; 122 on 10 mg), the 5 mg cohort was older, had worse ECOG PS, and was more heavily pretreated. Median OS was 43.7 months (5 mg) versus 81.5 months (10 mg; log‐rank p = .02). However, after multivariable adjustment ( N = 124 G1–G2 patients; 51 events), the association was no longer statistically significant (adjusted HR, 0.59; 95% CI, 0.31–1.12; p = .11). Median rwPFS was 7.0 versus 12.4 months (log‐rank p = .05); the adjusted rwPFS difference was not statistically significant (HR, 0.95; 95% CI, 0.56–1.61; p = .84). Nearly half (46.7%) of 10 mg starters required dose reduction. Any‐grade toxicity was more common with 10 mg (89% vs. 75%; p = .05). The apparent survival advantage of standard‐dose everolimus was substantially attenuated after adjustment. These findings do not establish dose equivalence and should be interpreted in the context of limited statistical power. Given its more favorable observed tolerability profile, RD everolimus warrants prospective evaluation as a starting strategy for patients at increased risk of treatment‐related toxicity who may not tolerate SD.

PURPOSE Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in various malignancies. However, the high cost of these therapies limits access for much of the global population. This systematic review aims to evaluate the efficacy of low-dose ICIs compared with standard doses in different malignancies, addressing financial and access barriers in global cancer care. METHODS We conducted a systematic review of studies comparing the efficacy of low-dose versus standard-dose ICI regimens in advanced solid tumors. A comprehensive search was performed across multiple electronic databases, including retrospective and prospective studies. Excluded were animal studies, editorials, conference papers, book chapters, and other immunotherapy modalities. Outcomes assessed included overall survival (OS), progression-free survival, and objective response rate. Results were summarized descriptively due to study heterogeneity. RESULTS From 1,010 screened articles, four studies with 435 Asian patients were included, covering a variety of solid tumors. All included studies were with a low quality of evidence and a high risk of bias due to retrospective design. Two studies used weight-based dosing (pembrolizumab <2 mg/kg and nivolumab <2.15 mg/kg), showing similar OS to standard dosing in non–small cell lung cancer (NSCLC) and renal cell carcinoma, respectively. Flat dose regimens in two studies (nivolumab 20 mg or 100 mg once every 3 weeks and pembrolizumab 100 mg once every 3 weeks) also demonstrated comparable OS in NSCLC. CONCLUSION Low-dose ICIs may offer equivalent clinical benefits to standard dosing, potentially reducing costs and expanding access in developing countries. Although awaiting more representative randomized clinical trials, weight-based ICI regimens could be a viable alternative in low- and middle-income countries.