ASCO Value Framework Research Articles

Comparison of Long-term Survival Benefits in Trials of Immune Checkpoint Inhibitor vs Non–Immune Checkpoint Inhibitor Anticancer Agents Using ASCO Value Framework and ESMO Magnitude of Clinical Benefit Scale

Recently, anticancer agents have generated excitement owing to their capacity to preserve long-term durable survival in some patients who are represented by a tail of the survival curve. However, because traditional measures of clinical benefit may not accurately capture durable survival, amendments to various valuation frameworks have been proposed to capture this benefit. To determine how frequently immune checkpoint inhibitor (ICI) anticancer agents vs non-ICI anticancer agents displayed trends of long-term durable survival, as defined by the American Society of Clinical Oncology Value Framework version 2 (ASCO-VF v2) and European Society of Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1), as well as to further analyze the degree of agreement between ASCO and ESMO frameworks. In this cohort study, anticancer agents from phase 2 or 3 randomized clinical trials (RCTs) cited for clinical efficacy evidence in drug approval by the US Food and Drug Administration between January 2011 and March 2018 were identified. Data required for the ASCO-VF v2 tail-of-the-curve bonus and the ESMO-MCBS v1.1 immunotherapy-triggered long-term plateau adjustments were extracted from relevant RCTs. Frequency and difference in proportions were calculated to determine how often survival benefits were awarded to anticancer agents overall and to ICI and non-ICI anticancer agents individually. American Society of Clinical Oncology Value Framework v2 tail-of-the-curve bonuses and ESMO-MCBS v1.1 immunotherapy-triggered long-term plateau adjustments. In total, 247 RCTs were identified, and 100 RCTs involving 57 164 patients were included, with 14 examining ICI agents (1 ipilimumab, 5 pembrolizumab, 5 nivolumab, 2 atezolizumab, and 1 durvalumab) and 86 examining non-ICI agents (74 targeted therapy, 8 chemotherapy, 3 hormone therapy, and 1 radiopharmaceutical). Randomized clinical trials were awarded ASCO-VF v2 tail-of-the-curve bonuses more often than ESMO-MCBS v1.1 immunotherapy-triggered long-term plateau adjustments (ASCO-VF v2, 45.0% [8 of 14 ICI RCTs and 37 of 86 non-ICI RCTs] vs ESMO-MCBS v1.1, 2.6% [1 of 12 ICI RCTs and 1 of 66 non-ICI RCTs). Randomized clinical trials for ICIs were not more likely to receive an ASCO-VF v2 bonus or ESMO-MCBS v1.1 adjustment than non-ICI RCTs (ASCO-VF: risk difference, 0.14; 95% CI, -0.14 to 0.42; P = .32; ESMO-MCBS: risk difference, 0.07; 95% CI, -0.09 to 0.23; P = .40). Poor agreement was found between the framework algorithms in identifying long-term survival benefits from RCTs (κ = 0.01; 95% CI, -0.23 to 0.22; P = .50). The ASCO-VF v2 and ESMO-MCBS v1.1 may require additional refinement to accurately capture the benefit of durable long-term survival, or ICI agents may not preserve long-term survival as conventionally thought.

Appraisal of cancer drugs: a comparison of the French health technology assessment with value frameworks of two oncology societies

ABSTRACT Objectives Our primary objective was to compare the grading of the value of cancer drugs (‘Amélioration du Service Médical Rendu’ [ASMR] level) by the French health technology assessment authority (‘Haute Autorité de santé’ [HAS]) with that by the American Society of Clinical Oncology Value Framework (ASCO-VF) and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Our secondary objective was to study the drivers of the French grading system. Methods We included new drugs for solid tumors assessed by the HAS between 2010 and 2016 and compared their ASMR level to scores calculated by the 2016-updated ASCO-VF and 2015 ESMO-MCBS. Results We investigated 27 new cancer drugs assessed by the French HAS between 2010 and 2016. Among the 17 drugs eligible for comparison, the correlation between ASMR levels and ASCO and ESMO scores was weak (r = 0.34 and r = 0.27, respectively). The agreement between the HAS and ESMO regarding the level of meaningful additional benefit was moderate (kappa = 0.43). We found no significant association between 12 potential variables and ASMR level of additional benefit of drugs. Conclusion Our findings show inconsistencies in cancer drug appraisals among the three appraisers.

PF646 ASSOCIATION BETWEEN BORTEZOMIB CUMULATIVE DOSE AND TREATMENT‐FREE INTERVAL IN TRANSPLANT‐INELIGIBLE PATIENTS WITH PREVIOUSLY UNTREATED MULTIPLE MYELOMA

Background:The phase III VISTA study has demonstrated that bortezomib‐melphalan‐prednisone (VMP) leads to improved clinical outcomes, such as significant improvement of overall survival (OS) for patients with myeloma who are ineligible for stem cell transplantation, in comparison with melphalan‐prednisone (MP) (San Miguel et al, J Clin Oncol, 3:448–455, 2013). It was demonstrated a higher cumulative bortezomib dose is associated with improved OS (Mateos MV et al, Am J Hematol 90:314–319, 2015). Treatment‐free interval (TFI) is another important clinical outcome measure proposed by ASCO and ESMO Draft Value Frameworks for neoplastic drugs (Becker DJ et al, J Oncol Practice, 13:e753‐e665, 2017; Richardson P et al, Expert Review of Hematology 10:933–939, 2017). However, it is not known whether higher cumulative bortezomib doses are associated with a prolonged TFI.Aims:To determine whether a higher cumulative bortezomib dose (obtained by longer treatment duration, more intensive therapy or both) is associated with longer TFI, or lower cumulative incidence of subsequent therapy.Methods:This is a post hoc analysis of the patients treated with VMP in the VISTA randomized clinical trial with the data cut of 2008. Baseline characteristics and clinical outcome (TFI, defined as time from the last dose of study drug to the start of subsequent treatment) were analysed in two groups based on median cumulative bortezomib dose. For subjects who were not known to have died, survival time was censored at the date last known to be alive. Multivariate competing risks hazard ratios (HR), as well as estimates of cumulative incidence (CI) of subsequent therapy, were computed using the Fine and Gray proportional hazards (PH) model for sub‐distributions. HR <1 is in favour of higher bortezomib cumulative group.Results:The median cumulative dose of bortezomib was 39 mg/m2. The median follow‐up was 25.9 months. Patients in the higher cumulative bortezomib dose group (n = 170) were significant younger (70.8 ± 4.6 vs. 73.6 ± 6.2, P < 0.0001) than the lower group (n = 170). No major differences between groups are identified in respect of gender, ISS, type of myeloma, ECOG, cytogenetic risk, and baseline creatinine clearance. Only 44 (25.9%) and 24 (4.1%) patients in the lower and higher dose group had documented subsequent therapy, respectively. Overall, 39 (22.9 %) and 10 (5.9%) patients died in lower and higher dose group, respectively. TFI did not reach the median for either dose group, though it was significantly longer in the higher (≥39 mg/m2) versus lower (<39 mg/m2) cumulative bortezomib dose group, with HR as 0.48 (P = 0.004) and age‐adjusted HR as 0.49 (P = 0.009). The CI at month 12 for subsequent therapy was 0.134 for the higher dose group vs. 0.258 for the lower dose group (Figure 1).Summary/Conclusion:With relative short follow up in this study, higher cumulative bortezomib dose was associated with significantly delayed subsequent therapy. Further studies are warranted to understand the relationship between cumulative bortezomib dose and TFI, OS and other clinical outcomes.image

Measuring the long-term “tail of curve” survival benefits in oncology trials: A comparison of the ASCO Value Framework and the ESMO Magnitude of Clinical Benefit Scale.

2585 Background: Recently, anti-cancer agents have generated excitement due to their capacity to preserve long-term survival in some patients, represented by a “tail of the survival curve”. However, as traditional measures of clinical benefit may not accurately capture long-term survival, amendments to various valuation frameworks have been proposed to capture this benefit. The purpose of this study was to determine how frequently immune checkpoint inhibitor vs. non-immune checkpoint inhibitor anti-cancer agents, displayed trends of long-term survival, as defined by the American Society of Clinical Oncology Value Framework (ASCO-VF) and European Society of Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS), as well as to analyze the degree of agreement between ASCO and ESMO frameworks. Methods: Anti-cancer agents from phase II or III randomized controlled trials (RCTs) cited for clinical efficacy evidence in drug approval by the Food and Drug Administration (FDA) between January 2011 and March 2018 were identified. Data required for ASCO-VF and ESMO-MCBS were extracted. Difference in how often long-term survival bonuses were awarded were calculated in all RCTs, as well as immune checkpoint inhibitor and non-immune checkpoint inhibitor RCTs individually. Cohen’s Kappa statistic was calculated to evaluate agreement between ASCO-VF and ESMO-MCBS. Results: 100 RCTs were analyzed. RCTs were awarded ASCO-VF version 2 (v2) “tail of the curve” bonuses more often than ESMO-MCBS version 1.1 (v1.1) “immunotherapy-triggered” long-term plateau adjustments (45% vs. 2.6%). Comparing to non-immune checkpoint inhibitor RCTs, immune checkpoint inhibitor RCTs were not more likely to receive ASCO-VF v2 bonuses/ESMO-MCBS v1.1 adjustments (p = 0.32/ p = 0.40). Long-term survival agreement between the two frameworks was poor (kappa: 0.01; p = 0.50). Conclusions: The ASCO-VF v2 and ESMO-MCBS v1.1 may require additional refinement in order to accurately capture the benefit of long-term survival or immune checkpoint inhibitor and non-immune checkpoint inhibitor agents may not preserve substantially different long-term survival populations.

Evaluating the value of checkpoint inhibitor therapy using the ASCO and ESMO frameworks.

17 Background: The advent of checkpoint inhibitor therapy (CIT) has dramatically changed the oncology landscape, but is associated with significant costs. A positive randomized clinical trial (RCT) may not translate to meaningful outcomes for patients. The American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) have developed frameworks to quantify the value of cancer treatment. We applied these frameworks to RCTs involving CIT in order to explore the relationship between trial outcomes and magnitude of clinical benefit. Methods: A literature search was conducted to identify CIT RCTs. Data extracted included study characteristics, pre-specified estimated hazard ratios (eHR) and observed HR (oHR). ASCO Value Framework version 2016 and ESMO Magnitude of Clinical Benefit (MCB) scale v1.1 were applied to each publication by 2 authors independently. Results: 30 RCTs (3 adjuvant, and 27 advanced setting) using CIT were identified between January 2010- October 2018. The majority of trials were in lung cancer (37%) and melanoma (36%). The eHR was 0.71±0.06 (range: 0.55-0.78), and oHR was 0.76±0.15 (range: 0.49 – 1.11). 54% RCTs did not achieve eHR, with a difference of 0.16±0.12 (range: 0.01 – 0.41). ASCO framework scores ranged -24.0 to 71.3, far below the maximum potential score of 180. 18 RCTs formed the basis for FDA approvals. The mean ASCO framework score was 45.6 ± 16.6 (range: 14.4 - 71.3) for FDA approved indications, and 14.0 ± 18.4 (range: -24 – 49) for non-FDA approvals (p < 0.001). All FDA approvals scored grade 4 or 5 on the ESMO MCB scale, indicating a meaningful clinical benefit. Many non-FDA approved RCTs did not receive an MCB grade as they were negative trials. There was no difference in the ASCO framework scores between MCB grade 4 and 5 RCTs. 3 adjuvant RCTs had an ASCO framework score ranging from 20.5 to 38.7 despite an MCB Grade A. Conclusions: Many trials did not meet the pre-specified eHR. FDA approval had statistically significantly higher NHB scores than non-FDA approvals, and they were deemed to have a meaningful clinical benefit according to the ESMO MCB scale. ASCO framework scores may require re-calibration since the highest score achieved in CIT RCTs was only 40% of the maximum score.

Anticancer drugs approved by the Food and Drug Administration for gastrointestinal malignancies: Clinical benefit and price considerations.

BackgroundThe cost of new anticancer drugs is rising. We aimed to assess the clinical benefit and price of anti‐cancer drugs approved by the US Food and Drug Administration (FDA) for advanced gastrointestinal cancers.MethodsDrugs approved between 2006 and 2017 for advanced GI malignancies were identified from FDA.gov, and their updated supporting trial data were searched. Incremental clinical benefit was quantified by using ESMO Magnitude of Clinical Benefit Scale version 1.1 (grade 0‐5) and ASCO Value Framework version 2 (score range −20 to 180). Higher scores indicate larger net benefit, and substantial benefit was defined as score 4 or 5 by the European Society for Medical Oncology (ESMO). The Micromedex REDBOOK was used to estimate the monthly average wholesale price (AWP) and total drug price (TDP) over the median treatment duration per patient. Clinical benefit, AWP and TDP of each drug class were assessed.ResultsIn total, 16 GI cancer drugs received FDA approval for 24 indications, including five monoclonal antibodies (mAbs), five oral targeted therapies (TT), two immunotherapeutics (IO), three cytotoxic chemotherapies (CT), and one recombinant fusion protein (aflibercept). Most supporting trials (82%) reported overall survival benefit of less than 3 months and no significant improvement in quality of life. Only five agents (including one TT and one IO) with 21% the of approved indications met the ESMO's threshold of substantial clinical benefit. Median incremental benefit scores of TT and IO were comparable to other drug classes. However their median TDP was much higher at $153 402 and $98 208, respectively, compared to $30 330 USD per patient for CT. The estimated TDP did not correlate with clinical benefit scores.ConclusionMost FDA–approved gastrointestinal cancer drugs do not meet the ESMO threshold of substantial clinical benefit. TT and IO are estimated to carry significant drug costs, and further cost analysis of these drugs is urgently needed.

Use of Late-Life Expectancy for Assessing the Long-Term Benefit of Immune Checkpoint Inhibitors.

To grade the long-term benefit of anticancer agents, the American Society of Clinical Oncology Value Framework (ASCO-VF) awards tail-of-the-curve bonus points by using milestone survival at twice the median control survival. Here, we propose an alternative, late-life expectancy that we defined as the area under the Kaplan-Meier curve from median control survival to the end of follow-up. We analyzed all indications of immune checkpoint inhibitors with survival data and found that 9 indications out of 13 (69.2%) qualified for ASCO-VF tail-of-the-curve bonus points either in progression-free or overall survival. Our proposed score recognized a long-term benefit not captured by the ASCO-VF, for example, for CHECKMATE-66 where twice the median overall survival was not reached. We found that nivolumab was associated with an increase of 65.3% (95% CI = 38.9 to 89.5) in overall survival late-life expectancy, which highlights its important long-term benefit. In conclusion, the ASCO-VF could be improved with the use of late-life expectancy.

Examining Convergent Construct Validity and Inter-Rater Reliability Between ESMO-MCBS and ASCO-VF When Evaluating Hematologic Malignancies

▪IntroductionThe American Society of Clinical Oncology Value Framework (ASCO-VF) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) have been developed to quantify clinical benefit and establish value of anticancer therapies. While ASCO-VF is indifferent to the cancer type, ESMO-MCBS does not endorse their framework for scoring hematologic malignancies. The reason for this exclusion and whether ESMO-MCBS can be applied in the hematologic setting is still unclear. The purpose of this study was to determine whether measurement characteristics of ESMO-MCBS are similar to ASCO-VF when evaluating hematologic malignancies.MethodsPhase III randomized controlled trials (RCTs) of hematological malignancy drugs approved by the US Food and Drug Administration, European Medicines Agency and Health Canada between 2006 to 2017 were identified and scored using ASCO-VF (version 2) and ESMO-MCBS (version 1.1) by two independent reviewers. We assessed the convergent construct validity of the two frameworks to determine the degree to which these two theoretically similar measures assess the same construct of clinical benefit. Spearman correlation coefficients were calculated for the preliminary framework scores (using only the survival efficacy components of the scores) and the final framework scores (following adjustment of the preliminary scores with toxicity and quality of life (QoL) data). Correlation coefficients were also calculated for each subtype of blood cancer separately. The inter-rater reliability of the frameworks was assessed using intra-class correlation coefficients (ICC).ResultsIn total, 48 studies were included and scored using the ASCO-VF (median score: 34.38; IQR: 22.26 - 51.69) and ESMO-MCBS (median score: 3; IQR: 2.75 - 4). Out of the 48 RCTs, 16 (33%) evaluated novel anticancer treatments for leukemia, 23 (48%) for myeloma, 8 (17%) for lymphoma and 1 (2%) for myelodysplastic syndromes. Spearman correlation coefficients between both frameworks for preliminary and final scores were 0.01 (95% CI, -0.23 to 0.25) and -0.02 (95% CI, -0.28 to 0.24), respectively. When stratified by indication, the correlation coefficients for the preliminary scores were -0.01 (95% CI, -0.50 to 0.49), -0.06 (95% CI, -0.46 to 0.29), and 0.58 (95% CI, -0.21 to 0.91) for leukemia, myeloma, and lymphoma, respectively. The correlation coefficients for the final scores by cancer indications were -0.09 (95% CI, -0.56 to 0.42), 0.15 (95% CI, -0.22 to 0.49), and -0.29 (95% CI, -0.86 to 0.52) for leukemia, myeloma, and lymphoma, respectively (Table 1). For both preliminary and final scores, ASCO-VF showed excellent and ESMO-MCBS showed good inter-rater reliability (Table 2).ConclusionsOur results suggest divergent validity of ESMO-MCBS and ASCO-VF when assessing hematologic malignancies, indicating that these frameworks likely measure different constructs of clinical benefit in this setting. Furthermore, the ASCO-VF demonstrated improved inter-rater reliability compared to ESMO-MCBS. It remains unclear which framework is correctly assessing the clinical benefit of hematologic drugs. To better understand if one framework is more accurate in its evaluation, future research that compares these frameworks to other established measures of clinical benefit (such as quality adjusted life years) in the hematologic setting is warranted. Due to the lack of construct validity and ESMO's endorsement of their framework solely for solid cancers, the ASCO-VF should currently be considered for use in the hematologic setting. DisclosuresNo relevant conflicts of interest to declare.

Reliability of Oncology Value Framework Outputs: Concordance Between Independent Research Groups.

Research groups are increasingly utilizing value frameworks, but little is known of their reliability. To assess framework concordance and interrater reliability between two major value frameworks currently in use, we identified all previously published datasets containing both scores from the American Society of Clinical Oncology Value Framework (ASCO-VF) and grades from the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). The intraclass correlation coefficient (ICC) was used to assess interrater reliability. Four eligible studies contained drugs evaluated by both value frameworks, resulting in a dataset of 39 grades/scores for discrete drug indications. ICC was 0.82 (95% confidence interval = 0.70 to 0.90) for ASCO-VF and 0.88 (95% confidence interval = 0.80 to 0.93) for ESMO-MCBS. Absolute concordance was found to be 5% for ASCO-VF and 44% for ESMO-MCBS, increasing to 74% and 80% when deviations within 20 points and 1 grade were considered, respectively. Interrater reliability of ASCO-VF and ESMO-MCBS is, therefore, near perfect, while absolute concordance is poor. This has implications when considering framework outputs in drug funding or treatment decision making.

PCN26 - ASSESSING THE POTENTIAL VALUE OF AN INNOVATIVE ONCOLOGY THERAPY FROM THE HEALTH TECHNOLOGY ASSESSMENT (HTA) PERSPECTIVE: MARRYING CLINICAL VALUE FRAMEWORKS WITH ECONOMIC ASSESSMENT METHODOLOGY

This study assessed the clinical benefit of oncology regimens for an ultra-rare tumor using concepts from European Society of Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) frameworks. It also enhanced clinical assessment of these frameworks by accounting for potential long-term benefits of a novel treatment. An enhanced value framework (EVF) was developed by combining ESMO and ASCO frameworks with well-validated approaches for projecting long-term survival. Published single-arm data for chemotherapies and patient-level data from recently approved immuno-oncology (IO) agent for treating aggressive ultra-rare tumor in metastatic setting was used. Under the ESMO Magnitude of Clinical Benefit Scale (MCBS), form 2a was selected due to lack of sufficient follow-up data on potential curative benefits in terms of overall survival (OS) at the time of approval. Along with OS benefit (1 to 4, indicating increasing OS benefit), MCBS also valued improvements in toxicity and/or quality of life (QoL) (1 for significant improvement in either). The ASCO value framework calculated incremental net health benefit (NHB) by combining scores attributable to clinical benefit, toxicity, and bonus benefits. The projected mean OS over life-time for IO was 42.5 months in the base case compared with 4.2 months for chemotherapies, driven mostly by improvements in progression-free survival (35.0 vs 2.5 months). Under ESMO MCBS version 1.1, IO scored 3 points higher than chemotherapies for efficacy (4 over 1) as well as 1 for improvement in both toxicity and QoL. Under the ASCO framework, the NHB of IO vs chemotherapies ranged from 212-218, with 193 attributable to clinical benefit, 0-5 to toxicity, and 20 bonus points. From HTA perspective, the IO agent for ultra-rare tumor in this case study was determined to provide considerable clinical benefit, irrespective of value framework used to assess benefits associated with the product.

P3.01-03 The Cost Benefit from Second Line Immunotherapy in Metastatic NSCLC: ASCO Value Framework Prospective

P3.01-03 The Cost Benefit from Second Line Immunotherapy in Metastatic NSCLC: ASCO Value Framework Prospective

Value Assessment in Oncology Drugs: Funding of Drugs for Metastatic Breast Cancer in Canada

Life expectancy for women with metastatic breast cancer has improved since the early 2000s, in part because of the introduction of novel therapies, including chemotherapy, hormonal therapy, and targeted agents. However, those treatments can come at a cost for the patient (short- and long-term toxicities from treatment) and at a financial cost for the health care system. Given the increase in the number of costly anticancer agents being introduced into the clinical setting, the American Society of Clinical Oncology (asco) and the European Society for Medical Oncology (esmo) have developed a system to quantify the value of new cancer treatments in terms of benefit, toxicities, and costs. In our value-assessment analysis, we included drugs that were funded in Canada between 2012 and 2017 for metastatic breast cancer. We reviewed the clinical benefit of those agents (survival, progression, quality of life), their costs, their value according to the asco and esmo value frameworks, and their assessments from the pan-Canadian Oncology Drug Review [pcodr (in Canada, except Quebec)] and the Institut national d'excellence en santé et en services sociaux [iness (in Quebec)]. Drugs funded in Canada showed variation in their asco net health benefit scores and esmo magnitude of clinical benefit scores, but all had a cost-effectiveness ratio greater than $100,000 per quality-adjusted life-year. The strength and magnitude of the clinical benefit (for example, overall survival benefit vs. progression-free survival benefit) was not necessarily associated with a higher value score. Although great progress has been made in developing value frameworks, use of those frameworks has to be refined to help patients and health care providers make informed decisions about the benefit of novel cancer therapies and to help policymakers make decisions about the societal benefit of funding those therapies.

Examining Trends in Cost and Clinical Benefit of Novel Anticancer Drugs Over Time

The purpose of this study was to determine if clinical benefits of novel anticancer drugs, measured by the ASCO Value Framework and European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale, have increased over time in parallel with increasing costs. Anticancer drugs from phase III randomized controlled trials cited for clinical efficacy evidence in drug approvals between January 2006 to December 2015 were identified and scored using both frameworks. For each drug, the monthly price and incremental anticancer drug costs were calculated. Relationships between cost and year of approval were examined using generalized linear regressions models. Ordinary least square models were used to evaluate relationships between ASCO and ESMO scores and year of approval. Spearman correlation coefficients between costs and clinical benefit scores were calculated. In total, 42 randomized controlled trials were included. Both monthly prices and incremental anticancer drug costs were significantly associated with year of approval and showed an average annual increase of 9% and 21%, respectively. The predicted mean incremental anticancer drug cost increased from $30,447 in 2006 to $161,141 in 2015 (greater than five-fold increase). Both ASCO and ESMO scores were not statistically associated with year of approval or correlated with monthly prices or incremental anticancer drug costs. Over the past decade, costs of novel oncology drugs have increased, while clinical benefits of these medications have not experienced a proportional positive change. The incremental anticancer drug costs have increased at a much greater rate than monthly prices, indicating that the increase in anticancer drug costs may be higher than commonly reported.

Application of the ASCO Value Framework and ESMO Magnitude of Clinical Benefit Scale to assess the value of abiraterone acetate (AA) and enzalutamide (E) in advanced prostate cancer: clinical value and cost considerations.

276 Background: AA and E improve overall survival (OS) in metastatic castration resistant prostate cancer (mCRPC). AA also improves OS in metastatic castration sensitive disease (mCSPC). However, concerns exist over the cost implications of earlier treatment versus the clinical benefit gained. We aimed to quantify and compare the clinical value of AA and E and their drug costs in both the mCRPC and mCSPC settings. Methods: We identified 6 randomized Phase 3 trials of AA and E in mCRPC and mCSPC. Net clinical benefit was quantified by the ASCO Value Framework version 2 (range < 180) and ESMO MCBS version 1.1 (range 1-5)—both consider benefits in overall survival, progression free survival, and quality of life, against increase in drug toxicity. A higher score indicates greater value. Incremental cancer drug costs were also calculated, using average wholesale price from the REDBOOK and the trials’ reported duration of treatment. Results: (Table). Conclusions: AA and E administered in early mCSPC do not provide consistent increases in net clinical benefit compared to mCRPC, but they incur exponential cost considerations. Alternatives such as chemotherapy, which may provide similar net clinical benefit at less incremental costs, still warrant major consideration for clinicians and patients. Until more information is available to define the optimal sequencing of AA, E and other available treatment modalities, current cost implications may hinder moving these agents to earlier treatment settings.[Table: see text]

Challenges in the Clinical Application of the American Society of Clinical Oncology Value Framework: A Medicare Cost-Benefit Analysis in Chronic Lymphocytic Leukemia.

The ASCO Value Framework calculates the value of cancer therapies. Given costly novel therapeutics for chronic lymphocytic leukemia, we used the framework to compare net health benefit (NHB) and cost within Medicare of all regimens listed in the National Comprehensive Cancer Network (NCCN) guidelines. The current NCCN guidelines for chronic lymphocytic leukemia were reviewed. All referenced studies were screened, and only randomized controlled prospective trials were included. The revised ASCO Value Framework was used to calculate NHB. Medicare drug pricing was used to calculate the cost of therapies. Forty-nine studies were screened. The following observations were made: only 10 studies (20%) could be evaluated; when comparing regimens studied against the same control arm, ranking NHB scores were comparable to their preference in guidelines; NHB scores varied depending on which variables were used, and there were no clinically validated thresholds for low or high values; treatment-related deaths were not weighted in the toxicity scores; and six of the 10 studies used less potent control arms, ranked as the least-preferred NCCN-recommended regimens. The ASCO Value Framework is an important initial step to quantify value of therapies. Essential limitations include the lack of clinically relevant validated thresholds for NHB scores and lack of incorporation of grade 5 toxicities/treatment-related mortality into its methodology. To optimize its application for clinical practice, we urge investigators/sponsors to incorporate and report the required variables to calculate the NHB of regimens and encourage trials with stronger comparator arms to properly quantify the relative value of therapies.

ASCO Value Framework Highlights the Relative Value of Treatment Options in Ovarian Cancer.

The ASCO value framework allows physicians and patients to compare the relative value of novel treatments. Our aim was to assess the value of three frontline ovarian cancer therapies by using this framework. From phase III, randomized controlled clinical trial (RCT) data, the net health benefits (NHBs) for three frontline ovarian cancer treatment options-dose-dense paclitaxel (Japanese Gynecologic Oncology Group study JGOG 3016), intraperitoneal (IP)/intravenous (IV) chemotherapy (Gynecologic Oncology Group [GOG] study GOG 172), and concurrent plus maintenance bevacizumab (GOG 218 and the Seventh International Collaborative Ovarian Neoplasm study [ICON7])-were calculated. The ASCO value framework calculates the NHB by using six criteria: clinical benefit, toxicity, tail of the curve, symptom palliation, treatment-free interval, and quality of life. Clinical benefit calculation uses ASCO-assigned importance weights for overall survival and progression-free survival. The maximum possible NHB points is 180. NHBs were presented alongside the drug-acquisition cost (DAC) of each therapy. A benefit-cost ratio of NHB points per additional cost was calculated. The NHB of dose-dense paclitaxel was 38, at an additional cost of $16 per cycle. IP cisplatin/IV + IP paclitaxel received 29 NHB points, at an additional cost of $1,629 per cycle. Concurrent plus maintenance bevacizumab received 24 NHB points, at an additional cost of $7,581 per cycle (GOG 218) or six NHB points ($3,790 per cycle; ICON7). The ratios of NHB points-to-dollar were as follows: dose-dense paclitaxel, 2.4 (highest); IP chemotherapy, 0.018; and bevacizumab, 0.003 (lowest). Using the ASCO value framework, we constructed value snapshots of three major frontline therapeutic options in ovarian cancer. Dose-dense paclitaxel provided the highest additional value when analysis accounted for NHB and cost. However, additional research is needed to include individual patient preferences and provide personalized value assessments.

The Evolution of Metastatic Colorectal Cancer Clinical Trials: Application of the ASCO Framework for Assessing Value.

Background: Phase III trials in metastatic colorectal cancer (mCRC) have collectively led to progressive advancements in patient outcomes over the past decades. This study characterizes the evolution of mCRC phase III trials through assessing the value of cancer therapy, as measured by the ASCO Value Framework. Methods: Phase III trial results of systemic therapy for mCRC published between 1980 and 2015 were identified, and their outcome, statistical significance, journal impact factor, and citation by the 2016 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CRC were recorded. For each trial, the net health benefit (NHB) score was calculated using the June 2015 (original) and May 2016 (revised) ASCO Value Framework: Advanced Disease. Results: There were 114 mCRC phase III trials eligible for calculation of the NHB score. Using the revised framework, the median NHB score was 4.6 (range, -30 to 43.5); 12% of trials received bonus points. Trials with statistically significant results had higher NHB scores compared with nonsignificant trials (median NHB score, 21.6 vs 2.9; P<.0001). Clinical trials cited in the NCCN Guidelines had higher NHB scores than those not cited (median score, 8.0 vs 0.3; P=.02). In multivariate linear regression analysis, the only significant predictor of high NHB score was statistically significant studies. Conclusions: The median NHB score for mCRC phase III trials was 4.6. Higher NHB scores are associated with statistically significant studies and are cited in the NCCN Guidelines, a surrogate for practice-changing trials. The 2016 ASCO Value Framework may not fully capture the benefits on an individual patient level.

Value-Based Calculators in Cancer: Current State and Challenges.

The ASCO Value Framework, National Comprehensive Cancer Network Evidence Blocks, Memorial Sloan Kettering's DrugAbacus, and Institute for Clinical and Economic Review incremental cost-effectiveness ratio calculator are value-based methodologies that attempt to address the disproportionate increase in cancer care spending. These calculators can be used as an initial step for discussing cost versus value, but they fall short in recognizing the importance of the cancer journey because they do not fully factor the patient's perspective or the global cost of care. This timely review highlights both the limitations and the advantages of each value calculator and suggests opportunities for refinement. Practicing oncologists, payers, and manufacturers should be familiar with value-based calculators because the role these tools play in cost containment is likely to be hotly debated.

Do the American Society of Clinical Oncology Value Framework and the European Society of Medical Oncology Magnitude of Clinical Benefit Scale Measure the Same Construct of Clinical Benefit?

Purpose Whether the ASCO Value Framework and the European Society for Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) measure similar constructs of clinical benefit is unclear. It is also unclear how they relate to quality-adjusted life-years (QALYs) and funding recommendations in the United Kingdom and Canada. Methods Randomized clinical trials of oncology drug approvals by the US Food and Drug Administration, European Medicines Agency, and Health Canada between 2006 and August 2015 were identified and scored using the ASCO version 1 (v1) framework, ASCO version 2 (v2) framework, and ESMO-MCBS by at least two independent reviewers. Spearman correlation coefficients were calculated to assess construct (between frameworks) and criterion validity (against QALYs from the National Institute for Health and Care Excellence [NICE] and the pan-Canadian Oncology Drug Review [pCODR]). Associations between scores and NICE/pCODR recommendations were examined. Inter-rater reliability was assessed using intraclass correlation coefficients. Results From 109 included randomized clinical trials, 108 ASCOv1, 111 ASCOv2, and 83 ESMO scores were determined. Correlation coefficients for ASCOv1 versus ESMO, ASCOv2 versus ESMO, and ASCOv1 versus ASCOv2 were 0.36 (95% CI, 0.15 to 0.54), 0.17 (95% CI, -0.06 to 0.37), and 0.50 (95% CI, 0.35 to 0.63), respectively. Compared with NICE QALYs, correlation coefficients were 0.45 (ASCOv1), 0.53 (ASCOv2), and 0.46 (ESMO); with pCODR QALYs, coefficients were 0.19 (ASCOv1), 0.20 (ASCOv2), and 0.36 (ESMO). None of the frameworks were significantly associated with NICE/pCODR recommendations. Inter-rater reliability was good for all frameworks. Conclusion The weak-to-moderate correlations of the ASCO frameworks with the ESMO-MCBS, as well as their correlations with QALYs and with NICE/pCODR funding recommendations, suggest different constructs of clinical benefit measured. Construct convergent validity with the ESMO-MCBS did not increase with the updated ASCO framework.

Oncologists’ awareness, knowledge, and perceptions of value frameworks.

e18317 Background: The increasing prevalence of cancer coupled with approvals of new drugs and technologies have brought increased scrutiny to cost/benefit of treatments in oncology. To address the rising concern about oncology drug costs, several stakeholders have developed frameworks to help assess the value of oncology regimens. The objective of this study was to assess oncologists’ perceptions, awareness and knowledge of all oncology value frameworks in the US. Methods: Data were collected from an electronic cross-sectional survey of 200 US-based oncologists recruited from an online panel. Oncologists were asked about their knowledge and perceptions of four value frameworks – the National Comprehensive Cancer Network’s (NCCN) Evidence Blocks, American Society of Clinical Oncology (ASCO) Value Framework, Institute for Clinical and Economic Review (ICER) Value Framework and Memorial Sloan Kettering (MSK) Drug Abacus framework. Findings were reported descriptively. Results: Oncologists were most familiar with the NCCN Evidence Blocks (90%) followed by the ASCO Value Framework (84%), ICER value framework (57%) and Drug Abacus (56%). Among those that were familiar with the value frameworks, almost equal proportions found the NCCN Evidence Blocks vs. ASCO Value Framework to be “useful/very useful” (75% vs. 74%) followed by ICER Value Framework (64%) and Drug Abacus (56%). More than three out of four oncologists surveyed (76%) had used value frameworks in the past, with NCCN Evidence Blocks being used most often (61.5%) followed by ASCO Value Framework (48.4%), ICER Value Framework (21%) and Drug Abacus (15%). NCCN Evidence Blocks was ranked highest for its ease of use, comprehensiveness, feasibility for use in the clinical setting, ability of patients to understand and most favorable overall, followed by ASCO Value Framework, ICER Value Framework and Drug Abacus. Conclusions: The majority of oncologists were familiar with value frameworks and had used them in the past. Of the four oncology Value Frameworks, NCCN Evidence Blocks were perceived most favorably by oncologists followed by ASCO Value Framework.