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Abstract
Background We previously demonstrated the effectiveness of 2nd-line immune checkpoint inhibitors (ICI) for stage 4 melanoma patients.1 2In late 2015, ICI was FDA-approved and NCCN-recommended in the 1st-line setting.3 4 Here we assess the real-world effectiveness and utilization of 1st-line ICI among advanced melanoma patients following 2015.
Methods Patients newly-diagnosed with stage 4 melanoma during 2010–2018 were identified using the U.S. National Cancer Database (comprises >70% of newly-diagnosed cancers).5 Post-approval 1st-line ICI’s overall survival (OS, estimated by Kaplan-Meier techniques) and utilization were assessed for patients diagnosed in 2016–2018, using multivariable Cox and logistic regression, respectively. To account for immortal time bias in receiving ICI, we only included those patients in regression analyses who survived at least until the landmark timepoint, defined as the median time from diagnosis to ICI initiation (49 days).1 2 The more conservative 75th percentile diagnosis-to-ICI-initiation landmark timepoint (80 days) was also evaluated. Analyses were adjusted for patient, tumor, treatment, socioeconomic, and care setting characteristics.
Results Among 14,912 stage 4 melanoma patients, 1st-line immunotherapy utilization increased from 8.4% in 2010 to 39.2% in 2015, and 57.9% in 2018.(Figure 1) Altogether, median OS improved from 8.0 mos (95%CI=7.3–8.8) in 2010 to 16.1 mos (95%CI=14.0–18.5) in 2017. For patients diagnosed in 2016+ who survived at least until the landmark timepoints, OS improved with 1st-line ICI (median OS=33.1 mos, 95%CI=29.4–40.5; vs just 13.6 mos for no ICI, 95%CI=12.1–16.1; HR=0.58, 99%CI=0.50–0.68; padj<0.001)(figure 2A-B)—even after adjusting for patient, disease, and treatment factors, and using either landmark.(Table 1) This included patients with either brain metastases (ICI median OS=16.7 mos, 95%CI=13.1–19.9; vs no ICI=7.8 mos, 95%CI=6.8–9.0; padj<0.001) or lung metastases (ICI median OS=26.0 mos, 95%CI=20.0–33.0; vs no ICI=9.3 mos, 95%CI=8.0–10.5; padj<0.001).(Figure 2C-F)We then used multivariable logistic regression (with landmark timepoints to reduce bias from early mortality) to identify putative barriers to receiving 1st-line ICI in 2016+. Advanced melanoma patients who had more comorbidities or brain metastases, or who were older, uninsured/Medicaid-insured, from the poorest quartile of households, or managed at community hospitals were less likely to receive ICI.(all p<0.05, table 2)
(A) The percent of stage 4 melanoma patients diagnosed each year who received 1st-line immune checkpoint inhibitor (ICI), with stratification by (B) brain or lung metastatic involvement, and (C) treating hospital type.
Multivariable Cox regression analysis of overall survival among stage 4 melanoma patients in 2016+. To account for immortal time bias, landmark timepoints were utilized, defined by the median (i.e. 49d; panels A, C, E) and 75th percentile (i.e. 80d; panels B, D, F) time from diagnosis to ICI initiation. Patients had to survive at least as long as the landmark timepoint to be included in the analysis. Results are shown for all stage 4 patients, as well as those with brain or lung metastases. p values are only displayed for the primary association of interest.
Multivariable logistic regression analysis of 1st-line immune checkpoint inhibitor (ICI) receipt among stage 4 melanoma patients in 2016+. To account for bias due to early mortality, landmark timepoints were utilized, defined by the median (i.e. 49d) and 75th percentile (i.e. 80d) time from diagnosis to ICI initiation. Patients had to survive at least as long as the landmark timepoint to be included in the analysis. Results are shown for all stage 4 patients, as well as those with brain or lung metastases. Variables that demonstrate a significant association with ICI receipt are highlighted in yellow.
Overall survival associated with 1st-line immune checkpoint inhibitors (ICI) for stage 4 melanoma patients diagnosed after 2015 (A-B), including patients with brain (C-D) and lung metastases (E-F). To account for immortal time bias, landmark timepoints were utilized, defined by the median (i.e. 49d; panels A, C, E) and 75th percentile (i.e. 80d; panels B, D, F) time from diagnosis to ICI initiation. Patients had to survive at least as long as the landmark timepoint to be included in the analysis.
Conclusions Following FDA-approval in 2015, 1st-line ICI was associated with dramatic improvements in OS for stage 4 melanoma patients—including those with brain or lung metastases. As of 2018, 42% of patients still weren’t receiving 1st-line ICI in the U.S.—particularly patients who were underinsured, from the poorest quartile of households, or managed at community hospitals—suggesting that disparities exist in guideline-recommended 1st-line ICI utilization for advanced melanoma patients.
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