Joris Diels

Efficacy of telaprevir and boceprevir in treatment-naïve and treatment-experienced genotype 1 chronic hepatitis C patients: an indirect comparison using Bayesian network meta-analysis

Abstract Background and aims: To indirectly compare the efficacy of telaprevir (TVR) and boceprevir (BOC) combined with peginterferon/ribavirin α-2a/2b (PR) in achieving sustained viral response (SVR) in treatment-naïve and treatment-experienced patients with genotype 1 chronic hepatitis C virus (HCV) infection. Methods: A systematic literature review was conducted to identify randomized controlled trials reporting the efficacy of PR-based treatment in genotype 1 chronic HCV patients. A Bayesian network meta-analysis was performed on the endpoint of SVR, assuming fixed study effects. For treatment-experienced patients, only previous relapsers and partial responders were included, as no results in prior null responders were available for boceprevir. Results: Eleven publications were included. In treatment-naïve patients, the odds ratios (OR) (posterior median [95% credible interval]) for telaprevir (12 weeks + response guided treatment [RGT] 24/48 weeks PR) and boceprevir (24 weeks + RGT 28/48 weeks PR) versus PR were respectively 3.80 (2.78–5.22) and 2.99 (2.23–4.01). The OR for telaprevir versus boceprevir was 1.42 (0.89–2.25), with a probability for telaprevir being more effective (P[OR > 1]) of 0.93. In treatment-experienced patients, the OR of telaprevir (12 weeks + 48 weeks PR) and boceprevir (32 weeks + RGT 36/48 weeks PR) versus PR were respectively 13.11 (7.30–24.43) and 5.36 (2.90–10.30). The OR for telaprevir versus boceprevir was 2.45 (1.02–5.80), with telaprevir having a probability of 0.98 of being more effective. Limitations: The main limitation of this study is the low number of trials included in the analysis, especially for the treatment-experienced patient population, which only allowed random-effect models to be explored. We tried to identify potential biases due to study heterogeneity. Conclusions: In the absence of direct comparative head-to-head studies between telaprevir and boceprevir for the treatment of chronic HCV genotype 1 patients, an indirect comparison based on Bayesian network meta-analysis suggests better efficacy for telaprevir than boceprevir in both treatment-naïve and treatment-experienced patients.

Daratumumab monotherapy compared with historical control data in heavily pretreated and highly refractory patients with multiple myeloma: An adjusted treatment comparison.

Daratumumab is a human CD38‐directed monoclonal antibody approved in the United States as monotherapy for patients with multiple myeloma (MM) who have received ≥3 prior lines of therapy (LOTs), including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double refractory to a PI and an IMiD, and in combination with lenalidomide/dexamethasone or bortezomib/dexamethasone for patients with MM who have received ≥1 prior LOT. This study compared the efficacy of daratumumab monotherapy versus historical controls through adjusted treatment comparison. Patient‐level data were pooled from two daratumumab monotherapy studies (16 mg/kg; GEN501 and SIRIUS) and two independent US databases (IMS LifeLink and OPTUM), which reflect treatments used in real‐world patients with MM who received ≥3 prior LOTs or were double refractory to a PI and an IMiD. Using a multivariate proportional hazards regression model, the relative treatment effect of daratumumab versus historical controls was estimated, adjusting for imbalances in characteristics between cohorts. Baseline characteristics that differed between patients treated with daratumumab (N = 148) and historical control (N = 658) were prior treatment with pomalidomide (55% vs 15%) or carfilzomib (41% vs 28%) and triple/quadruple refractory status (64% vs 14%). The adjusted overall survival–hazard ratio (OS‐HR) for daratumumab versus historical control was 0.33 (95% confidence interval, 0.24‐0.46) compared with 0.46 (0.35‐0.59) for unadjusted HR. Impact of adjustment was mainly driven by refractory status and prior pomalidomide/carfilzomib exposure. This adjusted treatment comparison suggests that daratumumab demonstrates improved OS compared with historical control data in heavily pretreated and highly refractory MM patients.

Health-related quality of life data from a phase 3, international, randomized, open-label, multicenter study in patients with previously treated mantle cell lymphoma treated with ibrutinib versus temsirolimus

Abstract Mantle cell lymphoma (MCL) is a rare, aggressive, incurable B-cell malignancy. Ibrutinib has been shown to be highly active for patients with relapsed/refractory (R/R) MCL. The RAY trial (MCL3001) was a phase 3, randomized, open-label, multicenter study that compared ibrutinib with temsirolimus in patients with R/R MCL. Active disease is frequently associated with impaired functional status and reduced well-being. Therefore, the current study employed two patient-reported outcome instruments, the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EQ-5D-5L, to assess symptoms, well-being, health status, and health-related quality of life of patients on treatment within the RAY trial. We found that patients on ibrutinib had substantial improvement in FACT-Lym subscale and total scores, and had improvement in EQ-5D-5L utility and VAS scores compared with temsirolimus patients, indicating a superior well-being. These improvements in well-being correlated with clinical response, indicating that better health-related quality of life was associated with decreased disease burden.

PHEDRA: using real-world data to analyze treatment patterns and ibrutinib effectiveness in hematological malignancies

AIM PHEDRA (Platform for Haematology in EMEA: Data for Real World Analysis) is a unique, noninterventional project based on secondary data collection from real-world (RW) patient-level (health record) databases to understand treatment patterns in hematological malignancies. It compares ibrutinibs effectiveness with alternative treatments using RW data (RWD) and randomized clinical trials data. MATERIALS & METHODS RWD are cleaned, validated, harmonized into a Common Data Model, and analyzed statistically alongside randomized clinical trial data. Treatment outcomes include overall and progression-free survival. RESULTS To date, RWD (four databases) are available for 2840 patients in three indications, collected between 1990 and 2017. CONCLUSION PHEDRA is an innovative approach to generate evidence to inform optimal treatment decisions in RW settings.

Improvement of fatigue, physical functioning, and well-being among patients with severe impairment at baseline receiving ibrutinib in combination with bendamustine and rituximab for relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma in the HELIOS study

Abstract Health-related quality of life (HRQoL) is an important endpoint, especially in clinical trials for malignancies with a long course of disease, such as chronic lymphocytic leukemia (CLL). Patient-reported outcomes were examined in the randomized, double-blind, placebo-controlled HELIOS study to assess the impact of treatment with the Bruton’s tyrosine kinase inhibitor ibrutinib, added to bendamustine plus rituximab (BR) background therapy. Measures included FACIT-Fatigue, EORTC QLQ-C30, QLQ-CLL16, and EQ-5D-5L. Of 578 patients enrolled, 540 (93%) provided FACIT-Fatigue responses at baseline. Most had only a moderate degree of impairment at baseline; mean values did not appear to change over time in either treatment arm, suggesting that adding ibrutinib to BR did not impact health-related quality of life. However, post-hoc analyses showed that subgroups of patients with the worst fatigue, physical functional status, and well-being at baseline had greater improvements in these outcomes with ibrutinib plus BR treatment versus placebo.

Ibrutinib for chronic lymphocytic leukemia: international experience from a named patient program

After first approval of ibrutinib for patients with B-cell malignancies in the US, an international named patient program (NPP) was initiated to provide ibrutinib to patients before local country approval. In this observational retrospective analysis of data collected from the NPP, estimated time on treatment and its relationship with baseline characteristics were analyzed for patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Ibrutinib outcomes were compared with those from the phase III RESONATETM study. Our findings suggest that ibrutinib is effective and well tolerated in the real world, with time on treatment similar to the clinical trial setting; younger age and complete response (CR)/partial response (PR) to prior therapy were predictive of longer time on treatment. In B-cell malignancies such as CLL, Bruton’s tyrosine kinase (BTK) is a rational target for therapy because it is needed for B-cell receptor signaling, plays a key role in Bcell maturation, and is overexpressed. Benefits of ibrutinib, a first-in-class, once-daily, oral, covalent inhibitor of BTK, have been demonstrated in phase II and III studies across multiple B-cell malignancies. Ibrutinib is approved in the EU, US and elsewhere to treat patients with CLL, Waldenström’s macroglobulinemia and relapsed/refractory mantle cell lymphoma. It is also indicated for marginal zone lymphoma in the US. NPPs enable controlled access to treatments that have shown a positive benefit-risk ratio for life-threatening conditions, in response to unsolicited requests by physicians and on behalf of patients, before the drug is licensed or commercially available in their country. NPPs can provide data on the clinical use, treatment duration, efficacy and relative safety of a drug in a real-world context. After the first approval of ibrutinib in the US in November 2013, an international ibrutinib NPP was initiated for patients with B-cell malignancies who met respective phase III trial eligibility criteria. Here we describe an observational retrospective analysis of data from patients with relapsed/refractory CLL enrolled in the international ibrutinib NPP from March 2014 through October 2015, to estimate time on treatment and explore related patient characteristics. Time on ibrutinib treatment in the international NPP was compared with the phase III RESONATETM (PCYC-1112) study of ibrutinib versus ofatumumab in patients with relapsed/refractory CLL. Inclusion criteria for the NPP were based on RESONATETM: age ≥18 years; confirmed diagnosis of CLL/small lymphocytic lymphoma (including patients with 17p deletion); Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of <2; relapsed/refractory disease after ≥1 prior therapy, defined as failure to achieve a PR with, or documented progression after, the most recent treatment regimen. Participation was approved by the local independent ethics committee or institutional review board as needed, and the enrolling physician obtained patients’ informed consent. Patients received oral ibrutinib 420 mg once daily continuously until progressive disease (PD) or unacceptable toxicity. Disease evaluations and safety monitoring were conducted by enrolling physicians, according to local standard of care. Ibrutinib was provided through the NPP until commercially available, at which point patients were transferred to commercial drug if appropriate, and follow up stopped. Data on the ordering/reordering of ibrutinib were collected. Treatment start and stop (discontinuation) dates were entered by the physician via a simple questionnaire on the Janssen Managed Access portal (MAcWeb; if not entered, reordering data were censored at the date of last ibrutinib supply). Patient baseline characteristics and reasons for stopping orders were collected from physicians at enrollment and treatment discontinuation, respectively, also via MAcWeb. Kaplan-Meier analysis and Cox proportional hazards regression were used to estimate time on treatment. Relationships between baseline characteristics and time on treatment were explored via multivariate analyses, included categorical variables of age, sex, number of prior therapy lines, time since CLL diagnosis, PD on prior therapy in the past 3 months, CR or PR to last therapy, relapsed disease and refractory disease. In total, 2908 patients with CLL from 30 countries were enrolled in the NPP. Baseline demographic and disease characteristics are shown in Table 1. Naïve comparison with patient baseline characteristics of the RESONATETM study ibrutinib arm suggests median age and proportion of males were similar, however, the proportion of patients with ≥3 prior lines of therapy was higher in the NPP (63% vs. 53% for NPP vs. RESONATETM). Fewer patients in the NPP relapsed after purine analogues (70% vs. 85%, respectively) or anti-CD20 therapy (68% vs. 94%, respectively). The estimated proportion of patients on treatment at 12 months was 77.3% (95% confidence interval [CI]: 74.7, 79.6) in the NPP, similar to RESONATETM (actual 12month time on treatment rate, 81.5%; 95% CI: 75.3, 86.3). Time on treatment for the international CLL NPP and RESONATETM populations were not statistically different (hazard ratio, 1.20 [95% CI: 0.86, 1.67]) (Figure 1). The median duration of follow up was 5.78 (range, 0.0318.73) months in the NPP, and 9.4 (range, 0.1-16.6) months in RESONATETM. In the multivariate analysis, younger age (<50 years) and achievement of CR/PR as a response to prior therapy were independent factors significantly associated with longer time on treatment. Having a CLL diagnosis for >5 years

Bortezomib-based therapy for relapsed/refractory multiple myeloma in real-world medical practice

The efficacy and safety of bortezomib‐based therapy for relapsed/refractory multiple myeloma (RRMM) in clinical trials may differ from the oncology practice experience. The electronic VELCADE® OBservational Study was designed to prospectively evaluate bortezomib for multiple myeloma (MM) in real‐world medical practice.

An Indirect Comparison of Changes in the Impact of Weight on Quality of Life Among Subjects with Type 2 Diabetes Treated with Antihyperglycemic Agents in Dual Therapy with Metformin

IntroductionIt is important to capture the patient experience with a diabetes treatment in clinical trials; however, use of instruments to assess patient-reported outcomes (PROs) in diabetes trials is inconsistent and results may not be reported alongside primary efficacy data. In lieu of head-to-head data, indirect comparisons can be used to compare competing interventions. In this study, we used indirect comparison methods to assess differences in PRO score changes between canagliflozin and other antihyperglycemic agents as add-on to metformin.MethodsLiterature searches were performed to identify studies that reported the same PRO instruments that were collected across four trials of canagliflozin in dual or triple therapy. Extensive searches identified only one study that was sufficiently similar in design and reported common PRO results using the Impact of Weight on Quality of Life-Lite (IWQoL-Lite): the DURATION-2 study of exenatide once-weekly (QW) versus sitagliptin and pioglitazone. This study was compared with the CANTATA-D study of canagliflozin versus sitagliptin. Bayesian indirect comparisons were performed to assess mean change in IWQoL-Lite total score. A fixed-effects model with noninformative priors was used to estimate between-treatment differences. Sensitivity analyses examined differences in trial populations.ResultsIn the primary analysis, the probability that canagliflozin treatment results in greater improvement in IWQoL-Lite total score versus exenatide, sitagliptin, and pioglitazone was 60.0%, 89.9%, and 99.5%, respectively. When the CANTATA-D population was restricted using DURATION-2 inclusion/exclusion criteria, canagliflozin was also associated with a higher probability of having greater improvement in IWQoL-Lite than exenatide, sitagliptin, and pioglitazone.ConclusionsThese findings suggest that improvements in the impact of weight on health-related quality of life may be greater with canagliflozin than exenatide, sitagliptin, and pioglitazone. This analysis also demonstrates the application of indirect comparison methodology to PRO data and provides examples of advantages and challenges associated with performing indirect comparisons of PRO data.

Adjusted comparison of daratumumab monotherapy versus real-world historical control data from the Czech Republic in heavily pretreated and highly refractory multiple myeloma patients

Abstract Objectives: We conducted an adjusted comparison of progression-free survival (PFS) and overall survival (OS) for daratumumab monotherapy versus standard of care, as observed in a real-world historical cohort of heavily pretreated multiple myeloma patients from Czech Republic. Methods: Using longitudinal chart data from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group, patient-level data from the RMG was pooled with pivotal daratumumab monotherapy studies (GEN501 and SIRIUS; 16 mg/kg). Results: From the RMG database, we identified 972 treatment lines in 463 patients previously treated with both a proteasome inhibitor and an immunomodulatory drug. Treatment initiation dates for RMG patients were between March 2006 and March 2015. The most frequently used treatment regimens were lenalidomide-based regimens (33.4%), chemotherapy (18.1%), bortezomib-based regimens (13.6%), thalidomide-based regimens (8.0%), and bortezomib plus thalidomide (5.3%). Few patients were treated with carfilzomib-based regimens (2.5%) and pomalidomide-based regimens (2.4%). Median observed PFS for daratumumab and the RMG cohort was 4.0 and 5.8 months (unadjusted hazard ratio [HR], 1.14; 95% confidence interval [CI], 0.94–1.39), respectively, and unadjusted median OS was 20.1 and 11.9 months (unadjusted HR, 0.61; 95% CI, 0.48–0.78), respectively. Statistical adjustments for differences in baseline characteristics were made using patient-level data. The adjusted HRs (95% CI) for PFS and OS for daratumumab versus the RMG cohort were 0.79 (0.56–1.12; p = .192) and 0.33 (0.21–0.52; p < .001), respectively. Conclusions: Adjusted comparisons between trial data and historical cohorts can provide useful insights to clinicians and reimbursement decision makers on relative treatment efficacies in the absence of head-to-head comparison studies for daratumumab monotherapy.

Comparative Efficacy of Daratumumab Monotherapy and Pomalidomide Plus Low‐Dose Dexamethasone in the Treatment of Multiple Myeloma: A Matching Adjusted Indirect Comparison

BACKGROUND Daratumumab (a human CD38-directed monoclonal antibody) and pomalidomide (an immunomodulatory drug) plus dexamethasone are both relatively new treatment options for patients with heavily pretreated multiple myeloma. A matching adjusted indirect comparison (MAIC) was used to compare absolute treatment effects of daratumumab versus pomalidomide + low-dose dexamethasone (LoDex; 40 mg) on overall survival (OS), while adjusting for differences between the trial populations. MATERIALS AND METHODS The MAIC method reduces the risk of bias associated with naïve indirect comparisons. Data from 148 patients receiving daratumumab (16 mg/kg), pooled from the GEN501 and SIRIUS studies, were compared separately with data from patients receiving pomalidomide + LoDex in the MM-003 and STRATUS studies. RESULTS The MAIC-adjusted hazard ratio (HR) for OS of daratumumab versus pomalidomide + LoDex was 0.56 (95% confidence interval [CI], 0.38-0.83; p = .0041) for MM-003 and 0.51 (95% CI, 0.37-0.69; p < .0001) for STRATUS. The treatment benefit was even more pronounced when the daratumumab population was restricted to pomalidomide-naïve patients (MM-003: HR, 0.33; 95% CI, 0.17-0.66; p = .0017; STRATUS: HR, 0.41; 95% CI, 0.21-0.79; p = .0082). An additional analysis indicated a consistent trend of the OS benefit across subgroups based on M-protein level reduction (≥50%, ≥25%, and <25%). CONCLUSION The MAIC results suggest that daratumumab improves OS compared with pomalidomide + LoDex in patients with heavily pretreated multiple myeloma. IMPLICATIONS FOR PRACTICE This matching adjusted indirect comparison of clinical trial data from four studies analyzes the survival outcomes of patients with heavily pretreated, relapsed/refractory multiple myeloma who received either daratumumab monotherapy or pomalidomide plus low-dose dexamethasone. Using this method, daratumumab conferred a significant overall survival benefit compared with pomalidomide plus low-dose dexamethasone. In the absence of head-to-head trials, these indirect comparisons provide useful insights to clinicians and reimbursement authorities around the relative efficacy of treatments.