Weight-based immunotherapy dosing may benefit patients with cancer and high BMI
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Patients with cancer and overweight or obesity had better outcomes with immune checkpoint inhibitors than lighter patients, but only when they received weight-based dosing of the therapy, study results showed.
In contrast, smaller patients tended to have better outcomes with fixed-dose immunotherapy, according to the analysis, published in Journal for ImmunoTherapy of Cancer.
“These findings were observed for overall survival, progression-free survival and radiographic response. They also persisted after controlling for multiple clinical variables, including demographics, tumor characteristics and receipt of concurrent therapies,” David E. Gerber, MD, professor of internal medicine in the division of hematology and oncology at UT Southwestern Medical Center and associate director of clinical research at Harold C. Simmons Comprehensive Cancer Center, told Healio.
Previous studies had examined the relationship between immune checkpoint inhibitor (ICI) efficacy and weight, but that research included patients who received them dosed according to body weight, before fixed-dosed regimens became widespread in 2016, Gerber said. Thus, Gerber and colleagues sought to determine whether patients with overweight and obesity would still have better outcomes with fixed-dose ICIs.
The analysis included 297 patients with cancer (median age, 68 years; range 27-92; 60% men; 76% non-Hispanic white) who received ICI therapy at UT Southwestern between November 2015 and December 2019. Among them, 204 received fixed dosing and 93 received weight-based dosing. The most common cancer types were non-small cell lung cancer (53%) and melanoma (19%).
Researchers compiled data including age, sex, BMI, ICI type, dosing strategy, OS, PFS and radiographic response, and they compared clinical outcomes between patients with low BMI (< 25 kg/m2, n = 121) and high BMI, or overweight ( 25 kg/m2, n = 176) with Kaplan-Meier curves, Cox regressions and Pearson product-moment correlation coefficients.
Median follow-up was 323 days.
Results showed associations of high vs. low BMI with improved PFS (median, 305 days vs. 160 days; HR = 0.69; 95% CI, 0.51-0.94) and a trend toward improved OS (median, 503 days vs. 414 days; HR = 0.77; 95% CI, 0.57-1.04).
However, improvements among the overweight cohort appeared limited to those receiving weight-based vs. fixed ICI dosing in terms of PFS (HR = 0.53; 95% CI, 0.3-0.62 vs. HR = 0.79; 95% CI, 0.54-1.14) and OS (HR = 0.56; 95% CI, 0.33-0.95 vs. HR = 0.89; 95% CI, 0.62-1.29).
“Even when we accounted for differences in tumor and treatment types, [patients with overweight] lived twice as long as smaller patients if they received weight-based dosing. However, there was no difference if they received fixed-dose immunotherapy,” Gerber said in a press release.
Researchers found no associations of BMI with PFS or OS in multivariable analysis, but they did observe a trend toward an association of overweight and weight-based dose interaction with PFS (HR = 0.53; 95% CI, 0.26-1.1), as well as an association of this interaction with OS (HR = 0.5; 95% CI, 0.25-0.99).
An analysis of radiographic response showed a trend toward a greater reduction in tumor measurements with weight-based dosing among patients with overweight, whereas with fixed dosing, researchers observed no association between BMI and radiographic response.
Notably, a subset analysis showed the association between BMI, ICI dosing strategies and clinical outcomes appeared limited to men.
“This is an important observation that certainly deserves more investigation,” Gerber told Healio. “Earlier studies have suggested that muscle mass may drive the benefit of heavier weight, as skeletal muscle may provide key nutrients for immune cell function such as glutamine. However, other studies have shown that adipose tissue and leptin may account for weight-associated outcomes through production of inflammatory cytokines and dysfunction of the PD-1 pathway. Clearly more research in this area is needed.”
Researchers noted study limitations, including use of data limited to a single-institution patient cohort, which may not be generalizable across centers, and that the proportion of patients with overweight in their population was lower than that of the general U.S. population (59% vs. 74%).
Further research into the associations between patient characteristics and ICI dosing strategy is warranted, Gerber and colleagues wrote, noting the increasing prevalence of overweight and obesity both nationally and globally. They also called for more studies on ICIs in general.
“Dose considerations for immune checkpoint inhibitors are more complex than for other cancer treatments,” Gerber said. “While conventional chemotherapy and molecularly targeted therapies directly attack cancer cells, checkpoint inhibitors work indirectly through the patient’s immune system. The identification of pharmacodynamic markers to help link checkpoint inhibitor dose, serum concentrations and antitumor effects is a priority.”
For more information:
David E. Gerber, MD, can be reached at Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Mail Code 8852, Dallas, TX 75390; email: david.gerber@utsouthwestern.edu.
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