§ M Rael was an employee of Evidera, Inc. at the time of study and manuscript development Aim: Comparison of clinical outcomes of nivolumab + ipilimumab versus BRAF + MEK inhibitors (dabrafenib + trametinib or vemurafenib + cobimetinib) in BRAF-mutant advanced melanoma. Methods: Matching-adjusted indirect comparisons were conducted between nivolumab + ipilimumab (Check-Mate 067/069 studies) and BRAF + MEK inhibitors (COMBI-d, COMBI-v and coBRIM studies). Overall survival (OS), progression-free survival and objective response rates were assessed. Results: After adjusting, nivolumab + ipilimumab showed improved OS versus dabrafenib + trametinib (hazard ratio [HR] = 0.64;95% CI: 0.46-0.89) or vemurafenib + cobimetinib (HR = 0.56; 95% CI: 0.36-0.89); OS outcomes were similar at 1 year, with benefits emerging after 12 months; progression-free survival and objective response rates were similar. Grade 3/4 adverse events occurred in 54.1% with nivolumab + ipilimumab, 31.6% with dabrafenib + trametinib and 59.5% with vemurafenib + cobimetinib. Conclusion: Nivolumab + ipilimumab had significantly improved clinical outcomes versus BRAF + MEK inhibitors, with benefits increasing after longer follow-up. Ongoing randomized trials directly comparing these treatments are necessary to prospectively validate these findings.
A719Objectives: Heterogeneity can distort traditional indirect comparisons of treatments. Simulated treatment comparisons (STC) can overcome this with regression equations to balance differences in populations. Equations are derived using patient-level data from one trial (drug A, index); however, only mean values of predictors are typically known for the comparator (B). Thus, adjusted results must be generated by plugging these means in the equation, which can be biased for non-linear outcomes (e.g., time-to-event) since it yields the geometric rather than the required arithmetic mean. We describe a solution and illustrate its application in an STC of treatments of non-valvular atrial fibrillation (NVAF). MethOds: Data from the trial of drug A were used to derive an equation for the rate of major bleeds (MB) using Poisson regression. Predictors included gender, age, region, history of stroke/transient ischemic attack, hypertension, diabetes, renal dysfunction, prior use of various treatments. To avoid non-linearity bias, patient profiles were simulated by sampling predictor values from a multivariate-normal distribution with means set to drug B's population and covariance matrix derived from the index trial. The average predicted rate for simulated patients represents the adjusted MB rate. To demonstrate that the approach works, we also apply it to the index trial. Results: A rate of 21 MBs/1000 person-years were observed with drug A. The predicted rate at the means of predictors of patients on drug A produced an estimate of 19 (16.4-21.0), whereas the mean of predicted rates with actual profiles was 22 (15.1-31.9). Repeating the calculations with simulated patients yielded 22.5 (15.3-33.0). The simulated MB rate in patients matching of the population of drug B was 30 (20.5-45.1), which contrasted with its observed rate (36.0) yielded a rate ratio of 0.84 (0.56-1.27). cOnclusiOns: Predicting outcomes with a simulated comparator population produces accurate adjusted results for use in STCs.
564 Background: TFS characterizes the antitumor activity of immuno-oncology agents after treatment discontinuation. In CheckMate 214, pts with IMDC intermediate/poor-risk aRCC who discontinued first-line NIVO+IPI experienced significantly longer TFS than those who discontinued SUN (McDermott et al, ESMO 2018). Here, we continue the analysis of TFS from CheckMate 214 in ITT and IMDC favorable-risk pts. Methods: Pts with previously untreated, predominantly clear cell aRCC were randomized 1:1 to intravenous NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks for 4 doses followed by NIVO 3 mg/kg every 2 weeks, or oral SUN 50 mg daily for 4 weeks on, 2 weeks off (6-week cycles). TFS was defined as the time from protocol therapy cessation to the start of subsequent systemic anticancer therapy or death, whichever occurred first. TFS in pts who discontinued NIVO+IPI or SUN was compared using Kaplan–Meier methods and log-rank tests. This analysis was conducted for all ITT (NIVO+IPI, 550; SUN, 546) and IMDC favorable-risk (NIVO+IPI, 125; SUN, 124) pts in CheckMate 214. Results: Among 463 NIVO+IPI and 477 SUN ITT pts who discontinued protocol therapy, the median TFS was 3.0 months with NIVO+IPI vs 1.3 months with SUN (HR [95% CI]; 0.54 [0.46–0.62]; P<0.0001); the TFS rates 2 years post-discontinuation were 21% vs 7%, respectively. In IMDC favorable-risk pts, 111 and 94 pts discontinued from NIVO+IPI and SUN, respectively. TFS in IMDC favorable-risk pts was also significantly longer with NIVO+IPI vs SUN (median, 6.3 vs 1.1 months; HR [95% CI]; 0.47 [0.34–0.65]; P<0.0001). The TFS rates 2 years post-discontinuation in favorable-risk pts were 29% for NIVO+IPI vs 13% for SUN. Conclusions: Similar to the TFS benefit seen in intermediate/poor-risk pts with aRCC, first-line therapy with NIVO+IPI resulted in reduced need for second-line therapy in ITT and IMDC favorable-risk pts compared with SUN. The durable TFS benefit across risk groups despite discontinuation of therapy provides further evidence of the encouraging benefit-risk profile of NIVO+IPI over SUN in pts with previously untreated aRCC. Clinical trial information: NCT02231749.
OBJECTIVES: Assess the relative overall survival (OS) and progression-free survival (PFS) of nivolumab + ipilimumab (NIVO+IPI) versus dabrafenib + trametinib (DAB+TRAM) and vemurafenib + cobimetinib (VEM+COBI) in treatment-naive patients with BRAF-mutant advanced melanoma. METHODS: In the absence of a direct head-to-head comparison, matching-adjusted indirect treatment comparisons (MAIC) were conducted using patient-level data for NIVO+IPI patients with BRAF-mutant tumors from the CheckMate 067 and 069 trials and published summary level results from BRAF+MEK pivotal trials (COMBI-d, COMBI-v, and coBRIM). NIVO+IPI baseline characteristics were matched to the DAB+TRAM or VEM+COBI patient characteristics by reweighting the NIVO+IPI patients by their odds of enrollment in the studies. Additional potential biases such as use of subsequent therapy were not controlled for. Cox proportional hazard models were fit to the weighted OS and PFS data for NIVO+IPI and virtual event and censor times derived from the published DAB+TRAM or VEM+COBI curves. To capture the non-proportionality observed in the OS and PFS curves, Cox models with separate hazard ratios (HRs) for <12 months and ≥12 months were also fit. RESULTS: The effective sample size of the NIVO+IPI patients was 106 after matching to DAB+TRAM and 59 after matching to VEM+COBI. The overall OS Cox models showed that NIVO+IPI had superior OS with HRs (95% confidence intervals) of 0.64 (0.46, 0.89) versus DAB+TRAM and 0.56 (0.36, 0.89) versus VEM+COBI. This benefit emerged with longer follow-up. At 12 months, the OS HRs were similar for NIVO+IPI versus DAB+TRAM (1.0; 0.67, 1.49) and VEM+COBI (1.01; 0.57, 1.80). However, beyond 12 months, NIVO+IPI had a significantly greater OS benefit versus DAB+TRAM (0.33; 0.18, 0.60) and versus VEM+COBI (0.29; 0.14, 0.63). PFS results were similar with insignificant differences observed at 12 months and superior PFS for NIVO+IPI beyond 12 months; HRs for ≥12 months were 0.29 (0.14, 0.62) for NIVO+IPI versus DAB+TRAM and 0.15 (0.04, 0.54) for NIVO+IPI versus VEM+COBI. CONCLUSION: After adjusting for patient population differences, NIVO+IPI had a significant OS benefit over DAB+TRAM and VEM+COBI. For both OS and PFS, the NIVO+IPI benefit emerges after 12 months of treatment. In the future, these results can be validated by ongoing randomized trials directly comparing sequential combination approaches. Disclosure: This research was funded by Bristol-Myers Squibb. Citation Format: Michael B. Atkins, David McDermott, Ahmad Tarhini, Michael Rael, Komal Gupte-Singh, Elliot O'Brien, Corey Ritchings, Sumati Rao. Matching-adjusted indirect comparison of nivolumab + ipilimumab and BRAF+MEK inhibitors for the treatment of BRAF-mutant treatment-naive advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3639.
The single‐pill combination (SPC) comprising nebivolol (5 mg), a vasodilatory β1‐selective antagonist/β3‐agonist, and valsartan (80 mg), a renin‐angiotensin‐aldosterone system inhibitor, is the only Food and Drug Administration–approved β‐blocker/renin‐angiotensin‐aldosterone system inhibitor SPC for hypertension. Additive effects of four nebivolol/valsartan SPC doses (5 mg/80 mg, 5/160 mg, 10/160 mg, 10/320 mg nebivolol/valsartan) were compared with five Food and Drug Administration–approved non–β‐blocker/renin‐angiotensin‐aldosterone system inhibitor SPCs (aliskiren/hydrochlorothiazide, aliskiren/amlodipine, valsartan/amlodipine, aliskiren/valsartan, and telmisartan/amlodipine). Additivity is the ratio of placebo‐adjusted SPC blood pressure (BP) reduction to the placebo‐adjusted monotherapy component BP reduction sums. A weighted average of comparator scores was calculated and compared vs nebivolol/valsartan. Additivity ratio scores for nebivolol/valsartan SPCs (diastolic BP range: 0.735–0.866; systolic BP range: 0.717–0.822) were similar to the comparator weighted average (diastolic BP: 0.837; systolic BP: 0.825). Among the nebivolol/valsartan SPCs, 5/80 mg had the greatest additivity (diastolic BP: 0.866; systolic BP: 0.822). BP reduction contributions with monotherapy were similar for nebivolol/valsartan 5/80 mg SPC. Additivity scores for nebivolol/valsartan and select non–β‐blocker/renin‐angiotensin‐aldosterone system inhibitor SPCs were comparable.
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