A matching-adjusted indirect comparison of combination nivolumab plus ipilimumab with BRAF plus MEK inhibitors for the treatment of BRAF-mutant advanced melanoma☆.

BACKGROUND: Approved first-line treatments for patients with BRAF V600-mutant advanced melanoma include nivolumab (a programmed cell death protein 1 inhibitor) plus ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor; NIVO+IPI) and the BRAF/MEK inhibitors dabrafenib plus trametinib (DAB+TRAM), encorafenib plus binimetinib (ENCO+BINI), and vemurafenib plus cobimetinib (VEM+COBI). Results from prospective randomized clinical trials (RCTs) comparing these treatments have not yet been reported. This analysis evaluated the relative efficacy and safety of NIVO+IPI versus DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma using a matching-adjusted indirect comparison (MAIC). PATIENTS AND METHODS: A systematic literature review identified RCTs for DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma. Individual patient-level data for NIVO+IPI were derived from the phase III CheckMate 067 trial (BRAF-mutant cohort) and restricted to match the inclusion/exclusion criteria of the comparator trials. Treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using Cox proportional hazards and time-varying hazard ratio (HR) models. Safety outcomes (grade 3 or 4 treatment-related adverse events) with NIVO+IPI and the comparators were compared. RESULTS: In the Cox proportional hazards analysis, NIVO+IPI showed improved OS compared with DAB+TRAM (HR = 0.53; 95% confidence interval [CI], 0.39-0.73), ENCO+BINI (HR = 0.60; CI, 0.42-0.85), and VEM+COBI (HR = 0.50; CI, 0.36-0.70) for the overall study period. In the time-varying analysis, NIVO+IPI was associated with significant improvements in OS and PFS compared with the BRAF/MEK inhibitors 12 months after treatment initiation. There were no significant differences between NIVO+IPI and BRAF/MEK inhibitor treatment from 0 to 12 months. Safety outcomes favored DAB+TRAM over NIVO+IPI, whereas NIVO+IPI was comparable to VEM+COBI. CONCLUSION: Results of this MAIC demonstrated durable OS and PFS benefits for patients with BRAF-mutant advanced melanoma treated with NIVO+IPI compared with BRAF/MEK inhibitors, with the greatest benefits noted after 12 months.

Network meta-analysis of direct-acting antivirals in combination with peginterferon-ribavirin for previously untreated patients with hepatitis C genotype 1 infection.

AIM: To conduct a network meta-analysis (NMA) to determine the comparative efficacy, as measured by sustained virological response (SVR), between boceprevir (BOC), telaprevir (TEL), faldaprevir (FAL), simeprevir (SIM) and sofosbuvir (SOF) in combination with peginterferon-ribavirin (PR) against a control of PR. DESIGN: A literature search was conducted to identify randomized controlled trials (RCTs) including adult patients with hepatitis C virus genotype 1 who were naive to any prior therapy. RCTs assessing standard duration therapy (SDT) or response-guided therapy (RGT) BOC, TEL, FAL, SIM or SOF in combination with PR against a control of PR were eligible for inclusion. All RCTs must have provided SVR at either 12 or 24 weeks post-therapy cessation. RESULTS: We included nine RCTs. All direct-acting antivirals (DAAs) were found to perform better than PR. Additionally, SDT FAL was found to be better than the 240 mg RGT FAL regimen with the PR lead-in. A sensitivity analysis excluding RCTs with only SVR at 12 weeks was consistent with the results of the primary analysis. A sensitivity analysis removing an RCT assessing SIM that reported SVR of >60% in the PR control group additionally found that RGT SIM was superior to the 240 mg RGT FAL regimen with the PR lead-in. DISCUSSION: Our analyses indicate that SDT and RGT regimens of DAAs plus PR do not differ greatly in terms of SVR among treatment-naive hepatitis C genotype 1 patients. More advanced Bayesian network meta-analyses are likely needed to incorporate a comprehensive evidence base, expanding beyond randomized clinical trials.

Clinical markers of endometriosis: have we been too quick to judge?

Numerous biochemical differences have been documented in women with endometriosis compared to controls; however, identification of a clinically useful marker of endometriosis remains elusive. We postulate that the diversity of clinical presentations, patient objectives, and complexity of the pathophysiology of endometriosis mandates rigorous attention to study design and standardization of procedures and questionnaires that has heretofore been overlooked in the pursuit of clinical markers of this enigmatic disease. We further propose that it is premature to conclude that clinical markers of endometriosis brought forward in the literature lack clinical value in the diagnosis of endometriosis. To address this hypothesis we reviewed the literature and assessed papers according to a modified version of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) criteria from which 55 high quality papers were reviewed. While pelvic inflammation and pain is a known significant component of endometriosis, control group definitions were widely divergent and included healthy women through to women with other inflammatory conditions. Although pain is a common presenting complaint in women with endometriosis, it was assessed in only 4 of 55 studies (7.3%) whereas infertility was documented in 34/55 studies (61.8%). Disease severity was assessed in 44 of 55 studies (80%) whilst the association between active vs. inactive disease was attempted in only 2 of the studies reviewed (3.6%). We conclude that experimental design criteria are inconsistently applied making comparisons across studies difficult. Thus, the clinical utility of previously described diagnostic markers of endometriosis remains uncertain.