Published Kaplan-Meier Curves Research Articles

Effectiveness of immune checkpoint inhibitors and other treatment modalities in patients with advanced mucosal melanomas: a systematic review and individual patient data meta-analysis

Mucosal melanomas (MM) are an aggressive subtype of melanoma. Given the rarity of this disease, the conduct of clinical trials is challenging and has been limited. Current treatment options have been extrapolated from the more common cutaneous melanoma even though MM is distinct in pathogenesis, etiology and prognosis. This is the first meta-analysis to comprehensively assess the efficacy of immune checkpoint inhibitors (anti-PD1 and anti-CTLA4) and other treatment modalities (targeted therapy such as KIT inhibitors and VEGF inhibitors, as well as radiotherapy) on survival outcomes in MM to develop clinical guidelines for evidence-based management. The protocol was prospectively registered on PROSPERO (PROSPERO ID: CRD42023411195). PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and Google Scholar were searched from inception until 25 July 2024, for all cohort and observational studies. Eligible studies included those with five or more participants with locally advanced or metastatic MM treated with anti-PD1, anti-CTLA4, VEGF inhibitors and/or KIT inhibitors. Titles and abstracts of potential articles were screened and full texts of all potentially eligible studies were retrieved and reviewed by two independent reviewers. Individual patient data (IPD) from published Kaplan-Meier curves were reconstructed using a graphical reconstruction method and pooled as a one-stage meta-analysis. A sensitivity analysis using a two-stage meta-analysis approach was conducted. Extracted outcomes included overall survival (OS) and progression-free survival (PFS). For each treatment arm, median survival time and 12-month survival proportion were estimated. Data from double-arm trials was pooled to estimate hazard ratios (HRs), ratios of restricted mean time lost (RMTL) and restricted mean survival time (RMST). From a total of 7402 studies, 35 eligible studies comprising a total of 2833 participants were included. Combined anti-PD1 and anti-CTLA4 therapy had the highest 12-month OS and 12-month PFS at 71.8% (95% CI: 67.6%, 76.2%, n=476) and 35.1% (95% CI: 30.5%, 40.4%, n=401) respectively, followed by anti-PD1 therapy alone (OS: 64.0% (95% CI: 61.4%, 66.7%, n=1399); PFS: was 28.3% (95% CI: 25.8%, 31.2%, n=1142), anti-PD1 and VEGF inhibitor combination therapy (OS: 57.1% (95% CI: 51.0%, 63.9%)), KIT inhibitors (OS: 48.2% (95% CI: 37.6%, 61.8%); PFS: 8.3% (95% CI: 3.7%, 18.7%)) and anti-CTLA4 therapy alone (OS: 33.3% (95% CI: 28.4%, 39.1%); PFS: 9.8% (95% CI: 5.9%, 16.5%)). In the double-arm studies, combination therapy with anti-PD1 and anti-CTLA4 had similar OS and PFS with anti-PD1 alone (OS: HR 0.856 (95% CI: 0.704, 1.04); RMTL ratio 0.932 (95% CI: 0.832, 1.044, P=0.225); RMST ratio 1.102 (95% CI: 0.948, 1.281, P=0.204); PFS: HR 0.919 (95% CI: 0.788, 1.07); RMTL ratio 0.936 (95% CI: 0.866, 1.013, P=0.100); RMST ratio 1.21 (95% CI: 0.979, 1.496, P=0.078)), however, anti-PD1 therapy alone had significantly better PFS than anti-CTLA4 alone (HR 0.548 (95% CI: 0.376, 0.799); RMTL ratio 0.715 (95% CI: 0.606, 0.844, P<0.001); RMST ratio 1.659 (95% CI: 1.316, 2.092, P<0.001)). Anti-PD1 therapy with radiotherapy versus anti-PD1 alone showed no significant difference (OS: HR 0.854 (95% CI: 0.567, 1.29); RMTL ratio 0.855 (95% CI: 0.675, 1.083, P=0.193); RMST ratio 1.194 (95% CI: 0.928, 1.536, P=0.168; PFS: HR 0.994 (95% CI: 0.710, 1.39); RMTL ratio 1.006 (95% CI: 0.87, 1.162, P=0.939); RMST ratio 0.984 (95% CI: 0.658, 1.472, P=0.939)). For the systemic treatment of MM, anti-PD1 is the best monotherapy. While combining anti-PD1 with other treatment options such as anti-CTLA4, VEGF inhibitors or radiotherapy might achieve better outcomes, these improvements did not reach statistical significance when evaluated by HR, RMTL and RMST ratios. This work was supported by theNational Medical Research CouncilTransition Award (TA20nov-0020),SingHealthDuke-NUSOncology Academic Clinical Programme (08/FY2020/EX/67-A143 and 08/FY2021/EX/17-A47), the Khoo Pilot Collaborative Award (Duke-NUS-KP(Coll)/2022/0020A), theNational Medical Research CouncilClinician Scientist-Individual Research Grant-New Investigator Grant (CNIGnov-0025), the Terry Fox Grant (I1056) and the Khoo Bridge Funding Award (Duke-NUS-KBrFA/2024/0083I).

Comparative Efficacy of Adagrasib and Sotorasib in KRAS G12C-Mutant NSCLC: Insights from Pivotal Trials

Background: The KRAS G12C mutation, prevalent in various malignancies, including non-small cell lung cancer (NSCLC), represents a unique therapeutic target. Adagrasib and sotorasib, two FDA-approved agents specifically targeting this mutation, have shown promise in clinical trials. This study aims to compare their efficacy in treating KRAS G12C-mutated NSCLC, drawing insights from pivotal clinical trials. Methods: We analyzed data from three key clinical trials: KRYSTAL-1, CodeBreak100, and CodeBreak200. Our methodology involved reconstructing individual patient data from published Kaplan–Meier curves using the IPDfromKM tool (Version 0.1.10). The primary endpoints were progression-free survival (PFS) and overall survival (OS), evaluated through hazard ratios (HRs) and the restricted mean survival time (RMST) method. Results: The HR for PFS favored adagrasib (HR: 0.90 [95% CI: 0.69, 1.19], p = 0.473), suggesting a non-significant trend toward better disease control compared to sotorasib. For OS, the HR was 0.99 [95% CI: 0.75, 1.33] (p = 0.969), indicating no significant difference between the two drugs. RMST analysis supported these findings, with adagrasib showing a consistently higher RMST in PFS at 6, 12, and 18 months. However, OS benefits converged over time, with adagrasib marginally surpassing sotorasib by the 18-month mark. Conclusions: This comprehensive analysis reveals that while adagrasib may offer a slight advantage in PFS, both drugs demonstrate comparable efficacy in OS for KRAS G12C-mutated NSCLC. The subtle differences observed, particularly in PFS, could inform clinical decision-making, emphasizing the need for personalized treatment strategies. Future research should focus on long-term effects and identifying patient subgroups that may benefit more from one drug over the other.

"Defendit Numerus": A Pooled Analysis of 6145 Locally Advanced Rectal Cancer Treated with Preoperative Chemoradiotherapy.

Objective: The optimal management of rectal cancer remains a subject of ongoing research. This meta-analysis of individual patient data assessed the benefit of chemoradiotherapy (fluorouracil-based) in local advanced rectal cancer: disease-free survival and overall survival. Methods: We pooled the data of 6145 patients from 24 studies of rectal cancer who received neoadjuvant radiotherapy with concomitant fluorouracil or capecitabine and surgery. The PRISMA 2020 abstract checklist was followed. Individual participant survival was reconstructed with an algorithm from published Kaplan-Meier curves. Results: The median OS was not reached; the mean survival time was 135.4 months (127.9-141.5). The median DFS was 176.9 months, and the mean disease-free survival time was 122.6 months (111.7-131.9). Conclusions: We provided a benchmark for future studies on rectal cancer treatment. The present results can be used in decision-making for locally advanced rectal cancer patients.

Proportional Hazards Violations in Phase III Cancer Clinical Trials: A Potential Source of Trial Misinterpretation.

Survival analyses of novel agents with long-term responders often exhibit differential hazard rates over time. Such proportional hazards violations (PHV) may reduce the power of the log-rank test and lead to misinterpretation of trial results. We aimed to characterize the incidence and study attributes associated with PHVs in phase III oncology trials and assess the utility of restricted mean survival time and maximum combination test as additional analyses. Clinicaltrials.gov and PubMed were searched to identify two-arm, randomized, phase III superiority-design cancer trials with time-to-event primary endpoints and published results through 2020. Patient-level data were reconstructed from published Kaplan-Meier curves. PHVs were assessed using Schoenfeld residuals. Three hundred fifty-seven Kaplan-Meier comparisons across 341 trials were analyzed, encompassing 292,831 enrolled patients. PHVs were identified in 85/357 [23.8%; 95% confidence interval (CI), 19.7%, 28.5%] comparisons. In multivariable analysis, non-overall survival endpoints [OR, 2.16 (95% CI, 1.21, 3.87); P = 0.009] were associated with higher odds of PHVs, and immunotherapy comparisons [OR 1.94 (95% CI, 0.98, 3.86); P = 0.058] were weakly suggestive of higher odds of PHVs. Few trials with PHVs (25/85, 29.4%) prespecified a statistical plan to account for PHVs. Fourteen trials with PHVs exhibited discordant statistical signals with restricted mean survival time or maximum combination test, of which 10 (71%) reported negative results. PHVs are common across therapy types, and attempts to account for PHVs in statistical design are lacking despite the potential for results exhibiting nonproportional hazards to be misinterpreted.

Natural history of initially asymptomatic severe aortic stenosis: a one-stage meta-analysis.

Current guidelines on the management strategy for patients with asymptomatic severe aortic stenosis (AS) remain unclear. This uncertainty stems from the lack of data regarding the natural history of these patients. To address this gap, we performed a systematic review and meta-analysis examining the natural history of asymptomatic severe AS patients receiving conservative treatment. The PubMed, Cochrane, and Embase databases were searched from inception to 24 January 2024 using the keywords "asymptomatic" AND "aortic" AND "stenosis". We included studies examining patients with asymptomatic severe AS. In interventional trials, only data from conservatively managed arms were collected. A one-stage meta-analysis was conducted using individual patient data reconstructed from published Kaplan-Meier curves. Sensitivity analysis was performed for major adverse cardiovascular outcomes in patients who remained asymptomatic throughout follow-up. A total of 46 studies were included (n = 9545). The median time to the development of symptoms was 1.11years (95% CI 0.90-1.53). 49.36% (40.85-58.59) of patients who were asymptomatic had suffered a major adverse cardiovascular event by 5years. The median event-free time for heart failure hospitalization (HFH) was 5.50years (95% CI 5.14-5.91) with 36.34% (95% CI 33.34-39.41) of patients experiencing an HFH by year 5. By 5years, 79.81% (95% CI 69.26-88.58) of patients developed symptoms (angina, dyspnoea, syncope and others) and 12.36% (95% CI 10.01-15.22) of patients died of cardiovascular causes. For all-cause mortality, the median survival time was 9.15years (95% CI 8.50-9.96) with 39.43% (CI 33.41-36.40) of patients dying by 5years. The median time to AVR was 4.77years (95% CI 4.39-5.17), with 52.64% (95% CI 49.85-55.48) of patients requiring an AVR by 5years. Our results reveal poor cardiovascular outcomes for patients with asymptomatic severe AS on conservative treatment. A significant proportion eventually requires an AVR. Further research is needed to determine if early intervention with AVR is more effective than conservative treatment.

Efficacy and safety of crizotinib in the treatment of advanced non-small cell lung cancer with ROS1 gene fusion: a systematic literature review and meta-analysis of real-world evidence

BackgroundCrizotinib was approved to treat patients with advanced non-small cell lung cancer (aNSCLC) with ROS proto-oncogene 1 (ROS1) gene fusion in 2016. We conducted a systematic literature review to identify real-world evidence (RWE) studies and estimated the efficacy and safety of crizotinib using meta–analyses (MA) for objective response rate (ORR), real-world progression-free survival (PFS), and overall survival (OS). MethodsWe searched MEDLINE®, Embase, and Cochrane CENTRAL from January 2016 to March 2023 using Ovid® for published single-arm or comparative RWE studies evaluating patients (N ≥ 20) receiving crizotinib monotherapy for aNSCLC with ROS1 gene fusion. Pooled estimates for ORR and grade 3/4 adverse events (AEs) were derived using the metafor package in R while pooled estimates for median real-world PFS (rwPFS) and OS were derived using reconstructed individual patient data from published Kaplan-Meier curves. The primary analysis included all studies regardless of crizotinib line of therapy; a subgroup analysis (SA) was conducted using studies evaluating patients receiving first-line crizotinib. ResultsFourteen studies met the eligibility criteria and were considered feasible for MA. For the primary analysis, the pooled ORR (N = 9 studies) was 70.6 % (95 % confidence interval [CI]: 57.0, 81.3), median rwPFS was 14.5 months (N = 11 studies), and OS was 40.2 months (N = 9 studies). In the SA, the pooled ORR (N = 4 studies) was 81.1 % (95 % CI: 76.1, 85.2) and the median rwPFS (N = 4 studies) and OS (N = 2 studies) were 18.1 and 60 months, respectively. All MAs were associated with significant heterogeneity (I2 > 25 %). Grade 3/4 AEs occurred in 18.7 % of patients (pooled estimate). ConclusionThe results from this study are consistent with clinical trial data and, taken collectively, supports crizotinib as a safe and effective treatment across different lines of therapy in patients with ROS1 aNSCLC in the real-world setting.

Evaluation of the Lifetime Benefits of Metformin and SGLT2 Inhibitors in Type 2 Diabetes Mellitus Patients with Cardiovascular Disease: A Systematic Review and Two-Stage Meta-Analysis.

Metformin and sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated cardiovascular benefits but their comparative effects on mortality in type 2 diabetes mellitus (T2DM) patients with cardiovascular disease (CVD) are unknown. Hence, we evaluated and compared lifetime benefits arising from metformin or SGLT2 inhibitors in T2DM patients with CVD. Studies published in the PubMed, EMBASE and CENTRAL databases before 28 October 2023 were retrieved. Treatment effects of metformin against US FDA-approved SGLT2 inhibitors in T2DM patients with CVD were evaluated and lifetime gains in event-free survival were estimated from our primary endpoints of all-cause and cardiovascular mortality. Risk ratios were derived to assess their impact on secondary outcomes such as major adverse cardiovascular events and hospitalizations for heart failure. Overall, 14 studies were included. Five studies published Kaplan-Meier curves for the primary outcome of all-cause mortality. Individual participant data were reconstructed from these Kaplan-Meier curves, from which we conducted our two-stage meta-analysis. Participants receiving metformin and SGLT2 inhibitors experienced a reduction in the risk for all-cause mortality as compared with those not taking metformin and placebo. However, participants receiving SGLT2 inhibitors had a higher all-cause mortality (hazard ratio 1.308, 95% confidence interval 1.103-1.550) versus metformin. Treatment with metformin was estimated to offer an additional 23.26months of survival free from all-cause mortality versus 23.04months with SGLT2 inhibitors. In patients with T2DM and CVD, metformin and SGLT2 inhibitors were associated with substantially lower all-cause mortality rates and slightly longer life expectancies than in patients without. Metformin presented an advantage over SGLT2 inhibitors in reducing all-cause mortality.

A Long-Term Comparative Analysis of Endovascular Coiling and Clipping for Ruptured Cerebral Aneurysms: An Individual Patient-Level Meta-Analysis Assessing Rerupture Rates.

Background: Although the initial functional outcome findings of the International Subarachnoid Aneurysm Trial (ISAT) study favored coiling at one year after aneurysmal subarachnoid hemorrhage (aSAH), concerns arose regarding limited long-term rerupture data. This meta-analysis is the first to analyze longitudinal individual patient data (IPD) of target aneurysm rerupture in terms of treatment modality. Methods: The present meta-analysis included studies that compared clipping with coiling of ruptured aneurysms regarding long-term rerupture. Rerupture rates' individual patient data (IPD) were extracted from published Kaplan-Meier curves utilizing the R package IPDfromKM in R Version 4.3.1. Results: A total of 3153 patients from two studies were included. The clipping arm included 1755 patients, whereas the coiling arm included 1398 patients. Median reconstructed follow-up was 6.1 years (IQR = 0.5-11.7). The rerupture rates in the clipping arm and the coiling arm were 0.5% and 1.5%, respectively (p = 0.002). Kaplan-Meier chart analysis of the 3153 patients revealed a shortened time to rerupture in the coiling arm (log-rank test: p = 0.01). The hazard ratio (HR) for coiling compared with clipping regarding rerupture was 3.62 (95% CI:1.21-10.86, p = 0.02). Conclusion: Target aneurysm rerupture was rare beyond the initial year. Pooled long-term IPD from the 3153 patients revealed that reruptures of target aneurysms are more common after coiling and might be considered in the pretherapeutic decision-making process for aSAH.

Recurrence-free survival dynamics following adjuvant chemotherapy for resected colorectal cancer: A systematic review of randomized controlled trials.

Several cytotoxic chemotherapies have demonstrated efficacy in improving recurrence-free survival (RFS) following resection of Stage II-IV colorectal cancer (CRC). However, the temporal dynamics of response to such adjuvant therapy have not been systematically quantified. The Cochrane Central Register of Trials, Medline (PubMed) and Web of Science were queried from database inception to February 23, 2023 for Phase III randomized controlled trials (RCTs) where there was a significant difference in RFS between adjuvant chemotherapy and surgery only arms. Summary data were extracted from published Kaplan-Meier curves using DigitizeIT. Absolute differences in RFS event rates were compared at matched intervals using multiple paired t-tests. The initial search yielded 1469 manuscripts. After screening, 18 RCTs were eligible (14 Stage II/III; 4 Stage IV), inclusive of 16,682 patients. In the absence of adjuvant chemotherapy, the greatest rate of recurrence was observed in the first year (mean RFS event rate; 0-0.5 years: 0.22 ± 0.21; 0.5-1 years: 0.20 ± 0.09). Adjuvant chemotherapy was associated with significant decreases in the RFS event rates for the intervals 0-0.5 years (0.09 ± 0.09 vs. 0.22 ± 0.21, p < 0.001) and 0.5-1 years (0.14 ± 0.11 vs. 0.20 ± 0.09, p = 0.001) after randomization, but not at later intervals (1-5 years). In Stage IV trials, RFS event rates significantly differed for the interval 0-0.5 years (p = 0.012), corresponding with adjuvant treatment durations of 6 months. In Stage II/III trials, which included therapies of 6-24 months duration, there were marked differences in the RFS event rates between surgery and chemotherapy arms for the intervals 0-0.5 years (p < 0.001) and 0.5-1 years (p < 0.001) with smaller differences in the RFS event rates for the intervals 1-2 years (p = 0.012) and 2-3 years (p = 0.010). In a systematic review of positive RCTs comparing adjuvant chemotherapy to surgery alone for Stage II-IV CRC, observed RFS improvements were driven by early divergences that occurred primarily during active cytotoxic chemotherapy. Late recurrence dynamics were not influenced by adjuvant therapy use. Such observations may have implications for the use of chemotherapy for micrometastatic clones detectable by cell-free DNA-based methodologies.

Catheter ablation for ventricular tachycardia after myocardial infarction: meta-analysis of randomised controlled trials

Abstract Background The prognostic impact of ventricular tachycardia (VT) catheter ablation is an important outstanding research question. Purpose We undertook a reconstructed individual patient data meta-analysis of randomised controlled trials comparing ablation to medical therapy in patients developing VT after myocardial infarction (MI). Methods We systematically identified all trials comparing catheter ablation to medical therapy in patients with VT and prior MI. The pre-specified primary endpoint was all-cause mortality assessed using reconstructed individual patient data obtained by digitisation of published Kaplan-Meier curves and subsequent construction of Cox proportional hazards regression models. Pre-specified secondary endpoints included trial-level assessment by random effects meta-analysis of all-cause mortality, VT recurrence, defibrillator shocks and all-cause hospitalisations. Meta-regression was performed to evaluate the effect of VT mapping in addition to substrate modification. Sensitivity analyses were performed depending on the proportion of patients with prior MI included. (PROSPERO ID CRD42023390799) Results Eight trials, recruiting a total of 874 patients, were included. 430 patients were randomised to catheter ablation and 444 to medical therapy. Catheter ablation reduced all-cause mortality compared to medical therapy when synthesising reconstructed individual patient data (hazard ratio 0.57, 95% confidence interval (CI) 0.38 to 0.85, p=0.007), but not in trial-level analysis (relative risk 0.91, 95%CI 0.67 to 1.23, p=0.53, I2=0%). Catheter ablation significantly reduced VT recurrence, defibrillator shocks and hospitalisations compared to medical therapy. Sensitivity analyses were consistent with the primary analyses. Conclusion In patients with post-infarct ventricular tachycardia, catheter ablation reduces mortality.

Updated Results from a Matching-Adjusted Indirect Comparison of Efficacy Outcomes of Isatuximab Plus Carfilzomib and Dexamethasone Versus Daratumumab Plus Lenalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma

Introduction: Findings from a previously conducted matching-adjusted indirect comparison (MAIC) between isatuximab plus carfilzomib with dexamethasone (IsaKd) and daratumumab plus lenalidomide and dexamethasone (DRd) among relapsed and/or refractory multiple myeloma (RRMM) patients receiving one to three prior lines of therapy (LoT) demonstrated a significantly better progression-free survival (PFS) and a positive trend for overall survival (OS) in favor of IsaKd compared with DRd (median follow up of 20.7 months for IKEMA trial). Additionally, IsaKd demonstrated an acceptable safety profile with significantly lower rates of several treatment-emergent adverse events than DRd [Richter J et al, Cancer Med 2023;12(7):8005-8017; Richter J et al.(Publication Number 1962), 63 rd ASH Annual Meeting and Exposition, 2021; Richter J, et al. P-213, Clin Lymphoma Myeloma Leuk. 2021;21(Suppl 2):S156-S157]. The present study used longer follow-up data from the phase 3 IKEMA trial (NCT03275285) to update the previous MAIC evaluating the comparative efficacy of IsaKd versus DRd. Methods: A MAIC was performed with the latest available individual patient-level data (IPD) from the IKEMA trial (IsaKd arm, n = 179) (data cutoff: February 2023 for OS and January 2022 for PFS), and aggregate data from study publications of phase 3 POLLUX trial (DRd arm, n = 286, NCT02076009) [Bahlis NJ et al. Leukemia 2020;34(7):1875-1884; Dimopoulos MA et al. Hemasphere 2022;6:13]. Patients were selected from the IsaKd arm of the IKEMA trial to match the inclusion and exclusion criteria of the POLLUX trial. Individual patients from the IKEMA trial were then assigned weights such that (1) weighted mean baseline characteristics for patients in the IsaKd arm matched those reported for patients in the DRd arm, and (2) each patient's weight was equal to their estimated odds (propensity) of being in the POLLUX trial versus the IKEMA trial. After matching, outcomes were compared across the two trial populations. For PFS and OS, hazard ratio (HR) and 95% confidence interval (CI) were reported from a Cox proportional hazards (PH) model using the weighted sample for IsaKd and the pseudo-IPD for DRd extracted from published Kaplan-Meier curves via digitization software [Mark M et al, Engauge Digitizer Software; http://markummitchell.github.io/engauge-digitizer]. For any violations of the PH assumption, the restricted mean survival time (RMST) at median follow-up of IKEMA for the outcome of interest was calculated instead. Results: After the MAIC adjustment, all available baseline characteristics were well balanced across the trial populations. For PFS, as the PH assumption was violated ( χ2 = 5.52, p = 0.019), RMST method was used to compare the two treatments. PFS was significantly better with IsaKd versus DRd (mean difference [95% CI]: 3.63 months [0.14-7.12]; p = 0.04) at 44 months follow-up using RMST method. For OS, the PH assumption ( χ2 = 0.89, p =0.35) was not violated. A numeric, statistically non-significant trend in favor of IsaKd versus DRd was observed for OS (Figure 1). Conclusions: This MAIC analysis demonstrated a significant benefit in PFS and a positive trend in the improvement of OS with IsaKd compared with that with DRd. These findings with a longer follow-up were consistent with the previous analyses conducted with a follow-up of 2 years. These data highlight the therapeutic potential of IsaKd, a lenalidomide-free regimen, in RRMM patients receiving one to three prior LoT compared with a lenalidomide-based regimen.

Time-Dependent Changes in Risk of Progression During Use of Bevacizumab for Ovarian Cancer

Although bevacizumab has been used in the treatment of ovarian cancer, its optimal use is unknown. To investigate time-dependent changes in the outcomes of bevacizumab therapy. This cohort study was conducted using published data from 7 previous randomized phase 3 clinical trials with bevacizumab (ICON7, GOG-0218, BOOST, GOG-0213, OCEANS, AURERIA, and MITO16B) from January 10 to January 31, 2023. From 2 ancillary analyses of the ICON7 trial with individual patient data and tumor gene expression profiles, an ICON7-A cohort was generated comprising 745 cases. From other studies, published Kaplan-Meier curves were graphically analyzed. Bevacizumab treatment vs placebo or no treatment. Restricted mean survival time and relative risk of progression at a given time point between bevacizumab treatment and control groups. In the ICON7-A cohort (n = 745), restricted mean survival analysis showed that bevacizumab treatment (n = 384) had significantly better progression-free survival (PFS) than the control (n = 361) before bevacizumab discontinuation (restricted mean survival time ratio, 1.08; 95% CI, 1.05-1.11; P < .001), but had significantly worse PFS after bevacizumab discontinuation (0.79; 95% CI, 0.69-0.90; P < .001), showing rebound. In a post hoc analysis, the rebound was similarly observed both in homologous recombination deficiency (HRD) (before, 1.05; 95% CI, 1.02-1.09; P < .001; after, 0.79; 95% CI, 0.63-0.98; P = .04) and non-HRD tumors (before, 1.08; 95% CI, 1.03-1.15; P < .001; after, 0.71; 95% CI, 0.56-0.90; P < .001) of the serous subtype, but not in the nonserous subtype (before, 1.11; 95% CI, 1.05-1.18; P < .001; after, 0.94; 95% CI, 0.78-1.15; P = .57). In Kaplan-Meier curve image-based analysis, the trend of rebound effect was consistently observed in the overall ICON7 and GOG-0218 cohorts and their subgroups stratified by prognostic factors, homologous recombination-associated mutations, and chemotherapy sensitivity. In contrast, no such trend was observed in the studies GOG-0213, OCEANS, AURERIA, and MITO16B, in which patients who experienced relapse received bevacizumab until progression. In ovarian cancer, bevacizumab may reduce progression for approximately 1 year after initiation, but discontinuation may increase subsequent progression in the serous subtype regardless of HRD status. The results suggest that in the first-line treatment, bevacizumab may be more beneficial in patients with a shorter prognosis who are less likely to experience the rebound outcome.

Cost-effectiveness analysis of 7 treatments in metastatic hormone-sensitive prostate cancer: a public-payer perspective.

Recently, several new treatment regimens have been approved for treating metastatic hormone-sensitive prostate cancer, building on androgen deprivation therapy alone. These include docetaxel androgen deprivation therapy, abiraterone acetate-prednisone androgen deprivation therapy, apalutamide androgen deprivation therapy, enzalutamide androgen deprivation therapy, darolutamide-docetaxel androgen deprivation therapy, and abiraterone-prednisone androgen deprivation therapy with docetaxel. There are no validated predictive biomarkers for choosing a specific regimen. The goal of this study was to conduct a health economic outcome evaluation to determine the optimal treatment from the US public sector (Veterans Affairs). We developed a partitioned survival model in which metastatic hormone-sensitive prostate cancer patients transitioned between 3 health states (progression free, progressive disease to castrate resistance state, and death) at monthly intervals based on Weibull survival model estimated from published Kaplan-Meier curves using a Bayesian network meta-analysis of 7 clinical trials (7208 patients). The effectiveness outcome in our model was quality-adjusted life-years (QALYs). Cost input parameters included initial and subsequent treatment costs and costs for terminal care and for managing grade 3 or higher drug-related adverse events and were obtained from the Federal Supply Schedule and published literature. Average 10-year costs ranged from $34 349 (androgen deprivation therapy) to $658 928 (darolutamide-docetaxel androgen deprivation therapy) and mean QALYs ranged from 3.25 (androgen deprivation therapy) to 4.57 (enzalutamide androgen deprivation therapy). Treatment strategies docetaxel androgen deprivation therapy, enzalutamide androgen deprivation therapy docetaxel, apalutamide androgen deprivation therapy, and darolutamide-docetaxel androgen deprivation therapy were eliminated because of dominance (ie, they were more costly and less effective than other strategies). Of the remaining strategies, abiraterone acetate-prednisone androgen deprivation therapy was the most cost-effective strategy at a willingness-to-pay threshold of $100 000/QALY (incremental cost-effectiveness ratios = $21 247/QALY). Our simulation model found abiraterone acetate-prednisone androgen deprivation therapy to be an optimal first-line treatment for metastatic hormone-sensitive prostate cancer from a public (Veterans Affairs) payer perspective.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Ibr is a standard therapy for CLL with demonstrated efficacy in first-line and R/R settings. Within R/R CLL, single-agent Ibr was evaluated in 3 randomized phase 3 trials: RESONATE (vs. ofatumumab), ALPINE (vs. zanubrutinib), and ELEVATE-RR (vs acalabrutinib in pts with del(11q) or del(17p)). This analysis evaluated outcomes of Bruton’s tyrosine kinase inhibitor (BTKi) treatment in pts with R/R CLL by comparing the efficacy of Ibr in RESONATE to ALPINE and ELEVATE-RR using a matching-adjusted indirect comparison analysis. Methods: Individual patient data (IPD) of Ibr-treated pts from RESONATE (NCT01578707) were separately match-adjusted to Ibr-treated arms of 1) ALPINE (NCT03734016) and 2) ELEVATE-RR (NCT02477696) for key baseline characteristics: age ≥75 y, bulky disease, ≥3 or ≥4 prior treatments, b2 microglobulin >3.5 mg/L, and del(11q) or del(17p). For comparison with ELEVATE-RR, only pts with del(17p) or del(11q) from RESONATE were included. After matching, adjusted ORR (CR + CRi + nPR + PR) and PFS from RESONATE were compared with published outcomes from ALPINE and ELEVATE-RR; for PFS, IPD for ALPINE and ELEVATE-RR were extracted from published Kaplan-Meier curves. Hazard ratios (HRs) were calculated using a weighted Cox model. Results: The analysis comprised 785 Ibr-treated pts across RESONATE (n = 195), ALPINE (n = 325), and ELEVATE-RR (n = 265). After omission of pts with missing values and the adjustment procedure, the effective RESONATE sample size was 95 pts (vs ALPINE) and 69 pts (vs ELEVATE-RR). Median follow-up was 36.0 versus 29.6 mo (RESONATE adjusted vs. ALPINE published) and 36.1 versus 40.9 mo (RESONATE adjusted vs. ELEVATE-RR published). 2-y PFS (95% CI) for Ibr-treated pts in RESONATE adjusted sample and ALPINE was 81% (74–90) and 66% (60–71), respectively; median PFS was 40.7 and 34.2 mo, with an HR (95% CI) of 0.57 (0.39–0.84) favoring RESONATE, P = 0.0048 (Figure). ORR (95% CI) was 90% (86–94) and 74% (69–79), respectively (P < 0.0001). Compared with the ELEVATE-RR Ibr arm, which included more pts with high-risk genetic features than ALPINE, the RESONATE adjusted sample had greater 2-y PFS (79% [69–89] vs. 69% [64–75], not statistically significant). Median PFS was 41.2 vs. 44.1 mo (HR [95% CI] 0.85 [0.55–1.31], P = 0.46), respectively; ORR was 89% (83–95) and 80% (75–85) (P = 0.0381). Encore Abstract - previously submitted to EHA 2023 The research was funded by: The research was funded by Pharmacyclics LLC, an AbbVie Company. Keywords: Chronic Lymphocytic Leukemia (CLL), Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. P. Ghia Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Merck Sharp & Dohme, Bristol Myers Squibb, Janssen, Eli Lilly/Loxo Oncology, and Roche Honoraria: AbbVie, AstraZeneca, BeiGene, Merck Sharp & Dohme, Bristol Myers Squibb, Janssen, Eli Lilly/Loxo Oncology, and Roche Research funding: AbbVie, AstraZeneca, and Janssen T. Munir Consultant or advisory role: Morphosys and Sunesis Honoraria: AbbVie, AstraZeneca, Gilead, Janssen, and Novartis Other remuneration: travel/accommodation expenses from AbbVie, Gilead, or Janssen J. Burger Consultant or advisory role: BeiGene, Gilead, Janssen, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics Honoraria: Gilead, Janssen, Novartis, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics Other remuneration: travel/accommodation expenses from Gilead, Janssen, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics J. F. Seymour Research funding: AbbVie, Celgene, Janssen, and F. Hoffmann-La Roche Ltd. Other remuneration: speakers’ bureau with AbbVie, Celgene, and F. Hoffmann-La Roche Ltd.; patents, royalties, or other intellectual property with AbbVie; and expert testimony for F. Hoffmann-La Roche Ltd. K. Rogers Consultant or advisory role: Acerta Pharma, AstraZeneca, Beigene, Genentech, Innate Pharma, and Pharmacyclics, LLC, an AbbVie company Research funding: AbbVie, Genentech, Janssen, and Novartis Other remuneration: travel/accommodation expenses from AstraZeneca H. Huang Employment or leadership position: Everest Clinical Research and AbbVie Consultant or advisory role: Everest Clinical Research and AbbVie Research funding: Everest Clinical Research and AbbVie C. Moreno Consultant or advisory role: AbbVie, Ascentage, AstraZeneca, and Janssen Research funding: AbbVie and Janssen Other remuneration: speakers’ bureau for Janssen L. Neumayr Employment or leadership position: AbbVie Consultant or advisory role: ApoPharma Stock ownership: AbbVie Honoraria: Novartis Research funding: Pfizer and Sancilio Other remuneration: travel accommodations from Forma Therapeutics C. Abbazio Employment or leadership position: AbbVie Stock ownership: AbbVie and Bristol Myers Squibb J. Sharman Consultant or advisory role: AbbVie, AstraZeneca, and BeiGene Honoraria: AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, Genentech, Lilly, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics

Cost-effectiveness analysis (CEA) of seven treatment regimens in metastatic hormone-sensitive prostate cancer (mHSPC): A public payer perspective using network meta-analysis.

5081 Background: Recently several new drug treatment regimens have been approved in mHSPC state, building on using androgen deprivation therapy (ADT) alone. These include docetaxel + ADT (DA), Abiraterone Acetate + Prednisone + ADT (AAP), Apalutamide + ADT (AAT), Enzalutamide + ADT (ET), Darolutamide + Docetaxel + ADT (DAD) and AAP + ADT + Docetaxel (AAD). At present, there are no predictive biomarkers for choosing a specific drug regimen over the other. The goal of this study was to conduct an economic evaluation of FDA-approved standard of care drug regimens in the current management of mHSPC state to determine a cost-effective optimal treatment from the US public sector (Veterans Affairs-VA) perspective with a 10-year time horizon. Methods: We developed a partitioned survival model in which mHSPC patients (pts) transitioned between three health states (progression free, progressive disease to castrate resistance state, and death) at monthly intervals based on Weibull survival model estimated from published Kaplan-Meier curves using a network meta-analysis. A Bayesian network meta-analysis of seven randomized clinical trials included 7,208 mHSPC pts. The effectiveness outcome in our model was quality-adjusted life-years (QALYs) with utility values obtained from published literature. Costs in our model included those associated with treatment regimens, subsequent therapies, terminal care, and for managing grade 3-4 drug related adverse events. Costs were obtained from the Federal Supply Schedule and published literature. Incremental cost-effectiveness ratios (ICERs) were calculated for nondominated treatments. Results: Average 10-year costs ranged from $32,697 (ADT) to $649,622 (DAD). Mean QALYs ranged from 3.25 (ADT) to 4.57 (ET). Treatment with DAT, EAD, and DAD were eliminated due to dominance (i.e. they were more costly and less effective than other treatments). AAT was the most cost-effective strategy at a willingness-to-pay threshold of $100,000/QALY (ICER = $70,150/QALY). Results from our analysis for all regimens are shown. Conclusions: Our CEA simulation model found AAT is an optimal cost-effective first-line treatment strategy in mHSPC state from a public (VA) payer perspective. [Table: see text]

The emerging use of immunotherapy as a treatment option in metastatic renal cell carcinoma: Real-world evidence from a single UK tertiary cancer centre.

e16509 Background: The landscape of systemic anticancer therapy (SACT) options for the treatment of metastatic renal cell carcinoma (mRCC) has recently evolved following results from the CheckMate 214 trial in 2018 which demonstrated improved overall survival in patients with International mRCC Database Consortium (IMDC) intermediate- and poor-risk mRCC clear cell histological subtype receiving combination immunotherapy (Ipilimumab/Nivolumab) in the first-line setting compared to Sunitinib. This is in addition to other treatment options including: vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) (e.g. Sunitinib, Pazopanib, Tivozanib, Cabozantinib, etc.), combination immunotherapy/TKI (e.g. Avelumab/Axitinib), VEGF/mammalian target of Rapamycin (mTOR) inhibitors (e.g. Lenvatinib/Everolimus) and single-agent immunotherapy (e.g. Nivolumab) in both first- and second-line settings. Methods: An audit of SACT prescribing practices in mRCC between 2019-2022 in a single UK tertiary cancer centre (Castle Hill Hospital, Hull, UK) was conducted as part of a national collaboration multi-centre UK audit looking into the real-world landscape and treatment choices in mRCC. Information was derived from the Somerset Cancer Registry and a dataset containing 87 patients with a coded diagnosis of ‘malignant neoplasm of kidney, except renal pelvis (CX64X)’ and ‘secondary malignant neoplasm of kidney &amp; renal pelvis (C790)’ was generated. Results: Of the 81 patients included in the final analysis, 65% (n = 53) were male and 81% (n = 66) had a clear cell histological subtype. The main sites of metastases were lung (n = 58) and lymph nodes (n = 45). Most of the patients (n = 72) received either one or two lines of SACT. Of those with clear cell mRCC, 74% (n = 51/69) were classed as having IMDC intermediate- or poor-risk features with almost half (n = 34/69) receiving combination Ipilimumab/Nivolumab. Comparing overall survival (OS) and progression-free survival (PFS) to the published Kaplan-Meier curves in the CheckMate 214 trial, no significant differences in OS (p = 0.6) and PFS (p = 0.13) were observed, although there was an overall trend towards improved PFS in the first 6 months (82.4% vs 63.3%) in our local dataset. Conclusions: The results of our real-world evaluation of prescribing practices in mRCC favoured the use of combination immunotherapy in the first-line setting for the treatment of IMDC intermediate- and poor-risk clear cell mRCC with similar outcomes to the published data in the CheckMate 214 trial. The overall trend towards improved PFS in the first 6 months in our local dataset highlights the importance of patient selection when using immunotherapy.

PD24-03 BEST TREATMENT FOR OLIGOMETASTATIC RENAL CANCER: A QUASI-INDIVIDUAL PATIENT DATA ANALYSIS

You have accessJournal of UrologyCME1 Apr 2023PD24-03 BEST TREATMENT FOR OLIGOMETASTATIC RENAL CANCER: A QUASI-INDIVIDUAL PATIENT DATA ANALYSIS Giuseppe Fallara, Giuseppe Rosiello, Alberto Martini, Giacomo Musso, Francesco Cei, Chiara Re, Federico Belladelli, Andrea Necchi, Daniele Raggi, Laura Marandino, Roberto Bertini, Pierre I. Karakiewicz, Alexandre Mottrie, Alberto Briganti, Andrea Salonia, Francesco Montorsi, Alessandro Larcher, and Umberto Capitanio Giuseppe FallaraGiuseppe Fallara More articles by this author , Giuseppe RosielloGiuseppe Rosiello More articles by this author , Alberto MartiniAlberto Martini More articles by this author , Giacomo MussoGiacomo Musso More articles by this author , Francesco CeiFrancesco Cei More articles by this author , Chiara ReChiara Re More articles by this author , Federico BelladelliFederico Belladelli More articles by this author , Andrea NecchiAndrea Necchi More articles by this author , Daniele RaggiDaniele Raggi More articles by this author , Laura MarandinoLaura Marandino More articles by this author , Roberto BertiniRoberto Bertini More articles by this author , Pierre I. KarakiewiczPierre I. Karakiewicz More articles by this author , Alexandre MottrieAlexandre Mottrie More articles by this author , Alberto BrigantiAlberto Briganti More articles by this author , Andrea SaloniaAndrea Salonia More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Alessandro LarcherAlessandro Larcher More articles by this author , and Umberto CapitanioUmberto Capitanio More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003302.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Oligometastatic renal cell carcinoma is a frequent diagnosis for which very few randomized control studies (RCTs) have been conducted and still represent a challenge for clinicians. Over the past few years, the results of two Phase I/II trials on this issue, the RESORT (Sorafenib+SBRT) and the RAPPORT (Pembrolizumab+SBRT) have been published. In addition, at ASCO23 the Kaplan Meier curves regarding the M1-NED group of the KEYNOTE-564 (surgery on metastases+Pembro) has been presented. In this hypothesis generating work, we aimed to assess which of these approaches has the best outcomes. METHODS: A comprehensive search for all published trials which included survival data on treatment for oligometastatic RCC was conducted in PubMed, EMBASE, Web of Science, and Scopus databases up to 10/2022. We reconstructed the survival data from published Kaplan-Meier curves on overall survival (OS) meta-analyzed Pembrolizumab+SBRT versus Sorafenib+SBRT versus surgery Pembro. The outcomes of interest were assessed using differences in restricted mean survival time (ΔRMST) at different time points and Cox regression. RESULTS: Three studies were included in the final analysis (RESORT, RAPPORT and KEYNOTE-564). Overall, 91 patients were included in the meta-analysis. In all the trials, patients had histologically confirmed clear cell RCC (nephrectomy in all the patients out of 3/30 in the RAPPORT) with ECOG≤2 and a number of one to five sites of metastatic disease at the time of enrollment. The small number of patients and the incomplete reporting of data did not allow statistical meaningful comparison among the studies. Pembrolizumab+NED obtained the higher OS benefit (Figure 1) (HR: 0.37 compared to Sorafenib+SBRT and 0.33 compared to Pembro+SBRT, all p<0.05), with ΔRMST at 24 months of 1.4 months (1.0-1.8) compared with Sorafenib+SBRT and of 1.2 months (0.9-1.3) compared to Pembro+SBRT. CONCLUSIONS: Despite lack of baseline differences, lack of power and presence of confounding, this hypothesis generating meta-analysis support the use of the combination of surgery+Pembro for oligometastatic ccRCC. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e722 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Giuseppe Fallara More articles by this author Giuseppe Rosiello More articles by this author Alberto Martini More articles by this author Giacomo Musso More articles by this author Francesco Cei More articles by this author Chiara Re More articles by this author Federico Belladelli More articles by this author Andrea Necchi More articles by this author Daniele Raggi More articles by this author Laura Marandino More articles by this author Roberto Bertini More articles by this author Pierre I. Karakiewicz More articles by this author Alexandre Mottrie More articles by this author Alberto Briganti More articles by this author Andrea Salonia More articles by this author Francesco Montorsi More articles by this author Alessandro Larcher More articles by this author Umberto Capitanio More articles by this author Expand All Advertisement PDF downloadLoading ...

Cost-effectiveness analysis of seven treatment regimens in metastatic hormone-sensitive prostate cancer (mHSPC): A public payer perspective using network meta-analysis.

268 Background: Recently several new treatment regimens have been approved for treating mHSPC, building on the previous standard of care using androgen deprivation therapy (ADT) alone. These include docetaxel+ADT (DA), Abiraterone Acetate+Prednisone+ADT (AAP), Apalutamide+ADT (AAT), Enzalutamide+ADT (ET), Darolutamide+Docetaxel+ADT (DAD) and Abiraterone+Prednisone+ADT+Docetaxel (AAD). There are no current predictive biomarkers for choosing any specific regimen. The goal of this study was to determine the cost-effectiveness of these new treatments from the US public sector perspective with a lifetime horizon. Methods: We developed a partitioned survival model in which mHSPC patients transitioned between three health states (progression free, progressive disease to castrate resistance state, and death) at monthly intervals based on Weibull survival model estimated from published Kaplan-Meier curves using a network meta-analysis. A Bayesian network meta-analysis of seven clinical trials included 7,208 patients. The effectiveness outcome in our model was quality-adjusted life-years (QALYs) with utility values obtained from published literature. Costs in our model included those associated with treatment regimens and subsequent therapies, terminal care, and for managing grade 3-4 drug related adverse events, and were obtained from the Federal Supply Schedule and published literature. Results: Average lifetime costs ranged from $154,139 (AAP) to $770,848 (DAD) and mean QALYs ranged from 3.33 (ADT) to 5.08 (ET). All treatment strategies other than AAP and ET were eliminated due to dominance. Compared to AAP, the incremental cost-effectiveness ratio for ET was $484,943/QALY. Results from our analysis including all regimens are shown. Conclusions: Our simulation model found that ET in mHSPC state yielded the most QALYs and would be the most cost-effective option with a WTP threshold as high as $500,000/QALY. However, for a WTP threshold of $150,000/QALY, AAP was the most cost-effective treatment strategy. [Table: see text]

Clinical outcomes of chemotherapy-based therapies for previously treated advanced colorectal cancer: a systematic literature review and meta-analysis.

The purpose of this study was to evaluate clinical outcomes of standard therapies in previously treated, advanced colorectal cancer (CRC) patients. A systematic literature review was conducted in Embase, MEDLINE, and CENTRAL databases (January 2000-July 2021), annual oncology conferences (2019-2021), and clinicaltrials.gov to identify studies evaluating the use of licensed interventions in second-line or later settings. The primary outcome of interest was objective response rate (ORR) and secondary outcomes included progression-free survival (PFS) and overall survival (OS). ORR was pooled using the Freeman-Tukey double arcsine transformation. For survival outcomes, published Kaplan-Meier curves for OS and PFS were digitized to re-construct individual patient-level data and pooled following the methodology described by Combescure et al. (2014). Twenty-three trials evaluating standard chemotherapies with or without targeted therapies across 4,791 advanced CRC patients contributed to our meta-analysis. In the second-line setting, the random effects pooled estimate of ORR was 22.4% (95% confidence interval (CI): 18.0, 27.1), median PFS was 7.0months (95% CI: 6.4, 7.4), and median OS was 14.9months (95% CI: 13.6, 16.1). In the third-line or later setting, the random effects pooled estimate of ORR was 1.7% (95% CI: 0.8, 2.7), median PFS was 2.3months (95% CI: 2.0, 2.8), and median OS was 8.2months (95% CI: 7.1, 9.1). Standard treatments have limited efficacy in the second-line or later setting with worsening outcomes in later lines. Given the global burden of CRC, further research into novel and emerging therapeutic options following treatment failure is needed.

Survival Trends in Sorafenib for Advanced Hepatocellular Carcinoma: A Reconstructed Individual Patient Data Meta-Analysis of Randomized Trials

Background: Emerging data suggest that outcomes for advanced hepatocellular carcinoma (HCC) treated with sorafenib may have improved over time. We aimed to provide robust, time-to-event estimates of survival outcomes for sorafenib in advanced HCC. Summary: In this systematic review and individual patient data meta-analysis of randomized-controlled trials (RCTs), we searched MEDLINE and Embase from inception till September 2022 for RCTs that provided data for overall survival (OS) and progression-free survival (PFS) for sorafenib monotherapy as first-line systemic therapy for advanced HCC. We performed a pooled analysis using reconstructed individual participant data from published Kaplan-Meier curves to obtain robust estimates for OS and PFS. Of 1,599 articles identified, 29 studies (5,525 patients) met the inclusion criteria. Overall, the median OS was 10.4 (95% CI: 9.6–11.4) months. Median OS increased over time, from 9.8 (95% CI: 8.8–10.7) months in studies before 2015 to 13.4 (95% CI: 11.03–15.24) months in studies from 2015 onwards (p < 0.001). OS did not differ by trial phase, geographical region, or study design. The overall median PFS was 4.4 (95% CI: 3.9–4.8) months, but PFS did not improve over time. Sensitivity analysis of studies from 2015 and onwards to account for the introduction of direct-acting antivirals determined that hepatitis C virus was associated with reduced mortality (p < 0.001). There was minimal heterogeneity in the estimates for OS (all I² ≤ 33). Key Messages: Survival outcomes for sorafenib in advanced HCC have improved over time. These data have important implications for clinical trial design.