Magnitude Of Clinical Benefit Research Articles

Correlation between clinical trial endpoints of marketed cancer drugs and reimbursement decisions in China.

This study aimed to assess whether different clinical trial endpoints in pivotal trials of cancer drugs were associated with reimbursement decisions in China. Cancer drugs marketed before June 30th, 2021 with publicly available technical review reports for application of drug registration on Center for Drug Evaluation (CDE) website were reviewed. The trial design characteristics and relevant clinical outcomes [e.g., overall survival (OS), progression-free survival (PFS) and objective response rate (ORR)] were extracted from the technical review reports, while the reimbursement decisions were reviewed from National Healthcare Security Administration (NHSA) website. The differences in trial characteristics and clinical outcomes between drugs with positive reimbursement decisions and negative ones were compared by hypothesis test (Pearson's chi-squared test, Fisher's exact test, independent samples t-test and Mann-Whitney U test). The correlation between different clinical trial endpoints and reimbursement decisions was analyzed by multivariate logistic regression. There were 112 cancer drug indications included in this study. Among these indications, 76 received a positive reimbursement decision, and the most common primary endpoints of them were PFS (42.1%) and ORR (30.3%). Taking PFS (OR = 7.333) and ORR (OR = 5.271) as the primary endpoints were more likely to receive a positive reimbursement decision compared with OS (P = 0.003). The proportion of drugs marketed with phase I (75.0%) and phase II (85.7%) clinical trials receiving positive reimbursement decisions are significantly higher than those marketed with phase III clinical trials (61.3%, P = 0.043). The magnitude of clinical benefit only had subtle influences (Prisk benefit - OS = 0.627, Prisk benefit - PFS = 0.087, Psurvival benefit - OS = 0.545, Psurvival benefit - PFS = 0.189) on the drug reimbursement decisions, however, the drug prices and clinical needs also made a difference on that. This study found that, in Chinese drug price negotiations from 2017 to 2021, policymakers have focused more on meeting clinical needs and filling therapeutical gaps in National Reimbursement Drug List (NRDL), while requirements for the selection of primary endpoints, clinical trial phases, and clinical benefits have been reduced. In the future, emphasis should be put on the use of surrogate endpoints and clinical benefits.

221 (PB-045) Poster - Lobular carcinoma of the breast and response to targeted therapy with CDK4/6 inhibitors – a single Portuguese center experience

Background: Invasive lobular carcinoma (ILC) represents 5–15% of all BC, and has a different biological behaviour from invasive ductal carcinoma (IDC). Clinical trials (CT) in luminal metastatic BC (mBC) have demonstrated the benefits of hormonal therapy (HT) + iCDK 4/6 combinations in survival. Data on the magnitude of clinical benefit in ILC mBC is scarce. The aim of this study is to evaluate the response of ILC mBC to HT+iCDK4/6 combinations.

Association between control group therapy and magnitude of clinical benefit of cancer drugs.

e18604 Background: Oncology societies have developed tools to quantify the magnitude of clinical benefit. These include the American Society of Clinical Oncology Value Framework (ASCO-VF) version 2, the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) version 1.1, the National Comprehensive Cancer Network (NCCN) Evidence Blocks and the ASCO Cancer Research Committee criteria (ASCO-CRC). Associations between the characteristics of approved drugs and magnitude of clinical benefit have been explored in depth. Here, we assess the association between characteristics of control group therapy and magnitude of clinical benefit. Methods: We searched Drugs@FDA to identify new solid tumor cancer drugs approved based on randomized trials (RCTs) between January 2012 and December 2021. Substantial clinical benefit was defined as: overall survival gain ≥ 2.5 months and progression-free survival gain ≥ 3 months for the ASCO-CRC (palliative setting only); ASCO-VF threshold score ≥45 (palliative and curative setting); NCCN Evidence Blocks threshold score ≥16 (palliative and curative setting); and grade A or B for trials of curative intent and 4 or 5 for those of non-curative intent using ESMO-MCBS. Associations between characteristics of control group therapy (e.g. type of active therapy, use of matched placebo and overlap between experimental and control therapy) and substantial clinical benefit scores were explored using logistic regression. Results: We identified 174 RCTs supporting the approval of 76 drugs for 164 indications. Of these, 47% (82/174) were placebo-controlled trials among which 42% (34/82) comprised active treatment with a matched placebo. Substantial clinical benefit was observed in 45%, 46%, 72% and 73% using the ESMO-MCBS, ASCO-VF, NCCN Evidence Blocks and ASCO-CRC, respectively. These low proportions resulted in an inability to fit multivariable models adequately. RCTs with a control group comprising of active treatment with a matched placebo were associated with significantly lower odds of substantial benefit with ESMO-MCBS (OR 0.27, P = .003) and ASCO-VF (OR 0.30, P = .008) but not with NCCN Evidence Blocks (OR 0.74, P = .55) or ASCO-CRC criteria (OR 1.36, P = .54). Similar results were observed when excluding trials in the curative setting. There was a non-significant association with higher odds of substantial benefit with ESMO-MCBS with trials in which the control group was chemotherapy (OR 1.97, P = .07). For ASCO-CRC a non-significant association in the opposite direction was observed (OR 0.40, P = .06). Conclusions: Clinical benefit scales can be sensitive to the type of control group therapy. RCTs with an active treatment and matched placebo in the control group were less likely to be scored as providing substantial clinical benefit using the ESMO-MCBS and the ASCO-VF scales. Control group therapy did not influence NCCN Evidence Blocks or ASCO-CRC scores.

A systematic review of racial disparities in enrollment into clinical trials and clinical outcomes in men with metastatic prostate cancer.

e17028 Background: Men of African ancestry have a disproportionately higher incidence of prostate cancer than Caucasians. Yet, men of African ancestry have historically been underrepresented in clinical trials for metastatic prostate cancer (MPC). Further, differences in the magnitude of clinical benefit from treatment by race have been reported. The objective of this study was to assess the racial disparities in clinical trial enrollment of men with MPC and the magnitude of difference in clinical benefit between men of African ancestry and Caucasians with MPC. Methods: A systematic review of MEDLINE was conducted to identify studies published between January 2001 to May 2021. We included: (a) studies that enrolled adults with metastatic castration-resistant prostate cancer (mCRPC) or metastatic hormone sensitive prostate cancer; (b) clinical trials with complete race-stratified frequencies for enrolled subjects; or (c) clinical trials or observational studies that reported race-stratified subgroup analyses or adjusted effect estimates for efficacy/effectiveness outcomes. Outcome measures included overall survival (OS) and progression-free survival (PFS). Results: Of 2,140 retrieved articles, 39 studies involving 39,181 subjects met eligibility criteria. The majority of the studies (n = 35) enrolled mCRPC subjects. Of the 39 studies, 24 were clinical trials and 15 were observational studies. Twenty-one studies enrolled only patients in the US while 18 were multinational studies. Of the 15,761 subjects enrolled in clinical trials, 1750 (11.1%) were men of African ancestry and 12,321 (78.1%) Caucasian. The median (interquartile range) enrollment rate of men of African ancestry in clinical trials was 5.7% (2.3%, 10.1%). Of the 39 eligible studies, 15 reported race-stratified clinical outcomes. Three studies compared men of African ancestry vs Caucasians, 2 men of African ancestry vs non-African ancestry, 3 Caucasian vs others or vice-versa. The remaining 7 studies reported separate estimates on survival by race. All 5 studies comparing men of African ancestry versus other racial groups were conducted in mCRPC subjects. No difference in survival risks by race was observed in the 3 studies that compared men of African ancestry vs Caucasian (HR: 1.09 [0.77, 1.53], 0.68 [0.36, 1.29] and 1.05 [0.97, 1.14]). HRs of 0.90 [0.52, 1.57] and 0.76 [0.61, 0.95] were reported in the 2 studies comparing OS in men of African ancestry vs non-African ancestry. No studies reported a significant increased risk of death by race. Conclusions: Overall, men of African ancestry were largely underrepresented in MPC clinical trials. Concerted efforts are needed to increase the enrollment of this at-risk population in future clinical trial programs. Additional studies are needed to confirm the absence of differences in survival by race in real-life settings.

Is It Time to Commit to a Process to Re-Evaluate Oncology Drugs? A Descriptive Analysis of Systemic Therapies for Solid Tumour Indications Reviewed in Canada from 2017 to 2021.

We undertook an analysis of the Canadian Agency for Drugs and Technologies in Health (CADTH)’s health technology assessments (HTAs) of systemic therapies for solid tumour indications to determine if a mechanism to re-evaluate HTA decisions is needed based on the level of certainty supporting the original recommendation. To measure the certainty in the evidence, we analysed if: (1) overall survival (OS) was the primary endpoint in the pivotal trial, (2) median OS was available at the time of the recommendation, and (3) the expert review committee explicitly identified gaps in the evidence. There were 96 drugs approved by Health Canada that met our eligibility criteria between 1 January 2017 and 31 October 2021. Median OS was not estimable at the time of the recommendation in 57% of the positive recommendations, and the uncertainty in the magnitude of clinical benefit was identified by the expert review committee in 21% of the positive recommendations. There is uncertainty at the time of the HTA recommendation for many drugs, and thus a need to implement a process to re-evaluate drugs in Canada to allow patients timely access to promising therapies while ensuring long-term value of therapies to patients and the healthcare system.

Impact of Value Frameworks on the Magnitude of Clinical Benefit: Evaluating a Decade of Randomized Trials for Systemic Therapy in Solid Malignancies.

In the era of rapid development of new, expensive cancer therapies, value frameworks have been developed to quantify clinical benefit (CB). We assessed the evolution of CB since the 2015 introduction of The American Society of Clinical Oncology and The European Society of Medical Oncology value frameworks. Randomized clinical trials (RCTs) assessing systemic therapies for solid malignancies from 2010 to 2020 were evaluated and CB (Δ) in 2010–2014 (pre-value frameworks (PRE)) were compared to 2015–2020 (POST) for overall survival (OS), progression-free survival (PFS), response rate (RR), and quality of life (QoL). In the 485 studies analyzed (12% PRE and 88% POST), the most common primary endpoint was PFS (49%), followed by OS (20%), RR (12%), and QoL (6%), with a significant increase in OS and decrease in RR as primary endpoints in the POST era (p = 0.011). Multivariable analyses revealed significant improvement in ΔOS POST (OR 2.86, 95% CI 0.46 to 5.26, p = 0.02) while controlling for other variables. After the development of value frameworks, median ΔOS improved minimally. The impact of value frameworks has yet to be fully realized in RCTs. Efforts to include endpoints shown to impact value, such as QoL, into clinical trials are warranted.

Serial right heart catheter assessment between balloon pulmonary angioplasty sessions identify procedural factors that influence response to treatment

Balloon pulmonary angioplasty (BPA) is delivered as a series of treatments for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) however, there is little published data on the procedural determinants of outcome.Pre- and post-BPA clinical and hemodynamic data, as well as serial hemodynamic and procedural data at each BPA session were evaluated to determine patient and procedure-related factors that influence hemodynamic response.Per procedure data from 210 procedures in 84 patients and per patient data from 182 procedures in 63 patients with completed treatment and 3-month follow-up were analyzed. A median of 3 (range 1-6) BPA procedures treating a median of 2 segments per procedure (range 1-3) were performed per patient with a median interval between procedures of 42 (range 5-491) days. Clinical outcome correlated with hemodynamic change (pulmonary vascular resistance [ΔPVR] vs Cambridge Pulmonary Hypertension Outcome Review [CAMPHOR] symptom score: p < 0.001, Pearson's r = 0.48, n = 49). Responders to BPA had more severe disease at baseline and 37.5 % of non-responders were post-PEA. There was a dose-response relationship between per procedure and total number of segments treated and hemodynamic improvement (ΔPVR: 1 segment: -0.9%, 2: -14.5%, 3 or more: -16.1%, p < 0.001). Treating totally occluded vessels had a greater hemodynamic effect (mean pulmonary artery pressure [ΔmPAP]: sessions with occlusion: -8.0%, without occlusion treated: -3.2%, p < 0.05) without an increased complication rate.The magnitude of clinical benefit is related to the hemodynamic effect of BPA which in turn is related to the number of segments treated and lesion severity. Patients who were post-PEA were less likely to respond to BPA.

ESMO Magnitude of Clinical Benefit Scale (MCBS): An evaluation of systemic treatment trials for soft tissue sarcomas (STS).

11553 Background: Patients with STS have poor prognosis in the metastatic setting. Although some treatment options are associated with improved outcomes, such as progression-free (PFS) or overall survival (OS), the overall magnitude of clinical benefit can be unclear. The ESMO MCBS is a validated and reproducible tool developed to quantify the clinical benefit of treatments evaluated in trials ( www.esmo.org/guidelines/esmo-mcbs ). Herein, we report the application of ESMO MCBS to systemic treatment trials involving metastatic STS patients. Methods: A systematic search of Medline, Embase and Cochrane databases for adult phase II and III trials in advanced STS (01/1998 to 12/2020) was carried out. Gastrointestinal stromal tumor trials were excluded. Outcomes, including but not limited to OS, PFS, objective response rate (ORR), toxicity and quality of life (QoL) data were extracted and analyzed. Studies with outcomes that met the criteria for ESMO MCBS v1.1 were evaluated to generate a score of 1 to 5 (score of ≥ 4: substantial benefit). MCBS scoring of each study was performed by at least 2 co-authors for consensus. Results: Among 3454 abstracts screened, a total of 140 Phase II and 28 phase IIII trials were identified. A total of 41 studies fulfilled the criteria for ESMO MCBS scoring. These include 5 phase III studies, as well as 9 randomized and 27 single-arm phase II trials. Fifteen studies involved specific histology, while remaining 26 studies were of all STS subtypes. Chemotherapy, alone or in combination was evaluated in 29 trials, while molecular-targeted agents (MTA) and immune checkpoint inhibitors (IO) were evaluated in 11 and 3 studies, respectively (Table). The median MCBS score was 2 (range 1-4), regardless of drug class or combination. Only 3 studies, all randomized in design, had a MCBS score of 4. All three trials were in the 2nd line setting or beyond, where there is no standard control treatment. None of the trials, irrespective of drug class had a score of 5 and no study showed evidence of significant improvement in QoL. The observed MCBS scores were low, partly because the trials evaluated mainly comprise single-arm studies without QoL assessments, restricting to a maximum MCBS score of 3. Conclusions: Most systemic therapy trials in advanced STS did not confer substantial clinical benefit when evaluated using MCBS. Although randomized phase 3 trials remain the gold standard of treatment evaluation, clinical benefit evaluation of STS trials using tools such as MCBS may be useful. Incorporation of QoL evaluation, even in single-arm studies should be prioritized in metastatic STS trials.[Table: see text]

Overall survival, quality of life and magnitude of clinical benefit of breast cancer drugs over the last 25 years.

6571 Background: The American Society of Clinical Oncology Cancer Research Committee (ASCO-CRC), the ASCO Value Framework Net Health Benefit score version 2 (ASCO-VF), and the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS) are validated tools quantifying the clinical benefit for cancer drugs. Here, we assess the overall survival (OS), quality of life (QoL) and magnitude of clinical benefit of trials supporting breast cancer drug approval by the US Food and Drug Administration (FDA) in the last 25 years. Methods: We searched Drugs@FDA website for all breast cancer drug approvals from January 1, 1995 to December 30, 2020. Drug labels and reports of registration trials were reviewed. We collected data on trial characteristics, efficacy, toxicity and QoL. When more than one study supported a single indication, we preferred efficacy-oriented endpoints (typically OS) to QoL. We excluded trials supporting accelerated-approval indications if these were converted to regular approval during the study period. We scored clinical benefit using the ASCO-CRC in palliative setting, and ASCO-VF and ESMO-MCBS in both curative and palliative setting. Substantial clinical benefit was defined as: OS gains ≥2.5 months and progression-free survival gains ≥ 3 months for ASCO-CRC criteria; ASCO-VF scores ≥ 45 and grade of A or B for trials of curative intent and 4 or 5 for those of non-curative intent using ESMO-MCBS. Trends over time were assessed using Chi-squared test for trend. Results: We identified 51 trials supporting the approval of 32 individual drugs for 51 indications; 12 (24%) were in the curative setting and 39 (76%) in the palliative setting. At the time of approval, 8 (16%) trials reported significant improvement in OS. QoL was reported in 22 trials (43%). Among these, 8 (36%) showed improvement in QoL. For curative intent, we applied ASCO-VF and ESMO-MCBS score to 11 (92%) trials, finding clinical benefit in 10 (91%) and 2 (18%) trials, respectively. In the palliative setting, we used ASCO-CRC, ASCO-VF and ESMO-MCBS scores to rate 32 (82%), 33 (85%) and 38 (97%) trials. Substantial clinical benefit was observed in 20 (63%), 12 (36%) and 7 (19%) trials, respectively. Over time, there has been a decrease in the number of trials supporting approval based on OS (1996-2003 50% vs 2004-12 38% vs 2013-20 13%, P trend = 0.033). There were no statistically significant changes over time in QoL, ASCO-CRC, ASCO-VF and ESMO-MCBS scores. Conclusions: For palliative intent, most trials supporting FDA approval of breast cancer drugs do not meet the ASCO-VF or ESMO-MCBS criteria for substantial clinical benefit. There is substantial inter-framework variability in the assessment of clinical benefit in the curative setting. Over time, there has been a substantial shift towards use of surrogate endpoints as the basis for approval without a clear improvement in substantial clinical benefit.

Are Quality of Randomized Clinical Trials and ESMO-Magnitude of Clinical Benefit Scale Two Sides of the Same Coin, to Grade Recommendations for Drug Approval?

The approval of a new drug for cancer treatment by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) is based on positive, well-designed randomized phase III clinical trials (RCTs). However, not all of them are analyzed to support the recommendations. For this reason, there are different scales to quantify and evaluate the quality of RCTs and the magnitude of the clinical benefits of new drugs for treating solid tumors. In this review, we discuss the value of the progression-free survival (PFS) as an endpoint in RCTs and the concordance between it and the overall survival (OS) as a measure of the quality of clinical trial designs. We summarize and analyze the different scales to evaluate the clinical benefits of new drugs such as the The American Society of Clinical Oncology value framework (ASCO-VF-NHB16) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the concordance between them, focusing on metastatic colorectal cancer (mCRC). We propose several definitions that would help to evaluate the quality of RCT, the magnitude of clinical benefit and the appropriate approval of new drugs in oncology.

Current Treatments of Metastatic Colorectal Cancer with Immune Checkpoint Inhibitors-2020 Update.

During the last 20 years, chemotherapy has improved survival rates of colorectal cancer (CRC). However, the majority of metastatic cases do not respond to or progress after first line conventional chemotherapy and contribute to the fatalities of patients with CRC. Insights into the immune contexture of the tumor microenvironment (TME) have enabled the development of new systemic treatments that boost the host immune system against the tumor—the immune checkpoint inhibitors (ICI). These promising drugs have already shown astonishing efficacies in other cancer types and have raised new hope for the treatment of metastatic CRC (mCRC). In this review, we will summarize the results of the clinical trials that led to their accelerated approval by the U.S. Food and Drug Administration (FDA) in 2017, as well as all relevant recent studies conducted since then—some of which are not published yet. We will focus on therapeutic efficacy, but also discuss the available data for drug safety and security, changes in quality of life indicators and predictive biomarkers for treatment response. The burgeoning evidence for a potential use of ICIs in other settings than mCRC will also be mentioned. For each trial, we have made a preliminary assessment of the quality of clinical trial design and of the “European Society of Medical Oncology (ESMO) magnitude of clinical benefit” (ESMO-MCBS) in order to provide the first evidence-based recommendation to the reader.

Assessing the risk-benefit profile of ramucirumab in patients with advanced solid tumors: A meta-analysis of randomized controlled trials.

BackgroundRamucirumab is a widely used cancer drug having gained six regulatory approvals in various advanced solid tumors. Thus, assessing the risk-benefit profile of such a commonly used drug across multiple tumor types is necessary to inform clinical and reimbursement decisions. To objectively assess the risks and benefits of ramucirumab in patients with advanced solid tumors, we performed a systematic review and meta-analysis of published randomized controlled trials (RCTs).MethodsA systematic search of PubMed, the Cochrane Library, Google Scholar and conference abstracts for all RCTs of ramucirumab in patients with advanced solid cancer was conducted according to the PRISMA guidelines. Data on treatment-related serious adverse events (SAEs), fatal adverse events (FAEs), primary endpoint, gains in median overall survival (OS), progression-free survival (PFS) with their hazard ratios (HR) and 95% confidence intervals (CIs) and quality of life (QOL) were extracted from each RCT. Summary relative risks (RR) with 95% CI for SAEs and FAEs were calculated by pooling data across the RCTs using random-effects model. Treatment benefit was evaluated descriptively in terms of median and HR with 95% CI of OS and PFS gains as well as improvements in QOL. ESMO-Magnitude of Clinical Benefit Scale (MCBS), a validated tool, was used to objectively quantify clinical benefit of ramucirumab in approved settings.FindingsTen RCTs met our inclusion criteria. Compared with the control arm, the use of ramucirumab was associated with a significantly increased risk of developing SAE (RR 1.13, 95% CI 1.05–1.21, incidence 37.5% v 33.5%). The increase in risk of FAE (RR 1.41, 95% CI 0.96–2.07, incidence 1.8% v 1.3%) was not statistically significant. Using the ESMO MCBS tool, clinical benefit with ramucirumab was not substantial in any indication, five of six approvals scoring a “negligible benefit” score of 1 or 2. QOL was either not reported (30%) or not improved (70%) in these RCTs.InterpretationIn this meta-analysis of RCTs, use of ramucirumab in patients with advanced cancer was associated with increased risk of treatment related serious and possibly fatal adverse events but the magnitude of clinical benefit from ramucirumab was mostly negligible with no trial reporting an improvement in QOL. These relative risks and benefits should be considered in clinical and regulatory decision making.FundingNone.

Factors associated with change in the magnitude of clinical benefit of anti-cancer drugs in the post-marketing period.

7052 Background: Initial drug approval is often based on surrogate endpoints. Definitive outcomes like Overall Survival (OS) or Quality of life (QoL) may not be available. Here, we evaluate changes in the magnitude of clinical benefit using the American Society of Clinical Oncology Value Framework (ASCO-VF) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) comparing the time of approval to the most recent available data for cancer drugs approved by the US Food and Drug Administration (FDA) between 2006 and 2015. Methods: We examined data on trials supporting FDA accelerated (AA) and regular (RA) cancer drug approvals between January 2006 and December 2015. We performed a systematic search of Pubmed and ClinicalTrials.gov to identify updated OS and/or QoL data, with follow up through April 2019. For AA drugs we analysed initial and confirmatory trials as follow-up. ASCO-VF and ESMO-MCBS grades were applied for trials at approval and after marketing. We explored variables associated with improved clinical benefit scores using multivariable logistic regression. Results: We identified 102 trials supporting the approval of 59 drugs for 96 solid tumour indications. Of these indications, 22 (23%) were granted AA and 21 (95%) were converted to RA. At time of approval, 38% of trials showed improved OS and 17% improved QoL. Substantial clinical benefit was observed in 26% of initial approval trials using ESMO-MCSB and in 34% using ASCO-VF. After a median post-marketing period of 3.3 years, updated results changed substantial clinical benefit in 20 trials with ESMO-MCBS (19 upgrades, 1 downgrade) and in 23 trials using ASCO-VF (19 upgrades, 4 downgrades). For 25% of trials no updated information was found. In the palliative setting, multivariable analysis showed association between improved ASCO-VF scores and initial approvals based on single-arm trials (OR 9.21, 95%CI 1.36-62.29, P=0.023), drugs with companion diagnostics (OR 4.95, 95%CI 1.01-24.22, P=0.049) and second or later lines (OR 7.80, 95%CI 1.35-45.02, P=0.022) while for ESMO-MCBS, drugs with companion diagnostics (OR 6.86, 95%CI 1.82-25.86, P=0.004) and immunotherapy drugs (OR 6.42, 95%CI 1.27-32.59, P=0.025) were associated with greater clinical benefit. Conclusions: Drugs with companion diagnostic tests, immunotherapy as well as approved based on single-arm trials were associated with increased clinical benefit after marketing approval. For a quarter of trials there were no updated data in the post-marketing period.

Impact of value frameworks on the magnitude of clinical benefit: Evaluating a decade of randomized trials for systemic therapy in solid malignancies.

e19410 Background: In the era of rapid development of new, expensive cancer therapies, value frameworks were developed to quantify clinical benefit. We assessed the evolution of the magnitude of clinical benefit since the 2015 introduction of the ASCO and ESMO value frameworks. Methods: Randomized phase II and III clinical trials assessing systemic therapies for solid malignancies from January 2010 to July 2019 were evaluated. Study characteristics were recorded, and magnitude of clinical benefit (Δ) was calculated for the endpoints overall survival (OS), progression-free survival (PFS), response rate (RR), and quality of life (QoL). Multivariable analyses compared ΔOS, ΔPFS, and ΔRR in 2010-2014 [pre-value frameworks (PRE)] to 2015-2019 [post-value frameworks (POST)]. Results: In the 290 studies analyzed [60 (21%) PRE and 230 (79%) POST], the most common primary endpoint was PFS (46%), followed by OS (20%), RR (16%), and QoL (8%), with a non-significant increase in OS and decrease in RR as a primary endpoint in the POST era (Table). Studies evaluating immunotherapy and palliative therapy significantly increased POST [0 (0%) v 39 (17%), Fisher’s exact p&lt;0.01 and 25 (42%) v 142 (62%), Chi squared p=0.01, respectively]. Studies reporting improvement in QoL doubled POST [3 (5%) v 22 (10%) Fisher’s exact p=0.56], however not statistically significant. Median ΔOS was significantly greater POST (N= 140 evaluable studies, 1.3 v -0.2 months, Wilcoxon p=0.005) but there was no significant difference in median ΔPFS or ΔRR. Multivariable analyses revealed significant improvement in ΔOS POST (OR 3.08, 95% CI 0.54-5.62, p=0.02) while adjusting for drug mechanism of action, line of therapy, disease setting, and primary endpoint. Conclusions: After the development of value frameworks, median OS improved minimally. The impact of value frameworks has yet to be fully realized in randomized clinical trials. Efforts to include endpoints shown to impact value, such as QoL, into clinical trials are warranted. [Table: see text]

Abstract PD10-06: Clinical benefit of breast cancer drugs approved by the United States Food and Drug Administration

Abstract Background: The American Society of Clinical Oncology Cancer Research Committee (ASCO-CRC), the ASCO Value Framework Net Health Benefit score version 2 (ASCO-NHB v2), and the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) are validated tools which quantify the clinical benefit for cancer drugs. Here, we assess the magnitude of clinical benefit of clinical trials supporting breast cancer drug approval by the United States Food and Drug Administration (FDA). Methods: We searched the Drugs@FDA website for breast cancer drug approvals from January 1, 2006 to June 30, 2019. Drug labels and reports of registration trials were reviewed and study characteristics, efficacy, toxicity and quality of life (QoL) outcomes were collected. For each indication, we scored clinical benefit from pivotal trials using the ASCO-CRC for non-curative trials and using the ASCO-NHB v2 and the ESMO-MCBS v1.1 for curative and non-curative intent trials. Substantial clinical benefit was defined as: overall survival (OS) gains of 2.5 or more months and progression-free survival gains of 3 or more months for all cancer types for the ASCO-CRC criteria; pragmatic threshold scores of 45 or greater for the ASCO-NHB v2; and grade of A or B for trials of curative intent and 4 or 5 for those of non-curative intent using ESMO-MCBS v1.1. Results: We identified 28 pivotal trials supporting the approval of 18 individual drugs for 24 indications. Among the 28 trials, 6 (21%) were in the curative setting and 22 (79%) in the palliative setting. At the time of approval, only 2 trials (7%) reported improvement in OS and only 4 trials (14%) a significant improvement in QoL. ASCO-CRC, ASCO-NHB v2 and ESMO-MCBS v1.1 scores were applied in the palliative setting to 19, 20 and 22 trials respectively, and ASCO-VF and ESMO-MCBS v1.1 in the curative setting in 4 and 5 trials respectively. Among included trials in advanced disease, 15 (79%), 9 (45%) and 5 (23%), trials met the thresholds established by the ASCO-CRC, ASCO-NHB v2 and ESMO-MCBS v1.1 respectively. Among trials with curative intent, 1 (25%) and 4 (80%) trials met the thresholds established by the ASCO-NHB v2 and ESMO-MCBS v1.1 respectively. Conclusion: In patients with metastatic breast cancer, most FDA approval trials do not meet the ASCO-NHB v2 and ESMO-MCBS v1.1 thresholds for substantial clinical benefit. Although most palliative trials reported a substantial clinical benefit according ASCO-CRC framework only 2 of them (7%) supported drug approvals based on an OS benefit. In patients with early breast cancer, low agreement observed between the ASCO-NHB v2 and ESMO-MCBS v1.1 suggest that the respective frameworks may require additional refinement to accurately capture substantial clinical benefit in the curative setting. Citation Format: J. Carlos Tapia, Consolación Molto, Aida Bujosa, Arnoud J Templeton, Agustí Barnadas, Eithan Amir, Ariadna Tibau. Clinical benefit of breast cancer drugs approved by the United States Food and Drug Administration [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD10-06.

Efficacy and safety of second-line nab-paclitaxel plus gemcitabine (nab-P+GEM) after progression on first-line FOLFIRINOX in advanced pancreatic ductal adenocarcinoma (PDAC): Multicenter retrospective analysis.

689 Background: FOLFIRINOX is one of standard 1st-line regimens for patients (pts) with advanced PDAC. However, there is no globally established 2nd-line regimen after failure of FOLFIRINOX. Although gemcitabine-based regimens are recommended by multiple guidelines and widely used in daily practice, further analysis is needed to reveal the magnitude of clinical benefit with these regimens. Nab-P+Gem is another standard 1st-line regimen for PDAC, but there are limited data as 2nd-line therapy in PDAC. Therefore, we conducted multicenter retrospective analysis of 2nd-line nab-P+Gem after progression on FOLFIRINOX in pts with advanced PDAC. Methods: Between Feb 2016 and Feb 2019, a total of 103 pts with histologically documented PDAC who received nab-P+GEM after progression on 1st-line FOLFIRINOX were identified among 5 referral cancer centers in South Korea. Results: Median age was 60 years and 50 pts (49%) were male. All but one pts had ECOG performance status of 0-1 at the time of nab-P+GEM. At the time of nab-P+GEM, 25 (24%) and 78 (76%) patients had locally advanced and metastatic disease, respectively. Median overall survival (OS) and progression-free survival (PFS) with nab-P+GEM was 9.8 months (95% CI: 8.9-10.6) and 4.6 months (95% CI: 3.7-5.5), respectively. Among pts with measurable disease (n = 95), partial response and stable disease were achieved in 8 (8%) and 56 (54%), respectively. Median OS from the start of 1st-line FOLFIRINOX was 20.9 months (95% CI: 15.2-26.6). Most common adverse event of all grade was anemia (77%), followed by neutropenia (60%), fatigue (52%), thrombocytopenia (45%), and peripheral neuropathy (30%). Most common grade 3-4 adverse events were neutropenia (36%), anemia (9%), and peripheral neuropathy (8%). Conclusions: In medically fit pts with advanced PDAC who failed on 1st-line FOLFIRINOX, nab-P+GEM was effective and well tolerated as 2nd-line therapy.

Building Hope by Restoring Breathing in Airways Diseases

Prof Agustí opened the session by explaining the new challenges in airway diseases including the changing paradigm of our understanding of chronic obstructive pulmonary disease (COPD) that considers the entire lung function trajectory from birth to death, the complexity and heterogeneity of the disease, and the need to diagnose and treat COPD earlier in life. Prof Siddiqui then explained that all of the airways, including small airways, are critically important in the pathophysiology of asthma and COPD. The world’s largest multi-centre ATLANTIS study focussed on small airways dysfunction (SAD) confirmed that a simple combination of different assessments like oscillometry and spirometry could identify patients with the SAD phenotype. The prevalence of airway dysfunction in the full asthma cohort was 91%. Prof Papi discussed that exacerbations are a crucial event in the natural history of COPD and that they drive several health-related outcomes. He reviewed the clinical evidence to demonstrate the benefits of triple therapy in general and specifically of the extrafine fixed triple combination (beclometasone dipropionate, formoterol fumarate, glycopyrronium bromide) to consistently reduce the risk of exacerbations, and improve lung function and quality of life (QoL) with a favourable benefit-to-harm ratio. Furthermore, triple therapy showed promising signals in terms of improved survival. Prof Celli debated that inhaled corticosteroid (ICS) should be given to many patients because scientific trials have shown that: 1) ICS combined with bronchodilator (BD) are effective in improving health status and reducing exacerbations; 2) they also impact lung function decline and mortality; 3) ICS increase pneumonia risk (depending on type, dose, airflow limitation, BMI, and age) but have no untoward effect on mortality or hospitalisations for pneumonia; 4) blood eosinophil count (BEC) (&lt;100 cell/µL) helps select patients unlikely to respond to ICS; and 5) ‘many’ COPD patients benefit from ICS combined with BD. Prof Singh focused on the fact that the magnitude of clinical benefit in preventing COPD exacerbations varies between individual patients, underlining the importance for clinicians of making the right decision for each patient when prescribing ICS, by balancing the potential risk/benefit. He concluded the debate by outlining that ICS have benefits in patients at increased exacerbation risk, and that the size of the benefits varies with BEC and the number/type of exacerbation.

1627O - Change in magnitude of clinical benefit, overall survival (OS) and quality of life (QoL) between time of approval and post-marketing among cancer drugs approved by the US Food and Drug Administration (FDA) 2006-2015

BackgroundClinical trials supporting approval for new drugs often evaluate surrogate endpoints, and data on meaningful outcomes like OS or QoL may not be available. Here, we evaluated changes in the magnitude of clinical benefit, OS and QoL after approval. MethodsWe examined data on pivotal trials supporting FDA accelerated (AA) and regular (RA) cancer drug approvals between January 2006, and December 2015. For AA drugs, if conversion to RA was granted, only the confirmatory trial was analysed. To determine any new evidence on OS and QoL in the postmarketing period (PMP) we performed a systematic search of Pubmed and ClinicalTrials.gov. European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) grades were applied for trials at approval and in the PMP. Substantial clinical benefit was defined as a grade of A or B for trials of curative intent and 4 or 5 for those of palliative intent. ResultsWe identified 96 pivotal trials supporting the approval of 47 drugs for 94 solid tumour indications. Of these indications, 22 (23%) were granted AA and 21 (22%) were converted to RA. At time of approval, 45 (48%) trials showed improved OS, 15 (16%) improved QoL and 33 (34%) had substantial clinical benefit. With a median PMP of 3.7 years, 50 (52%) trials reported OS data and 27 (28%) on QoL. Of these, 48 could be graded by the ESMO-MCBS. Of the updated 51 trials approved based on surrogate endpoints, only 7 (14%) showed an improvement in OS. In advanced disease, out of 74 trials for which there was no evidence on QoL at the time of approval, 12 (16%) showed improved QoL subsequently. Updated results led to changes in clinical benefit in 11 trials (10 upgrades, 1 downgrade) with 30 (62%) showing substantial clinical benefit. Among all trials, 52 (54%) showed improved OS, 27 (28%) improved QoL and 42 (44%) met the threshold for substantial clinical benefit. ConclusionsAfter 3.7 years of post-marketing time, 54% of FDA approved cancer drugs showed statistically significant improvement in OS and 28% in QoL. Less than a half of trials supporting FDA approval met the threshold for substantial clinical benefit using ESMO-MCBS. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureE. Amir: Speaker Bureau / Expert testimony: Genentech/Roche; Advisory / Consultancy: Apobiologix; Advisory / Consultancy: Agendia; Advisory / Consultancy: Myriad Genetics. All other authors have declared no conflicts of interest.

Abemaciclib, a Potent Cyclin-Dependent Kinase 4 and 6 Inhibitor, for Treatment of ER-Positive Metastatic Breast Cancer

CDK 4/6 inhibitors have given patients with estrogen receptor (ER)-positive/HER2-negative (ER+/HER2ࢤ) advanced metastatic breast cancer important new therapeutic options. Abemaciclib is different to the other two licensed and approved CDK 4/6 inhibitors, palbociclib and ribociclib, both in dosing schedule (continuous vs intermittent) and toxicity profile (less neutropenia, more diarrhea), yet the magnitude of clinical benefit seen in first- and second-line studies is very similar. One of the key issues for clinicians is when to use these therapies. Ultimately, the biggest impact of abemaciclib could be in the adjuvant setting if the current MONARCH-E trial in high-risk node-positive patients is positive. The emerging biomarker work in the early breast cancer setting (i.e., neoMONARCH) may determine which tumors are most sensitive to abemaciclib.

Primary Therapy of Early Breast Cancer: Evidence, Controversies, Consensus: Spectrum of Opinion of German Specialists on the 16th St.Gallen International Breast Cancer Conference (Vienna 2019).

The results of the international St. Gallen Consensus Conference for the treatment of patients with primary breast cancer were discussed this year by a working group of leading breast cancer experts in view of the therapy recommendations for everyday clinical practice in Germany. Three of the breast cancer experts are also members of this yearʼs St. Gallen panel. The comparison of the St. Gallen recommendations with the annually updated treatment recommendations of the AGO 2019 as well as the S3 guideline is useful, since the recommendations of the St. Gallen panel represent the opinions of experts from various countries and disciplines. The recommendations of the S3 guideline and AGO are based on evidence-based research of the literature. This yearʼs 16th St. Gallen conference featured the motto “Magnitude of clinical benefit”. In addition to the evidence-based data, each therapeutic decision must also undergo a benefit/risk assessment of the patientʼs individual situation and be discussed with the patient.