Adjusted comparison of outcomes between patients from CARTITUDE-1 versus 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.

High dimensional surrogacy: computational aspects of an upscaled analysis.

Identification of genomic biomarkers is an important area of research in the context of drug discovery experiments. These experiments typically consist of several high dimensional datasets that contain information about a set of drugs (compounds) under development. This type of data structure introduces the challenge of multi-source data integration. High-Performance Computing (HPC) has become an important tool for everyday research tasks. In the context of drug discovery, high dimensional multi-source data needs to be analyzed to identify the biological pathways related to the new set of drugs under development. In order to process all information contained in the datasets, HPC techniques are required. Even though R packages for parallel computing are available, they are not optimized for a specific setting and data structure. In this article, we propose a new framework, for data analysis, to use R in a computer cluster. The proposed data analysis workflow is applied to a multi-source high dimensional drug discovery dataset and compared with a few existing R packages for parallel computing.

Comparative Efficacy of Talquetamab vs. Current Treatments in the LocoMMotion and MoMMent Studies in Patients with Triple-Class-Exposed Relapsed/Refractory Multiple Myeloma.

INTRODUCTION: Talquetamab, a bispecific antibody targeting GPRC5D × CD3, is approved for the treatment of patients with triple-class -exposed (TCE) relapsed/refractory multiple myeloma (RRMM) on the basis of the results from the phase I/II MonumenTAL-1 trial. The relative effectiveness of talquetamab vs. real-world physician's choice of therapy (RWPC) was assessed using adjusted comparisons. METHODS: An external control arm for MonumenTAL-1 (subcutaneously administered talquetamab 0.4 mg/kg weekly [QW] and 0.8 mg/kg every other week [Q2W]) was created from two observational real-world studies: LocoMMotion and MoMMent. Imbalances in baseline covariates were adjusted using inverse probability weighting. The relative effectiveness of talquetamab vs. RWPC was estimated for overall response rate (ORR), ≥ very good partial response (VGPR), and ≥ complete response (CR); odds ratios and relative response ratios (RRs) were derived from weighted logistic regression. Hazard ratios (HRs) for duration of response (DOR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) were estimated using a weighted Cox proportional hazards model. RESULTS: After reweighting, baseline characteristics were balanced across cohorts. In adjusted comparisons, patients treated with talquetamab QW (n = 143) had significantly improved outcomes vs. RWPC; RRs were ORR 2.67, p < 0.0001; ≥ VGPR 4.70, p < 0.0001; ≥ CR 78.05, p = 0.0002; and HRs were PFS 0.52, p < 0.0001; TTNT 0.48, p < 0.0001; OS 0.36, p < 0.0001. Patients treated with talquetamab Q2W (n = 145) also had significantly improved outcomes vs. RWPC; RRs were ORR 2.62, p < 0.0001; ≥ VGPR 5.04, p < 0.0001; ≥ CR 101.14, p = 0.0002; and HRs were PFS 0.40, p < 0.0001; TTNT 0.39, p < 0.0001; OS 0.37, p < 0.0001. CONCLUSION: Effectiveness of talquetamab for both schedules was significantly better than RWPC for ORR, ≥ VGPR, ≥ CR, PFS, OS, and TTNT, highlighting its clinical benefit for patients with TCE RRMM. TRIAL REGISTRATION: MonumenTAL-1, ClinicalTrials.gov identifier NCT03399799/NCT04634552; LocoMMotion, ClinicalTrials.gov identifier NCT04035226; MoMMent, ClinicalTrials.gov identifier NCT05160584.

Indirect adjusted comparison of 6-month clinical outcomes between esketamine nasal spray and other real-world polypharmacy treatment strategies for treatment resistant depression: results from the ICEBERG study.

Background: The efficacy of esketamine nasal spray (NS) as a rapid-acting agent for treatment resistant depression (TRD) was demonstrated in comparisons with placebo, when both were given in addition to a newly initiated selective serotonin reuptake inhibitor (SSRI)/serotonin norepinephrine reuptake inhibitor (SNRI). How esketamine NS compares with commonly used real-world (RW) polypharmacy treatment strategies is not known. Method: ICEBERG was an adjusted indirect treatment comparison that analysed data from SUSTAIN-2 (NCT02497287; clinicaltrials.gov), a long-term, open-label study of esketamine NS plus SSRI/SNRI, and the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov), an observational study of routine clinical practice. Data were compared between patients receiving esketamine NS (SUSTAIN-2) and those from the EOTC treated with polypharmacy treatment strategies, either combination or augmentation. Analyses were adjusted for potential confounders, using rescaled average treatment effect among treated estimates. Threshold analyses were conducted to assess potential impact of unmeasured confounders on the robustness of analyses where esketamine NS was found to be significantly superior. Sensitivity analyses were used to understand the impact of analysis method selection and data handling. Results: Esketamine NS treatment resulted in a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6-53.9]) and remission (33.6% [95% CI 29.7-37.6]) versus RW polypharmacy (26.8% [95% CI 21.0-32.5] and 19.4%, [95% CI 14.2-24.6], respectively). Relative risk calculations showed esketamine NS was 1.859 (95% CI 1.474-2.345; p < 0.0001) times as likely to result in response and 1.735 (1.297-2.322; p = 0.0002) times as likely to result in remission versus RW polypharmacy at 6 months. Threshold and extensive sensitivity analyses supported that analyses of esketamine NS superiority were robust. Conclusion: ICEBERG supports esketamine NS being superior to current RW individualized polypharmacy strategies, including augmentation, with benefits extending beyond acute use, to improved chance of 6-month response and remission. While unobserved confounding factors may certainly impact results of an indirect comparison, threshold analysis supported a low likelihood of this affecting the conclusions.To view an animated summary of this publication, please click on the Supplementary video.

ICEBERG study: an indirect adjusted comparison estimating the long-term benefit of esketamine nasal spray when compared with routine treatment of treatment resistant depression in general psychiatry.

Background: Treatment resistant depression (TRD) affects 10-30% of patients with major depressive disorder. In 4-week trials, esketamine nasal spray (NS) was efficacious vs. placebo when both were initiated in addition to a new selective serotonin or serotonin norepinephrine reuptake inhibitor. However, comparison with an extended range of real-world treatments (RWT) is lacking. Methods: ICEBERG was an adjusted indirect treatment comparison using propensity score-based inverse probability weighting, performed on 6-month response and remission data from patients receiving esketamine NS plus oral antidepressant from the SUSTAIN-2 (NCT02497287; clinicaltrials.gov) study, compared with patients receiving other RWT from the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov) study. SUSTAIN-2 was a long-term open-label study of esketamine NS, while the EOTC was conducted at a time when esketamine NS was not available as RWT. Threshold and sensitivity analyses were conducted to assess how robust the primary analyses were. Results: Patients receiving esketamine NS had a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6-53.9]) and remission (33.6% [95% CI 29.7-37.6]) vs. patients receiving RWT (26.4% [95% CI 21.5-31.4] and 18.2% [95% CI 13.9-22.5], respectively), according to rescaled average treatment effect among treated estimates. Resulting adjusted odds ratios (OR) and relative risk (RR) favoured esketamine NS over RWT for 6-month response (OR 2.756 [95% CI 2.034-3.733], p < 0.0001; RR 1.882 [95% CI 1.534-2.310], p < 0.0001) and remission (OR 2.276 [95% CI 1.621-3.196], p < 0.0001; RR 1.847 [95% CI 1.418-2.406], p < 0.0001). Threshold analyses suggested that differences between the two studies were robust, and results were consistent across extensive sensitivity analyses. Conclusion: ICEBERG supports that, at 6 months, esketamine NS has a substantial and significant benefit over RWT for patients with TRD. While results may be affected by unobserved confounding factors, threshold analyses suggested these were unlikely to impact the study conclusions.To view an animated summary of this publication, please click on the Supplementary video.

An Adjusted Treatment Comparison Comparing Amivantamab Versus Real-World Clinical Practice in Europe and the United States for Patients with Advanced Non-Small Cell Lung Cancer with Activating Epidermal Growth Factor Receptor Exon 20 Insertion Mutations.

INTRODUCTION: Patients with advanced, epidermal growth factor receptor (EGFR)-mutated, non-small cell lung cancer (NSCLC) with Exon 20 insertion mutations (Exon20ins) have poor prognoses, exacerbated by a previous lack of specific treatment guidelines and unmet need for targeted therapies. Amivantamab, an EGFR and MET bispecific antibody, demonstrated efficacy and tolerability in patients with advanced EGFR-mutated NSCLC with Exon20ins following platinum-based therapy in CHRYSALIS (NCT02609776; Cohort D+). Since CHRYSALIS was single-arm, individual patient data (IPD)-based adjusted analyses versus similar patients in real-world clinical practice (RWCP) were conducted to generate comparative evidence. METHODS: RWCP cohorts were derived from seven European and US real-world sources, comprising patients fulfilling CHRYSALIS Cohort D+ eligibility criteria. Amivantamab was compared with a basket of RWCP treatments. Differences in prognostic characteristics were adjusted for using inverse probability weighting (IPW; average treatment effect among the treated [ATT]). Balance between cohorts was assessed using standardized mean differences (SMDs). Overall response rate (ORR; investigator- [INV] and independent review committee-assessed [IRC]), overall survival (OS), progression-free survival (PFS; INV and IRC) and time-to-next treatment (TTNT) were compared. Binary and time-to-event endpoints were analyzed using weighted logistic regression and proportional hazards regression, respectively. RESULTS: Pre-adjustment, baseline characteristics were comparable between cohorts. IPW ATT-adjustment improved comparability, giving closely matched characteristics. ORR (INV) was 36.8% for amivantamab versus 17.0% for the adjusted EU + US cohort (response rate ratio [RR]: 2.16). Median OS, PFS (INV) and TTNT were 22.77 versus 12.52 months (hazard ratio [HR]: 0.47; p < 0.0001), 6.93 versus 4.17 months (HR: 0.55; p < 0.0001) and 12.42 versus 5.36 months (HR: 0.44; p < 0.0001) for amivantamab versus the adjusted EU + US cohort, respectively. Results were consistent versus EU- and US-only cohorts, and when using IRC assessment. CONCLUSION: Adjusted comparisons demonstrated significantly improved outcomes for amivantamab versus RWCP, highlighting the value of amivantamab in addressing unmet need in patients with advanced EGFR Exon20ins NSCLC following platinum-based therapy. TRIAL REGISTRATION: CHRYSALIS: NCT02609776.

Adjusted Comparison of Outcomes between Patients from CARTITUDE-1 versus Multiple Myeloma Patients with Prior Exposure to PI, Imid and Anti-CD-38 from a German Registry.

Ciltacabtagene autoleucel (cilta-cel) is a Chimeric antigen receptor T-cell therapy with the potential for long-term disease control in heavily pre-treated patients with relapsed/refractory multiple myeloma (RRMM). As cilta-cel was assessed in the single-arm CARTITUDE-1 clinical trial, we used an external cohort of patients from the Therapie Monitor registry fulfilling the CARTITUDE-1 inclusion criteria to evaluate the effectiveness of cilta-cel for overall survival (OS) and time to next treatment (TTNT) vs. real-world clinical practice. Individual patient data allowed us to adjust the comparisons between both cohorts, using the inverse probability of treatment weighting (IPW; average treatment effect in the treated population (ATT) and overlap population (ATO) weights) and multivariable Cox proportional hazards regression. Outcomes were compared in intention-to-treat (HR, IPW-ATT: TTNT: 0.13 (95% CI: 0.07, 0.24); OS: 0.14 (95% CI: 0.07, 0.25); IPW-ATO: TTNT: 0.24 (95% CI: 0.12, 0.49); OS: 0.26 (95% CI: 0.13, 0.54)) and modified intention-to-treat (HR, IPW-ATT: TTNT: 0.24 (95% CI: 0.09, 0.67); OS: 0.26 (95% CI: 0.08, 0.84); IPW-ATO: TTNT: 0.26 (95% CI: 0.11, 0.59); OS: 0.31 (95% CI: 0.12, 0.79)) populations. All the comparisons were statistically significant in favor of cilta-cel. These results highlight cilta-cel's potential as a novel, effective treatment to address unmet needs in patients with RRMM.

Adjusting Overall Survival Estimates for Treatment Switching in Metastatic, Castration-Sensitive Prostate Cancer: Results from the LATITUDE Study.

BACKGROUND: LATITUDE was the first phase 3 trial examining the survival benefit of adding abiraterone acetate (AA) + prednisone (P) to androgen-deprivation therapy (ADT) in newly diagnosed metastatic, castration-sensitive prostate cancer (mCSPC). Due to significant improvement in overall survival after the first interim analysis, patients in the placebos + ADT arm could switch to AA + P + ADT during an open-label extension. As in other studies where switching is allowed, statistical adjustments are needed to assess the real benefit of new drugs. PATIENTS AND METHODS: This was a post hoc analysis to estimate the true survival benefit of AA + P + ADT in patients with newly diagnosed mCSPC by applying statistical adjustments commonly used to adjust for treatment switching. RESULTS: Of 112 patients still receiving placebos + ADT at the first interim analysis, 72 switched to AA + P + ADT during the open-label extension. Final analysis was conducted after median follow-up of 51.8 months. Compared to the placebos + ADT arm, the risk of death in the AA + P + ADT arm was 34% lower [hazard ratio (HR) = 0.663 (95% confidence interval 0.566-0.778)] by unadjusted intent-to-treat analysis, 37% lower [HR = 0.629 (95% confidence interval 0.526-0.753)] by rank preserving structure failure time modeling, and 38% lower [HR = 0.616 (95% confidence interval 0.524-0.724)] by inverse probability of censoring weights. CONCLUSIONS: Analyses adjusting for treatment switching using two different statistical approaches confirm the improved survival benefit of adding AA + P to ADT in patients with newly diagnosed mCSPC. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01715285.