Application of ASCO Value Framework to Treatment Advances in Hepatocellular Carcinoma

2021 ◽  
pp. OP.20.00558 ◽  
Author(s):  
Emerson Y. Chen ◽  
Madeline Cook ◽  
Christopher Deig ◽  
Asad Arastu ◽  
Vinay Prasad ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Secondary Analysis ◽  
Health Benefit ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Primary Analysis ◽  
Free Survival ◽  
Drug Registration ◽  
Phase Iii Trials

BACKGROUND: Determination of the comparative efficacy of one therapy over another for hepatocellular carcinoma (HCC) can be challenging. Application of a recognized value framework to published studies could objectively compare the potential benefit across available therapies. MATERIALS AND METHODS: An umbrella review of phase III trials for HCC therapies was performed. ASCO Value Framework Net Health Benefit Score version 2 (ASCO-NHB v2) scores, the primary analysis, and European Society of Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 scores, the secondary analysis, were computed using selected drug registration trials. Both scores were compared between drugs that were Food and Drug Administration (FDA)-approved by 2020 and those that were not. RESULTS: Of the 22 studies identified, nine were FDA-approved and 13 were not. Across 22 trials, the median overall survival (OS) was 9.2 months (range, 1.9-16.4 months), with a median gain of 0.35 month (range, 2.3-3.3 months). HCC therapies that were FDA-approved showed longer OS (median 10.7 v 7.9 months, P < .01) and higher ASCO NHB scores (+18.4 v −5.7 scores, P < .01). The median gain in OS was 2.2 months in the approved treatments compared with −0.3 months in the unapproved group, with no difference in progression-free survival between the two groups. CONCLUSION: The nine FDA-approved therapies for HCC have higher mean NHB score than those that were not FDA-approved. The application of ASCO-NHB v2 and other proposed value frameworks could examine data of future therapies for HCC through a patient-oriented approach.

Role of Sensitivity Analyses in Assessing Progression-Free Survival in Late-Stage Oncology Trials

2009 ◽  
Vol 27 (35) ◽  
pp. 5958-5964 ◽  
Author(s):  
Suman Bhattacharya ◽  
Gwen Fyfe ◽  
Robert J. Gray ◽  
Daniel J. Sargent
Keyword(s):  
Clinical Trial ◽  
Late Stage ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Sensitivity Analyses ◽  
Potential Bias ◽  
Primary Analysis ◽  
Free Survival ◽  
End Point ◽  
Phase Iii Trials

Sensitivity analysis is an important statistical technique that assesses whether the results of phase III trials are robust and likely to be generalizable. Until recently, sensitivity analyses were rarely included in phase III trials, and they remain poorly understood by many oncologists. Sensitivity analyses are critical to understanding the strength of conclusions made in the primary analysis of a late-stage clinical trial. They examine the influence of protocol design errors, unintended biases, deviations from assumptions underlying statistical models, and any unanticipated treatment delivery or practice patterns on trial results. In trials with complex or subjective end points, they also allow an understanding of the extent to which a positive outcome is driven by a single, possibly subjective, and therefore biased, element of an end point. The purposes of this article are to explain how sensitivity analyses are performed, to discuss areas of a clinical trial where sensitivity analyses should focus, and to illuminate the importance of this technique in the rigorous evaluation of late-stage clinical trial data, using specific examples. This article focuses on late-stage trials that use progression-free survival or time to progression as their primary end point, because sensitivity analyses are particularly important in these cases for which the end point is potentially subject to bias. Three sources of potential bias are explored: assessment time, symptomatic (ie, nonradiologic) disease progression, and missing data. For each source of potential bias, case studies are presented to highlight the role that sensitivity analyses play in determining whether the trial's conclusions are robust.

scholarly journals P14.15 Benefit of Bevacizumab for recurrent glioblastoma. Results of 81 patients from a single institution

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii69-iii69
Author(s):  
O Absalyamova ◽  
G Kobiakov ◽  
G Agabekyan ◽  
A Poddubsky ◽  
A Belyashova ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Recurrent Glioblastoma ◽  
Phase Iii ◽  
Rapid Progression ◽  
Concomitant Disease ◽  
Free Survival ◽  
Phase Iii Trials ◽  
Continuous Application

Abstract BACKGROUND No standard of care has been established for patients with progressive glioblastoma (rGBM). Previous studies suggested that bevacizumab (BEV) is safe and produces responses that result in a decreased use of glucocorticoids and increased progression-free survival (PFS) with an unclear effect on overall survival (OS). Crossover to BEV in the control arm is the possible reason why the advantage of BEV has not been proven in Phase III trials. We retrospectively analyzed own results of BEV treatment in rGBM. MATERIAL AND METHODS 81 patients progressed after radiotherapy plus concomitant and maintenance temozolomide (TMZ) and undergo BEV as monotherapy (BevMo, 11 patients) or in combinations (Irinotecan (BevI) - 53, lomustine (BevL)- 11, TMZ (BevT) - 6. Median age 54 years. Among them 33 patients were re-irradiated: 11 - radiosurgery (RS), 20 fractionated irradiation (RT), 2 - RS+RT. 33 patients continued BEV after progression with changing or adding cytostatic. PFS was calculated from the date of verification, PFS1 - from the date of 1-st progression, PFS2 - from the date of 2-nd progression. RESULTS Median PFS was 9.0 ([CI] 7.0–10.9) months. Median PFS1 was 10.5 ([CI] 8.1–12.9) months. In the BevMo, BevI, BevL, BevT group PFS1 was 15.7, 10.1, 10.5, 13.2 months, respectively, p=0.7. Objective response (OR) was reached in 34%, stable disease (SD) in 28%, progression (PD) in 37% patients. 16 patients stopped BEV without progression (4-patient`s decision, 7- doctor`s decision, 2 - adverse event, 3 - concomitant disease). Median time of BEV treatment was 11.6 months. Median BEV-free interval till progression was 3.7 months. 33 patients continued or restarted BEV after progression. Median PFS2 was 8.0 ([CI] 4.9–11.1) months. The median OS from the date of 1-st progression was 23.5 months ([CI] 18.7–27.4). In groups with RT, RS, RS+RT and no re-irradiarion OS was 24.6 ([CI] 17.6–31.5), 35.4 ([CI] 35.0–35.8), 17.8, 20.6 ([CI] 15.2–26.0), respectively, p=0.2. CONCLUSION OS in our group is outrageously high. Maintaining BEV after progression was effective. In our group BEV discontinuation led to rapid progression. The resumption of Bev with progression was effective, which indicates the advisability of its continuous application.

scholarly journals Cisplatin-Based First-Line Treatment of Elderly Patients With Advanced Non–Small-Cell Lung Cancer: Joint Analysis of MILES-3 and MILES-4 Phase III Trials

2018 ◽  
Vol 36 (25) ◽  
pp. 2585-2592 ◽  
Author(s):  
Cesare Gridelli ◽  
Alessandro Morabito ◽  
Luigi Cavanna ◽  
Andrea Luciani ◽  
Paolo Maione ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Advanced Nsclc ◽  
Performance Status ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Free Survival ◽  
Phase Iii Trials ◽  
Health Status Score

Purpose To test the efficacy of adding cisplatin to first-line treatment for elderly patients with advanced non–small-cell lung cancer (NSCLC) within a combined analysis of two parallel phase III trials, MILES-3 and MILES-4. Patients and Methods Patients with advanced NSCLC who were older than age 70 years with Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to gemcitabine or pemetrexed, without or with cisplatin. In each trial, 382 events were required to detect a hazard ratio (HR) of death of 0.75, with 80% power and two-tailed α of .05. Trials were closed prematurely because of slow accrual, but the joint database allowed us to analyze the efficacy of cisplatin on the basis of intention-to-treat and adjusted by trial, histotype, non-platinum companion drug, stage, performance status, sex, age, and size of the study center. Results From March 2011 to August 2016, 531 patients (MILES-3, 299; MILES-4, 232) were assigned to gemcitabine or pemetrexed without (n = 268) or with cisplatin (n = 263). Median age was 75 years, 79% were male, and 70% had nonsquamous histology. At a median 2-year follow-up, 384 deaths and 448 progression-free survival events were recorded. Overall survival was not significantly prolonged with cisplatin (HR, 0.86; 95% CI, 0.70 to 1.05; P = .14) and global health status score of quality of life was not improved, whereas progression-free survival (HR, 0.76; 95% CI, 0.63 to 0.92; P = .005) and objective response rate (15.5% v 8.5%; P = .02) were significantly better. Significantly more severe hematologic toxicity, fatigue, and anorexia were found with cisplatin. Conclusion The addition of cisplatin to single-agent chemotherapy does not significantly prolong overall survival, and it does not improve global health status score of quality of life in elderly patients with advanced NSCLC.

Clinical Equipoise for Trials of Novel Biologic Therapies, Therapeutic Success Rates, and Predictors of Success: A Meta-Analysis

2017 ◽  
pp. 1-12
Author(s):  
Doah Cho ◽  
Felicia T. Roncolato ◽  
Johnathan Man ◽  
John Simes ◽  
Sarah J. Lord ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Predictors Of Success ◽  
Biologic Therapies ◽  
Therapeutic Success ◽  
Free Survival ◽  
Randomized Controlled ◽  
Phase Iii Trials

Purpose The demand for more rapid access to novel biologic therapies than randomized controlled trials can deliver is a topic of ongoing study and debate. We aimed to inform this debate by estimating therapeutic success from phase III trials comparing novel biologic therapies with standard of care and identifying predictors of success. Methods This was a meta-analysis of phase III trials evaluating novel biologic therapies in advanced breast, colorectal, lung, and prostate cancers. Therapeutic success was defined as statistically significant results for the primary end point favoring novel biologic therapies. Results Of 119 included phase III trials (76,726 patients), therapeutic success was 41%, with a statistically significant relative reduction in disease progression and death for novel biologic therapies over standard of care of 20% and 8%. Therapeutic success did not improve over time (pre-2010, 33%; 2010 to 2014, 44%; P = .2). Predictors of success were a biomarker-selected population (odds ratio, 4.74; 95% CI, 2.05 to 10.95) and progression-free survival end point compared with overall survival (odds ratio, 5.22; 95% CI, 2.41 to 11.39). Phase III trials with a biomarker-selected population showed a larger 28% progression-free survival benefit than phase III trials overall (hazard ratio, 0.72; 95% CI, 0.70 to 0.75) but similar 8% overall survival benefit (hazard ratio, 0.92; 95% CI, 0.90 to 0.94). Therapeutic success of phase III trials with and without a preceding phase II trial were 43% and 30%, respectively Conclusion Therapeutic success of novel biologic therapies in phase III trials, including therapies with a matching predictive biomarker, was modest and has not significantly improved over time. Equipoise remains and supports the ongoing ethical and scientific requirement for phase III randomized controlled trials to estimate treatment efficacy and assess the value of potential biomarkers.

Progression-free survival and overall survival in phase III trials of molecular-targeted agents in advanced non-small-cell lung cancer

Lung Cancer ◽  
2013 ◽  
Vol 79 (1) ◽  
pp. 20-26 ◽  
Author(s):  
Katsuyuki Hotta ◽  
Etsuji Suzuki ◽  
Massimo Di Maio ◽  
Paolo Chiodini ◽  
Yoshiro Fujiwara ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Small Cell Lung Cancer ◽  
Progression Free Survival ◽  
Small Cell ◽  
Phase Iii ◽  
Targeted Agents ◽  
Small Cell Lung ◽  
Free Survival ◽  
Phase Iii Trials

Tandem Autologous Stem Cell Transplants (auto-auto) with or without Maintenance Therapy Versus Single Autologous Transplant Followed by HLA-Matched Sibling Non- Myeloablative Allogeneic Stem Cell Transplant (auto-allo) for Patients (pts) with High Risk (HR) Multiple Myeloma (MM): Results From the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) 0102 Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 526-526 ◽  
Author(s):  
Edward A Stadtmauer ◽  
Amrita Krishnan ◽  
Marcelo C Pasquini ◽  
Marian Ewell ◽  
Edwin P Alyea ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplant ◽  
Chronic Gvhd ◽  
Secondary Analysis ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Cell Transplant ◽  
Primary Analysis ◽  
Hematopoietic Stem

Abstract Abstract 526 The prognosis of patients with high-risk myeloma (HR MM) continues to be dismal, despite the early incorporation of novel agents. Early phase trials of allogeneic hematopoietic stem cell transplant (alloHCT) suggest the possibility of an immunologic graft-versus-myeloma effect that might favorably affect survival. Less toxic reduced-intensity HCT preparative regimens now allow more widespread use of alloHCT in the MM population. BMT CTN 0102 is a phase III multicenter clinical trial that biologically assigned patients to either melphalan 200mg/m2 (MEL 200) auto-auto without (obs) or with 1 year of thalidomide and dexamethosone (ThalDex), or an auto-allo approach using MEL 200 followed by alloHCT using 2 Gy total body irradiation. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine and mycophenolate mofetil. Patients were stratified by biological prognostic factors that were considered to be high risk at the time of the trial design: chromosome 13 deletions by metaphase karyotype and beta-2 microglobulin ≥4 mg/dl. The primary endpoint was 3-year progression free survival (PFS). Between December 2003 and March 2007, 710 patients from 43 US centers were enrolled, and 85 fulfilled the criteria of HR MM. Among them, 48 were assigned to auto-auto (24 Thal-Dex and 24 obs) and 37 to auto-allo. Groups differed in age (median 57 y and 51y, p=0.02) but were otherwise balanced. Compliance with second transplant was 65% for auto-auto and 78% for auto-allo. Compliance with ThalDex was poor, so the two auto-auto arms were pooled for the primary analysis. Three-year PFS was 33% (95% Confidence Interval (CI), 22–50%) and 40% (95% CI, 27–60%, p=0.74) and 3-year OS was 67% (95% CI, 54–82%) and 59% (95% CI, 49–78%, p=0.46) for auto-auto and auto-allo, respectively. Corresponding probabilities for 3-year progression/relapse was 53% and 33% (p=0.09), and 3 year treatment-related mortality was 8% and 20% (p=0.3). Among auto-allo patients, probabilities of grade 3–4 acute and chronic GVHD were 9% and 48%, respectively. Among the 59 (31 auto-auto, 28 auto-allo) patients who received second transplant, 3 year PFS was 35% and 46% (p=0.6). Disease response at day 56 after second transplant was 57% for very good partial response (VGPR) or better and 37% for complete response (CR) and near CR (nCR) in the auto-auto group; and 48% (VGPR or better) and 41% (CR+nCR) in the auto-allo group. In conclusion, this planned secondary analysis of a cohort of HR MM patients demonstrated equivalent 3-year PFS and OS for auto-auto and auto-allo in both intention-to-treat and as-treated analyses. However, trends in late PFS and time to progression/relapse suggest further follow-up is needed before final conclusions regarding the utility of auto-allo in this HR cohort can be made. Finally, this study shows the feasibility of an alloHCT approach for HR MM patients and may serve as a platform for future studies seeking to enhance graft-versus-myeloma effects. Disclosures: Stadtmauer: Celgene: Speakers Bureau. Krishnan:Celgene: Speakers Bureau. Qazilbash:Celgene: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Giralt:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.

An update on BREAK-3, a phase III, randomized trial: Dabrafenib (DAB) versus dacarbazine (DTIC) in patients with BRAF V600E-positive mutation metastatic melanoma (MM).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9013-9013 ◽  
Author(s):  
Axel Hauschild ◽  
Jean Jacques Grob ◽  
Lev V. Demidov ◽  
Thomas Jouary ◽  
Ralf Gutzmer ◽  
...  
Keyword(s):  
Median Overall Survival ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Braf V600e ◽  
Phase Iii ◽  
Primary Analysis ◽  
Free Survival ◽  
Independent Review ◽  
Clinical Trial Information

9013 Background: Dabrafenib is a selective BRAF inhibitor with demonstrated efficacy in BRAF V600E-positive mutation in MM. The primary analysis of BREAK-3 (NCT01227889) compared progression-free survival (PFS) in patients (pts) with BRAF V600E-positive mutation MM treated with dabrafenib or DTIC. Methods: Median PFS for dabrafenib of 5.1 months (mo) and study methods were previously described (Hauschild A, et al. Lancet. 2012,380:358–365). Independent review ended at the primary analysis. PFS was updated in Jun 2012 at median follow-up of 10.5 mo for dabrafenib (67% of PFS events), and 9.9 mo for DTIC. Median overall survival (OS) was not reached, so another analysis of OS and safety was performed with data as of Dec 2012, at which time the median follow-up was 15.2 (dabrafenib) and 12.7 (DTIC) mo. PFS of subjects who crossed over was also evaluated at that time. Results: PFS hazard ratio was 0.37 [95% CI; 0.23, 0.57]; median PFS was 6.9 mo dabrafenib and 2.7 mo DTIC. In Dec 2012, 36/63 DTIC pts crossed over; median PFS was 4.3 [95% CI; 4.1, 6.1] mos. OS is presented in the Table.The four most common adverse events (AE) on the dabrafenib arm were hyperkeratosis (39%), headache (35%), arthralgia (35%), and pyrexia (32%). Serious AEs ≥ 5% on the dabrafenib arm included cutaneous squamous cell carcinoma/keratoacanthoma (10%) and pyrexia (5%). Conclusions: Longer follow-up confirms the benefits of dabrafenib on PFS and response rate. Median OS in the dabrafenib arm was over 18 mo and over 15 mo in the DTIC arm. OS results are confounded by crossover of DTIC pts to dabrafenib and likely by subsequent therapy after progression. The effects of subsequent therapy results will be investigated. The safety profile had no significant changes. Clinical trial information: NCT01227889. [Table: see text]

INTEGRATE: A randomized phase II double-blind placebo-controlled study of regorafenib in refractory advanced oesophagogastric cancer (AOGC)—A study by the Australasian Gastrointestinal Trials Group (AGITG), first results.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 9-9 ◽  
Author(s):  
Nick Pavlakis ◽  
Katrin Marie Sjoquist ◽  
Eric Tsobanis ◽  
Andrew Martin ◽  
Yoon-Koo Kang ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Secondary Analysis ◽  
Progression Free Survival ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Prognostic Indicators ◽  
Controlled Study ◽  
Primary Analysis ◽  
Double Blind

9 Background: Advanced Oesophago-Gastric Carcinoma (AOGC) has limited options following failure of first or second line chemotherapy (CT). Regorafenib (REG) is an oral multi-kinase inhibitor of kinases involved in angiogenesis, tumor microenvironment, and oncogenesis. This study examined whether REG has sufficient activity and safety for further evaluation. Methods: International (Australia & New Zealand (ANZ), Korea, Canada (NCIC CTG)) randomised phase II trial with 2:1 randomisation and stratification by: (1) Lines of prior CT for advanced disease (1 vs. 2) and (2) Region. Eligible patients received best supportive care plus 160mg REG or matching PBO orally on days 1-21 each 28-day cycle until disease progression or prohibitive adverse events. Primary endpoint was progression free survival (PFS) in the REG arm, assuming median 8 weeks (wks) in PBO arm, aiming for 13.2 wks with REG to be of interest. Results: From Nov 2012 to Feb 2014, 152 patients were enrolled, 147 evaluable [pre-specified primary analysis population]: (REG n=97: PBO n=50); well matched for key baseline prognostic indicators; male:female (118:29); primary location: OG Junction (56), stomach (85); lines of prior therapy: 1 (63), 2 (84); ECOG 0 (62): 1 (85). Time on treatment: Median: 7.9 (REG) v 4 (PBO) wks. In the evaluable population median PFS was 11.1 wks (95% CI: 7.7 - 12.3) (REG) and 3.9 wks (95% CI: 3.7 - 4.0) (PBO), log-rank p <0.0001; HR 0.41 (95% CI: 0.28 to 0.59). PFS results were maintained for secondary analysis including all randomized patients (n = 152). REG was well tolerated, with the spectrum of toxicity in keeping with previous reports. Conclusions: PFS was clearly significantly longer with REG than PBO, though PBO PFS was less than anticipated. The pre-specified exploratory comparisons provide compelling evidence that REG has sufficient activity with acceptable tolerability in refractory AOGC to warrant phase III evaluation. Mature OS results will be presented at the meeting. Clinical trial information: 12612000239864.

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