Date of Award

2020

Embargo Period

12-31-2022

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Public Health Sciences

College

College of Graduate Studies

First Advisor

Kristin Wallace

Second Advisor

Kelly Hunt

Third Advisor

Mulugeta Gebregziabher

Fourth Advisor

Bruce Thiers

Fifth Advisor

Chrystal Paulos

Sixth Advisor

John Wrangle

Abstract

Background: Recent gains in melanoma mortality have been attributed, in part, to immune checkpoint inhibitors (ICIs). However, their use in older patients has been under-studied and there is reason to suspect the risk-benefit ratio for ICIs may differ in older populations due to the influence of age-related immune dysfunction, comorbidities, and polypharmacy. This research aimed to better characterize the safety and effectiveness of ICIs in older patients with melanoma, paying special attention to comorbidity burden and concomitant medications. Methods: Using the SEER-Medicare data, we conducted a retrospective study of survival and safety outcomes in patients age 65 and older diagnosed with melanoma (2012-2015). We used Cox proportional hazard regression to compare survival by first systemic treatment type, ICI type, and age. We also tested for an ICI x age interaction. Negative binomial regression was used to evaluate rates of immune-related adverse events (irAEs) and hospitalizations for irAEs by age and ICI type. Results: In 541 patients diagnosed with stage IV melanoma, initial treatment with CTLA-4 or PD-1 inhibitors was associated with prolonged survival compared to no systemic therapy, chemotherapy, or targeted therapy (HR=0.48, 95% CI: 0.37-0.63 and HR=0.35, 95% CI: 0.42-0.52, for CTLA-4 and PD-1 inhibitors, respectively, compared to no systemic therapy). Among 1,435 patients ever treated with ICIs, we found survival was longest for PD-1 inhibitors and combination ICIs. Furthermore, the treatment effect of PD-1 inhibition (vs CTLA-4 inhibition) was stronger in older patients (≥80) compared to younger ones (65-79). The incidence of irAEs was two-fold higher and irAE hospitalizations nearly three-fold higher (RR=2.74, 95% CI: 1.68-4.48) with combination ICIs versus PD-1 inhibitors. Older age was also associated with a lower irAE incidence (RR=0.83, 95% CI: 0.71-0.98). Neither comorbidity score nor concurrent use of NSAIDs were associated with irAE incidence. Conclusions: This research confirmed the safety and effectiveness of ICIs in older patients with melanoma treated in routine practice. Our results indicate PD-1 inhibitors are the safest, most effective ICI option for the majority of older patients with melanoma. Combination ICIs should be reserved for patients with a high metastatic burden and administered with caution due to high rates of toxicities.

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