Real-world analyses of therapy discontinuation of checkpoint inhibitors in metastatic melanoma patients

Abstract

the 'real-world' patient population of metastatic melanoma is not fully represented in clinical trials investigating checkpoint inhibitors. We described therapy discontinuation in an unselected population-based cohort of adults with metastatic melanoma who started therapy with pembrolizumab, nivolumab, or nivolumab/ipilimumab from January 2015 to August 2017. Therapy discontinuation was defined as a gap between doses beyond 120 days, and/or initiation of another cancer therapy. We estimated drug-specific rate ratios for therapy discontinuation adjusted for age, sex, comorbidities, health care use, and past cancer therapies. We included 876 metastatic melanoma patients initiating pembrolizumab (44.3%), nivolumab/ipilimumab (31.2%), and nivolumab (24.5%). At 12 months of follow-up, the probabilities of therapy discontinuation were 49.9% (95% confidence interval, CI 43.6-56.5) for pembrolizumab, 58.8% (95% CI 50.5-67.3) for nivolumab, and 59.2% (95% CI 51.7-66.8) for nivolumab/ipilimumab. Stratified analyses based on prior cancer therapy, brain metastases at baseline, and sex showed similar trends. In multivariable analyses, compared with pembrolizumab, patients starting nivolumab (rate ratio 1.38, 95% CI 1.08-1.77) or nivolumab/ ipilimumab (rate ratio 1.30, 95% CI 1.02-1.65) were more likely to discontinue therapy. Our findings indicate frequent discontinuations of checkpoint inhibitors at one year. The lower discontinuation associated with pembrolizumab should be confirmed in further studies. Each year, over 100,000 new cases of melanoma are diagnosed in North America. Since 2007, melanoma incidence has been on the rise, while death rates have slowly improved 1. In the United States (US), melanoma is the third most prevalent cancer among men and the fifth among woman 2 , and melanoma incidence is higher in men (29.3/100,000 persons per year) than women (17.8/100,000 persons per year) 1. The survivorship considerably reduces from 99% for localized melanoma to 25% for patients diagnosed with distant metastases (5-year relative survival estimates in the US between 2009 and 2015) 1. The advent of checkpoint inhibitors has dramatically changed the landscape of treatment for metastatic melanoma. These agents are so-called because they act on key regulators, called checkpoints, of the immune system to help effectively eradicate cancer cells. In the US, ipilimumab (anti-CTLA-4) was approved in 2011 and pembrolizumab and nivolumab (both inhibitors of the programmed death-1, PD-1, pathway) were launched on the market in 2014. Since 2015, the National Comprehensive Cancer Network (NCCN)'s Clinical Practice Guidelines recommended checkpoint inhibitors as first-line treatment for metastatic melanoma. These guidelines shifted slightly in 2016 when monotherapy with pembrolizumab and nivolumab and combination nivolumab/

Development of a Metastatic Uveal Melanoma Prognostic Score (MUMPS) for Use in Patients Receiving Immune Checkpoint Inhibitors

“…In cutaneous melanoma, it is well established that responses can be maintained for an extended period of time after ICI treatment discontinuation [ 40 ]. However, the fundamental underlying biology of uveal melanoma is different from cutaneous melanoma [ 41 ], and we do not yet know if ICI responses are maintained after treatment discontinuation in this population.…”

Development of a Metastatic Uveal Melanoma Prognostic risk Score (MUMPS) for use in patients receiving immune checkpoint inhibitors

“…In cutaneous melanoma, it is well established that responses can be maintained for a long period of time after ICI treatment discontinuation[39]. However, the fundamental underlying biology of uveal melanoma is different from cutaneous melanoma[40], and we do not yet know if ICI responses are maintained after treatment discontinuation in this population.…”

The lung, the niche, and the microbe: Exploring the lung microbiome in cancer and immunity

“…Due to the promise of immunotherapy as a treatment option, especially for patients who have had limited success with other types of treatment, it becomes important to better understand if the effect of immunotherapy on the microbiota may be involved in the experienced toxicity from immunotherapy. Despite showing promise in the reduction of metastatic disease and increased survival rate, immunotherapy has high rates of discontinuation among patients due to toxicity ( 116 , 117 ). Common immunotherapies utilized for the treatment of cancer, such as CTLA-4, PD-1 and PD-L1 inhibitors, promote T cell antitumor activities, but also result in a distinct multi-organ inflammatory profile, which could in turn influence the microbiota ( 118 , 119 ).…”