Outcomes in Melanoma Patients Treated with BRAF/MEK-Directed Therapy or Immune Checkpoint Inhibition Stratified by Clinical Trial versus Standard of Care

Abstract

Objectives: Since 2011, metastatic melanoma treatment has evolved with commercial approval of BRAF- and MEK-targeted therapy and CTLA-4- and PD-1-blocking antibodies (immune checkpoint inhibitors, ICI). While novel therapies have demonstrated improved prognosis in clinical trials, few studies have examined the evolution of prognosis and toxicity of these drugs among an unselected population. We assess whether survival and toxicity reported in trials, which typically exclude most patients with brain metastases and poor performance status, are recapitulated within a commercial access population. Methods: 182 patients diagnosed with stage IV melanoma from July 2006 to December 2013 and treated with BRAF- and/or MEK-targeted therapy or ICI were prospectively studied. Outcomes and clinicopathologic differences between trial and commercial cohorts were assessed. Results: Patients receiving commercial therapy (vs. on trial) had poorer prognostic features (i.e., brain metastases) and lower median overall survival (mOS) when assessed across all treatments (9.2 vs. 17.5 months, p = 0.0027). While toxicity within trial and commercial cohorts did not differ, patients who experienced toxicity had increased mOS (p < 0.001), irrespective of stratification by trial status or therapy. Conclusion: Metastatic melanoma patients receiving commercial treatment may represent a different clinical population with poor prognostic features compared to trial patients. Toxicity may prognosticate treatment benefit.

Are cancer patients better off if they participate in clinical trials? A mixed methods study

“…Identification and review of research literature We identified nine eligible studies that included twelve comparisons of trial and non-trial patients: Arrieta et al [28], Bertelli et al [29], De Placido et al [30], Field et al [31], Goldman et al [32], Khera et al [33], Led Du et al [34], Svensson et al [35] and Templeton et al [36]. Figure 2 contains a PRISMA flow diagram showing the selection of studies.…”

“…Characteristics of the studies All nine studies included comparisons concerning overall survival [28][29][30][31][32][33][34][35][36], some also included progression-free survival [29,30,32,34]. Eight of the nine studies were retrospective cohort The Kaplan-Meier analyse showed a trial effect (p = 0.007), but the univariate Cox proportional hazard ratio did not (p = 0.089) studies.…”

“…Non-trial patients restricted to those meeting trial eligibility criteria In the five other studies, study design or trial phase could not be identified [28,31,32,34,36] e Three studies reported no baseline difference [28,30,34], and two studies adjusted using multivariate or multivariable analyses [31,33] f Two studies adjusted using multivariate analysis [28,32], one through restriction of cohort [34], and another did not identify any baseline difference [33]. For three studies, control of the confounder was not applicable [29,35,36] g One study explicitly adjusted for stage in the multivariate analysis [28], one study according to high vs low risk in multivariate analysis [33].…”

“…metastatic sites, prior treatment and specific mutations [30,[34][35][36]. Not applicable for two studies [31,32] h Accounted for in multivariate or multivariable analyses [28,[31][32][33]36] i One study accounted for this in a multivariate analysis as described in the method section, but the result is not presented [28], and another study by restriction of cohort [34]. Two studies did not identify any baseline difference [33,36] j Two studies adjusted by restriction of cohort [31,34], and two studies found no baseline difference [33,36] k For three studies, adjusting for treatment centre was not applicable [28,32,36].…”

“…a Arrieta et al [28]. ], Field et al [31], Goldman et al [32] b Goldman et al [32] c Arrieta et al [28], Field et al [31] regardless of the kind of examinations being undertaken:…”