Progression-free survival as a surrogate endpoint for overall survival in patients with relapsed or refractory multiple myeloma

Objectives: The goal of the research was to assess the quantitative relationship between median progression-free survival (PFS) and median overall survival (OS) specifically among patients with relapsed/refractory multiple myeloma (RRMM) based on published randomized controlled trials (RCTs). Methods: Two bibliographic databases (PubMed and Embase, 1970–2017) were systematically searched for RCTs in RRMM that reported OS and PFS, followed by an updated search of studies published between 2010 and 2022 in 3 databases (Embase, MEDLINE, and EBM Reviews, 2010–2022). The association between median PFS and median OS was assessed using the nonparametric Spearman rank and parametric Pearson correlation coefficients. Subsequently, the quantitative relationship between PFS and OS was assessed using weighted least-squares regression adjusted for covariates including age, sex, and publication year. Study arms were weighted by the number of patients in each arm. Results: A total of 31 RCTs (56 treatment arms, 10,450 patients with RRMM) were included in the analysis. The average median PFS and median OS were 7.1 months (SD 5.5) and 28.1 months (SD 11.8), respectively. The Spearman and Pearson correlation coefficients between median PFS and median OS were 0.80 (P &lt; 0.0001) and 0.79 (P &lt; 0.0001), respectively. In individual treatment arms of RRMM trials, each 1-month increase in median PFS was associated with a 1.72-month (95% CI 1.26–2.17) increase in median OS. Conclusion: Analysis of the relationship between PFS and OS incorporating more recent studies in RRMM further substantiates the use of PFS to predict OS in RRMM.</p

Extrapolation of Survival Data Using a Bayesian Approach:A Case Study Leveraging External Data from Cilta-Cel Therapy in Multiple Myeloma

Introduction: Extrapolating long-term overall survival (OS) from shorter-term clinical trial data is key to health technology assessment in oncology. However, extrapolation using conventional methods is often subject to uncertainty. Using ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy for multiple myeloma, we used a flexible Bayesian approach to demonstrate use of external longer-term data to reduce the uncertainty in long-term extrapolation. Methods: The pivotal CARTITUDE-1 trial (NCT03548207) provided the primary efficacy data for cilta-cel, including a 12-month median follow-up snapshot of OS. Longer-term (48-month median follow-up) survival data from the phase I LEGEND-2 study (NCT03090659) were also available. Twelve-month CARTITUDE-1 OS data were extrapolated in two ways: (1) conventional survival models with standard parametric distributions (uninformed), and (2) Bayesian survival models whose shape prior was informed from 48-month LEGEND-2 data. For validation, extrapolations from 12-month CARTITUDE-1 data were compared with observed 28-month CARTITUDE-1 data. Results: Extrapolations of the 12-month CARTITUDE-1 data using conventional uninformed parametric models were highly variable. Using informative priors from the 48-month LEGEND-2 dataset, the ranges of projected OS at different timepoints were consistently narrower. Area differences between the extrapolation curves and the 28-month CARTITUDE-1 data were generally lower in informed Bayesian models, except for the uninformed log-normal model, which had the lowest difference. Conclusions: Informed Bayesian survival models reduced variation of long-term projections and provided similar projections as the uninformed log-normal model. Bayesian models generated a narrower and more plausible range of OS projections from 12-month data that aligned with observed 28-month data. Trial Registration: CARTITUDE-1 ClinicalTrials.gov identifier, NCT03548207. LEGEND-2 ClinicalTrials.gov identifier, NCT03090659, registered retrospectively on 27 March 2017, and ChiCTR-ONH-17012285

Meta-analysis of ciltacabtagene autoleucel versus physician’s choice therapy for the treatment of patients with relapsed or refractory multiple myeloma

[Objective]: In the absence of head-to-head trials, indirect treatment comparisons (ITCs) between ciltacabtagene autoleucel (cilta-cel; in CARTITUDE-1) and treatments used in real-world clinical practice (physician’s choice of treatment [PCT]), were previously conducted. We conducted multiple meta-analyses using available ITC data to consolidate the effectiveness of cilta-cel versus PCT for patients with triple-class exposed relapsed or refractory multiple myeloma (RRMM). [Methods]: Five ITCs were assessed for similarity to ensure robust comparisons using meta-analysis. Effectiveness outcomes were overall survival (OS), progression-free survival (PFS), time to next treatment (TTNT), and overall response rate (ORR). A robust variance estimator was used to account for the use of CARTITUDE-1 in each pairwise ITC. Analyses were conducted in both treated and enrolled populations of CARTITUDE-1. [Results]: Four ITCs were combined for evaluation of OS. Results were statistically significantly in favor of cilta-cel versus PCT in treated patients (hazard ratio [HR]: 0.24, 95% confidence interval [CI]: 0.22–0.26). Three ITCs were combined for evaluation of PFS and TTNT. Cilta-cel reduced the risk of progression and receiving a subsequent treatment by 80% (HR: 0.20 [95% CI: 0.06, 0.70]) and 83% (HR: 0.17 [95% CI: 0.12, 0.26]), respectively. Three ITCs were combined for evaluation of ORR. Cilta-cel increased the odds of achieving an overall response by 86-times versus PCT in treated patients. Findings were consistent in the enrolled populations and across sensitivity analyses. [Conclusions]: Evaluating multiple indirect comparisons, cilta-cel demonstrated a significantly superior advantage over PCT, highlighting its effectiveness as a therapy in patients with triple-class exposed RRMM.The CARTITUDE-1 study and these analyses were funded by Janssen Research & Development, LLC, and Legend Biotech, Inc. Medical writing support was provided by EVERSANA and funded by Janssen Global Services, LLC

Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1) : a phase 3, randomised, double-blind, multicentre trial

BACKGROUND : mTOR inhibition has been shown to reverse trastuzumab resistance from hyperactivated the PIK/AKT/mTOR pathway due to PTEN loss, by sensitizing PTEN-deficient tumors towards trastuzumab. The BOLERO-1 study evaluated the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line therapy for HER2+ advanced breast cancer (ABC). METHODS : In this phase III, randomized, double-blind trial, patients were enrolled across 141 sites in 28 countries. Eligible patients were ≥18 years of age, with locally assessed HER2+ advanced breast cancer (ABC), with Eastern Cooperative Oncology Group performance status of 0-1, who had not received prior trastuzumab or chemotherapy for ABC, had measurable disease as per Response Evaluation Criteria in Solid Tumors or bone lesions in the absence of measurable disease, without prior systemic therapy for advanced disease except endocrine therapy. The patients were randomized 2:1 (with an interactive voice and web response system) to receive either daily everolimus (10 mg/day) orally or placebo plus weekly trastuzumab intravenously at 4 mg/kg loading dose on Day-1 with subsequent weekly doses of 2 mg/kg of each 4-week cycle plus paclitaxel intravenously at a dose of 80 mg/m2 on days 1, 8, and 15 of each 4- week cycle. Randomization was stratified according to prior use of trastuzumab and visceral metastasis. Patients and investigators were blinded to the assigned treatments. Identity of experimental treatments was concealed by use of everolimus and placebo that were identical in packaging, labelling, appearance, and administration schedule. The two primary objectives were investigator-assessed progression-free survival (PFS) in the full study population and in the subset of patients with hormone receptor-negative (HR) breast cancer at baseline; the latter was added during the course of the study, prior to unblinding based on new clinical and biological findings from other studies. All efficacy analyses were based on the intention-to-treat population. Enrolment for this trial is closed and results of the final PFS analyses are presented here. Clinicaltrials.gov identifier: NCT00876395. FINDINGS : Between 10-Sep-2009 and 16-Dec-2012, 719 patients were randomized to receive everolimus (n=480) or placebo (n=239). Median follow-up was 41.3 months (IQR: 35.4 – 46.6 months). INTERPRETATION : The primary objective in the full population was not met; median PFS was 15.0 months with everolimus vs 14.5 months with placebo (hazard ratio, 0.89; 95% CI, 0.73-1.08; p=0.1166). In the HR subpopulation (n=311), median PFS with everolimus was 20.3 months vs 13.1 months with placebo (hazard ratio, 0.66; 95% CI, 0.48-0.91; p=0.0049), however, the protocol-specified statistical significance threshold (p=0.0044) was not crossed. The most common adverse events (AEs) with everolimus vs placebo were stomatitis (314 [66.5%] vs 77 [32.4%] patients), diarrhea (267 [56.6%] vs 111 [46.6%] patients), and alopecia (221 [46.8%] vs 125 [52.5%]). The most frequently reported grade 3/4 AEs in the EVE arm vs PBO arm were neutropenia (117 [24.8%] of 472 patients vs 35 [14.7%] of 238 patients), stomatitis (59 [12.5%] of 472 patients vs 3 [1.3%] of 238 patients), anemia (46 [9.7%] of 472 patients vs 6 [2.5%] of 238 patients) and diarrhea (43 [9.1%] of 472 patients vs 10 [4.2%] of 238 patients) On-treatment AE-related deaths were reported in 17 [3.6%] vs 0% of patients respectively.Interpretation: The primary objective of PFS was not met. However, consistent with the preliminary observations from BOLERO-3, everolimus prolonged median PFS by 7.2 months in patients with HR, HER2+ ABC, which warrants further investigation. The safety profile was generally consistent with what was previously reported in BOLERO-3. Proactive monitoring and early management of AEs in patients treated with everolimus and chemotherapy is critical..Novartis Pharmaceuticals Corporation.http://www.journals.elsevier.com/the-lancet-oncology2016-07-31hb201

Adjusted comparison of outcomes between patients from CARTITUDE-1 <i>versus</i> multiple myeloma patients with prior exposure to proteasome inhibitors, immunomodulatory drugs and anti-CD38 antibody from the prospective, multinational LocoMMotion study of real-world clinical practice

Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy studied in patients with multiple myeloma exposed to three classes of treatment in the single-arm CARTITUDE-1 study. To assess the effectiveness of cilta-cel compared to real-world clinical practice (RWCP), we performed adjusted comparisons using individual patients’ data from CARTITUDE-1 and LocoMMotion, a prospective, multinational study of patients with multiple myeloma triple-class exposed of treatment. Comparisons were performed using inverse probability weighting. In CARTITUDE-1, 113 patients were enrolled, and 97 patients were infused with cilta-cel. In LocoMMotion, 248 patients were enrolled, and 170 patients were included in the comparisons versus infused patients. Ninety-two unique regimens were used in LocoMMotion, most frequently carfilzomib-dexamethasone (13.7%), pomalidomide-cyclophosphamide-dexamethasone (13.3%) and pomalidomidedexamethasone (11.3%). Adjusted comparisons showed that patients treated with cilta-cel were 3.12-fold more likely to respond to treatment than those managed by RWCP (response rate, 3.12, 95% confidence interval [95% CI]: 2.24-4.00), had their risk of progression or death reduced to by 85% (progression-free survival hazard ratio=0.15, 95% CI: 0.08-0.29), and a risk of death lowered by 80% (overall survival hazard ratio HR=0.20, 95% CI: 0.09-0.41). The incremental improvement in healthrelated quality of life from baseline for cilta-cel versus RWCP at week 52, as measured by EORTC QLQ-C30 Global Health Status, was 13.4 (95% CI: 3.5-23.6) and increased to 30.8 (95% CI: 21.8-39.8) when including death as additional information regarding patients’ health status. Patients treated with cilta-cel experienced more adverse events than those managed with RWCP (any grade: 100% vs. 83.5%). The results from this study demonstrate improved efficacy outcomes of cilta-cel versus RWCP and highlight its potential as a novel and effective treatment option for patients with multiple myeloma triple-class exposed of antimyeloma treatment. CARTITUDE-1 is registered with clinicaltrials gov. Identifier: NCT03548207. LocoMMotion is registered with clinicaltrials gov. Identifier: NCT04035226

Meta-analysis of ciltacabtagene autoleucel versus physician’s choice therapy for the treatment of patients with relapsed or refractory multiple myeloma [Dataset]

Figure A.1: Selection of Comparator Arms for ITC Analyses Figure A.2: Results of sensitivity analyses with OIs removed for OS at all (A) and first (B) index dates Figure A.3: Results of sensitivity analyses with LocoMMotion removed for OS at all (A) and first (B) index dates, and PF at first index dates (C) Table A.1: Characteristics of Data Sources for PCT arms in ITCs Table A.2: Published ITC Results and Augmented Results Included in Meta-analyses (All Index Dates) Table A.3: Published ITC Results and Augmented Results Included in Meta-analyses (First Index Dates) Table A.4: Baseline Covariates After Adjustment (mITT Populations; All Index Dates) Table A.5: Baseline Covariates After Adjustment (mITT Populations; First Index Dates) Table A.6: Outcome Definitions in ITC Analyses[Objective]: In the absence of head-to-head trials, indirect treatment comparisons (ITCs) between ciltacabtagene autoleucel (cilta-cel; in CARTITUDE-1) and treatments used in real-world clinical practice (physician’s choice of treatment [PCT]), were previously conducted. We conducted multiple meta-analyses using available ITC data to consolidate the effectiveness of cilta-cel versus PCT for patients with triple-class exposed relapsed or refractory multiple myeloma (RRMM). [Methods]: Five ITCs were assessed for similarity to ensure robust comparisons using meta-analysis. Effectiveness outcomes were overall survival (OS), progression-free survival (PFS), time to next treatment (TTNT), and overall response rate (ORR). A robust variance estimator was used to account for the use of CARTITUDE-1 in each pairwise ITC. Analyses were conducted in both treated and enrolled populations of CARTITUDE-1. [Results]: Four ITCs were combined for evaluation of OS. Results were statistically significantly in favor of cilta-cel versus PCT in treated patients (hazard ratio [HR]: 0.24, 95% confidence interval [CI]: 0.22–0.26). Three ITCs were combined for evaluation of PFS and TTNT. Cilta-cel reduced the risk of progression and receiving a subsequent treatment by 80% (HR: 0.20 [95% CI: 0.06, 0.70]) and 83% (HR: 0.17 [95% CI: 0.12, 0.26]), respectively. Three ITCs were combined for evaluation of ORR. Cilta-cel increased the odds of achieving an overall response by 86-times versus PCT in treated patients. Findings were consistent in the enrolled populations and across sensitivity analyses. [Conclusions]: Evaluating multiple indirect comparisons, cilta-cel demonstrated a significantly superior advantage over PCT, highlighting its effectiveness as a therapy in patients with triple-class exposed RRMM.Peer reviewe

Progression-free survival as a surrogate endpoint for overall survival in patients with relapsed or refractory multiple myeloma

Objectives: The goal of the research was to assess the quantitative relationship between median progression-free survival (PFS) and median overall survival (OS) specifically among patients with relapsed/refractory multiple myeloma (RRMM) based on published randomized controlled trials (RCTs). Methods: Two bibliographic databases (PubMed and Embase, 1970–2017) were systematically searched for RCTs in RRMM that reported OS and PFS, followed by an updated search of studies published between 2010 and 2022 in 3 databases (Embase, MEDLINE, and EBM Reviews, 2010–2022). The association between median PFS and median OS was assessed using the nonparametric Spearman rank and parametric Pearson correlation coefficients. Subsequently, the quantitative relationship between PFS and OS was assessed using weighted least-squares regression adjusted for covariates including age, sex, and publication year. Study arms were weighted by the number of patients in each arm. Results: A total of 31 RCTs (56 treatment arms, 10,450 patients with RRMM) were included in the analysis. The average median PFS and median OS were 7.1 months (SD 5.5) and 28.1 months (SD 11.8), respectively. The Spearman and Pearson correlation coefficients between median PFS and median OS were 0.80 (P &lt; 0.0001) and 0.79 (P &lt; 0.0001), respectively. In individual treatment arms of RRMM trials, each 1-month increase in median PFS was associated with a 1.72-month (95% CI 1.26–2.17) increase in median OS. Conclusion: Analysis of the relationship between PFS and OS incorporating more recent studies in RRMM further substantiates the use of PFS to predict OS in RRMM.</p