Best Supportive Care Research Articles

LBA25 FRESCO-2: A global phase III multiregional clinical trial (MRCT) evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer

Effective treatment options are limited for patients (pts) with refractory metastatic colorectal cancer (mCRC). Fruquintinib (F), a highly selective, potent, oral tyrosine kinase inhibitor of VEGFR-1, -2, and -3, was approved in China in the 3L+ mCRC setting based on results from the FRESCO trial (NCT02314819). FRESCO-2 (NCT04322539) evaluated F in more heavily pre-treated pts reflecting current global practices. FRESCO-2 was a randomized, double-blind, placebo (P)-controlled, phase 3 MRCT conducted in the US, Europe, Japan & Australia, comparing F + best supportive care (BSC) with P + BSC. F or P was given 5 mg PO, QD, 3 wks on, 1 wk off, in 28-d cycles. Key criteria: Prior chemotherapy, anti-VEGF therapy, and, if RAS wild type (WT), anti-EGFR therapy; if BRAFV600E mutant (MT) or MSI-H, ≥1 targeted regimen; & prior exposure to trifluridine/tipiracil (T) and/or regorafenib (R). Pts were randomized 2:1 to F + BSC or P + BSC and stratified by: prior therapy T, R or both; RAS status (WT, MT) & duration of metastatic disease (≤18, >18 months [m]). The primary endpoint was overall survival (OS). Key secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) & safety. Final analysis was after 480 OS events. From 2Sep2020 to 14Dec2021, 691 pts were randomized; F:461 vs P:230. Baseline characteristics were balanced. F significantly improved OS (median: 7.4 m vs 4.8 m P; HR=0.66; [95% CI: 0.55, 0.80]; p<0.001) & PFS (median: 3.7 m vs 1.8 m P; HR=0.32; [95% CI: 0.27, 0.39]; p<0.001). The median duration of follow-up was 11.3 m F vs 11.2 m P. Subsequent anti-cancer therapies were 29.4% F vs 34.3% P. DCR was 55.5% F vs 16.1% P & ORR was 1.5% F vs 0% P. Grade ≥3 adverse events were 62.7% F vs 50.4% P; those occurring in ≥5% on F were hypertension (13.6% vs 0.9% P), asthenia (7.7% vs 3.9% P) & hand-foot syndrome (6.4% vs 0% P). F had a significant and clinically meaningful improvement in OS in pts with refractory mCRC. F was well tolerated, with a safety profile consistent with the established profile for F monotherapy. FRESCO-2 results are consistent with FRESCO and should support a new treatment option in refractory mCRC.

Comparison of Overall Survival between Transarterial Chemoembolization and Best Supportive Care in Intermediate- Stage Hepatocellular Carcinoma.

The Thailand management guideline allows the use of transarterial chemoembolization (TACE) for the treatment of intermediate-stage hepatocellular carcinoma (HCC) in patients with decompensated cirrhosis, whereas other guidelines do not. The aim of this study was to compare the overall survival between TACE and the best supportive care (BSC) in HCC patients with Child-Pugh score 5-8 cirrhosis and in subgroups with compensated cirrhosis (Child-Pugh score 5-6) and early decompensated cirrhosis (Child-Pugh score 7-8). This retrospective study comprised 118 patients with intermediate-stage HCC. The overall survival was compared between TACE and BSC using the Kaplan-Meier method. The median overall survival time for all patients was 21.4 months in the TACE group and 8.2 months in the BSC group (P <0.001). In the subgroup analyses, the overall survival times for TACE and BSC were 26 months and 9 months, respectively, for compensated cirrhosis (P <0.001), and 14.5 months and 6.9 months, respectively, for early decompensated cirrhosis (P <0.001). In the Cox proportional-hazards model, TACE was an independent prognostic factor for prolonged overall survival in all patients [hazard ratio (HR) 0.29; 95% confidence interval (CI), 0.17-0.49; P <0.001], patients with compensated cirrhosis (HR, 0.31; 95% CI, 0.16-0.62; P <0.001), and patients with early decompensated cirrhosis (HR, 0.16; 95% CI, 0.061-0.44; P <0.001). TACE improves the overall survival in patients with intermediate-stage HCC and compensated or early decompensated cirrhosis.

1760P Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): Results from patients with ≥12 mo of treatment in JAVELIN Bladder 100

In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), patients (pts) with aUC that had not progressed with 1L platinum-based chemotherapy had significantly prolonged overall survival and progression-free survival with avelumab 1L maintenance + best supportive care (BSC) compared with BSC alone. Results led to avelumab 1L maintenance being approved worldwide and adopted into international treatment guidelines as standard of care. Here, we report long-term data from pts with ≥12 mo of avelumab 1L maintenance treatment as part of the JAVELIN Bladder 100 trial. Eligible pts had unresectable locally advanced or metastatic UC that had not progressed with 1L platinum-based chemotherapy. This analysis included pts randomized to receive avelumab + BSC. Study treatment continued until confirmed progression, unacceptable toxicity, or withdrawal of consent. After a median follow-up of 38.0 mo in the avelumab arm (data cutoff June 4, 2021; ≥2 y in all pts), 118/350 pts (33.7%) had received ≥12 mo of treatment. Characteristics of these pts were similar to those in the overall avelumab arm (Table). Among all treated pts in the overall avelumab arm (N=344), grade ≥3 treatment-related adverse events (TRAEs) occurred in 67 (19.5%) and grade ≥3 immune-related AEs (irAEs) occurred in 26 (7.6%). Among pts treated for ≥12 mo (n=118), grade ≥3 TRAEs occurred after ≥12 mo in 14 (11.9%) and grade ≥3 irAEs occurred after ≥12 mo in 5 (4.2%). Efficacy outcomes will be presented. In the JAVELIN Bladder 100 trial, prolonged avelumab 1L maintenance treatment was associated with a safety profile consistent with prior avelumab monotherapy studies, with no new safety signals identified with longer treatment duration. These results further support the use of avelumab 1L maintenance until progression for pts with aUC that has not progressed with 1L platinum-based chemotherapy.Table: 1760PPts with ≥12 months of avelumab treatment (n=118)Overall avelumab arm (N=350)Median age (range), years69 (43-86)68 (37-90)Sex, n (%)MaleFemale91 (77.1)27 (22.9)266 (76.0)84 (24.0)ECOG PS, n (%)01283 (70.3)35 (29.7)0213 (60.9)136 (38.9)1 (0.3)Site of metastasis at start of chemotherapy, n (%)VisceralNonvisceral56 (47.5)62 (52.5)191 (54.6)159 (45.4)Best response to 1L chemotherapy, n (%)CR or PRSD87 (73.7)31 (26.3)253 (72.3)97 (27.7)PD-L1 status, n (%)PositiveNegativeUnknown72 (61.0)39 (33.1)7 (5.9)189 (54.0)139 (39.7)22 (6.3)CR, complete response; PR, partial response; SD, stable disease. Open table in a new tab

1314O Cost-effectiveness of molecularly matched off-label therapies for end-stage cancer: The MetAction precision medicine study

Precision cancer medicine (PCM), the expensive and often modestly efficacious off-label treatment with medications matched to the tumour genome of end-stage cancer, challenges the healthcare resources. We compared health effects, costs and cost-effectiveness of our MetAction PCM study with corresponding data from comparator populations given best supportive care (BSC) in two external randomised controlled trials. We designed three partitioned survival models to evaluate the healthcare costs and quality-adjusted life years (QALYs) as the main outcomes. Cost-effectiveness was calculated as the incremental cost-effectiveness ratio (ICER) of PCM relative to BSC with an annual willingness-to-pay (WTP) threshold of EUR 56,384 (NOK 605,000). One-way and probabilistic sensitivity analyses addressed uncertainty. We estimated total healthcare costs (relating to next-generation sequencing (NGS) equipment and personnel wages, molecularly matched medications to the patients with an actionable tumour target and follow-up of the responding patients) and the health outcomes for the MetAction patients versus costs (relating to estimated hospital admission) and outcomes for the BSC cases. The ICERs for incremental QALYs were twice or more as high as the WTP threshold and relatively insensitive to cost decrease of the NGS procedures, while reduction of medication prices would contribute significantly towards a cost-effective PCM strategy. Our health economic modelling compared patients with end-stage cancer analysed by NGS for the opportunity to provide molecularly matched therapies, with comparator populations instead receiving BSC, and showed that the high ICERs of PCM were driven by costs relating to the NGS diagnostics and molecularly matched medications, with a likelihood for the strategy to be cost-effective defying WTP constraints. Reducing drug expenses to half the list price would likely result in an ICER at the WTP threshold, which can be an incentive to a public-private partnership of sharing the costs of molecularly matched medicines in PCM, exemplified by the models used in the ongoing IMPRESS-Norway and Dutch DRUP trials.

PL03.09 IMpower010:Overall Survival Interim Analysis of a Phase III Study of Atezolizumab vs Best Supportive Care in Resected NSCLC

IMpower010 (NCT02486718) was the first Phase III immunotherapy study to show a statistically significant disease-free survival (DFS) benefit with adjuvant atezolizumab vs best supportive care (BSC) in resected NSCLC following platinum-based chemotherapy (Felip et al. Lancet 2021). Based on these findings, atezolizumab was approved as adjuvant treatment after resection and platinum-based chemotherapy in patients with programmed death-ligand 1 (PD-L1) tumour cell (TC) ≥1% stage II-IIIA NSCLC in the US, China, and other countries; and in PD-L1 TC ≥50% stage II-IIIA NSCLC in the EU and other countries The key secondary OS endpoint was not mature at the IMpower010 DFS interim analysis (IA) but is of considerable clinical interest in this curative setting.

EP04.01-017 Cost-Effectiveness of Atezolizumab for Adjuvant Treatment of Patients with Stage II-IIIA PD-L1+ Non-small Cell Lung Cancer

Chemotherapy was the historical standard of care for adjuvant treatment of early-stage resectable NSCLC. Atezolizumab demonstrated a significant disease-free survival (DFS) benefit versus best supportive care (BSC) as adjuvant treatment following resection and platinum-based chemotherapy for adults with stage II-IIIA (AJCC 7th edition) NSCLC and PD-L1 expression on ≥1% of tumor cells (PD-L1+). This regimen was FDA-approved based on the randomized, open-label, phase 3 IMpower010 clinical trial (NCT02486718). Understanding the economic impact of therapeutic innovations is essential to prioritizing healthcare resources. This study evaluated the cost-effectiveness of atezolizumab vs BSC in this setting from a US commercial payer perspective.

305P The role of surgery in addition to chemotherapy in the second-line treatment of glioblastomas

Gliomas are brain tumours that develop from glial cells and the most common type is Glioblastoma (GBM). The initial standard treatment is the STUPP protocol. These patients (pts) are often previously submitted to surgery to remove the lesion. Its treatment is not curative and it will recur at some point. Treatment options in case of disease recurrence are chemotherapy (CT), surgery, radiotherapy (RT) and, in the case of poor performance status and advanced age, best supportive care (BSC). Some studies have compared treatments used in 2nd line of GBM but the results have been inconsistent.

400P Impact of regorafenib dose optimization on comparative outcomes in the treatment of relapsed/refractory metastatic colorectal cancer (mCRC)

Previous network meta-analyses (NMA) showed favorable overall survival (OS), progression-free survival (PFS), and safety profiles for regorafenib dose optimization (rego 80+) compared to best supportive care (BSC), regorafenib standard dosing (rego 160), and trifluridine/tipiracil (TAS) in the treatment of relapsed/refractory mCRC. This update adds fruquintinib (fruq) as a comparator.

Suprachoroidal Injection of Triamcinolone Acetonide Injectable Suspension for the Treatment of Macular Edema Associated With Uveitis in the United States: A Cost-Effectiveness Analysis

ObjectivesSuprachoroidal injection of triamcinolone acetonide is the first Food and Drug Administration–approved treatment for macular edema associated with uveitis. A cost-effectiveness analysis was performed comparing this treatment with best supportive care (BSC) for the management of this indication from US Medicare and commercial payer perspectives. MethodsA patient-level simulation was developed per the patient characteristics and changes in best-corrected visual acuity letter scores observed in a phase III study of triamcinolone acetonide (PEACHTREE). The wholesale acquisition cost of triamcinolone acetonide was $1650/injection; suprachoroidal injection cost was assumed at $200/injection. Healthcare costs were informed by a US claims–based analysis. Mortality risk associated with severe vision loss and blindness was modeled by applying a hazard ratio to all-cause mortality rates of the US general population. Health-related quality of life weights, obtained from a regression model fitted to the Visual Function Questionnaire-25 data from PEACHTREE, were applied based on the best-corrected visual acuity scores of both eyes. Costs (2020 US dollar) and benefits were discounted at 3% annually. Incremental cost-effectiveness ratios were estimated over a 10-year horizon. ResultsIn the base-case, the incremental cost-effectiveness ratio comparing triamcinolone acetonide with BSC was $28 479 per quality-adjusted life-year gained. The wholesale acquisition cost for triamcinolone acetonide for suprachoroidal use was ∼68%, ∼56%, and ∼27% below the willingness-to-pay thresholds of $150 000, $100 000, and $50 000 per quality-adjusted life-year gained, respectively. Results were robust in sensitivity and scenario analyses. ConclusionsTriamcinolone acetonide for suprachoroidal use is cost-effective compared with BSC for patients with macular edema associated with uveitis.

Cost-effectiveness of molecularly matched off-label therapies for end-stage cancer – the MetAction precision medicine study

Background Precision cancer medicine (PCM), frequently used for the expensive and often modestly efficacious off-label treatment with medications matched to the tumour genome of end-stage cancer, challenges healthcare resources. We compared the health effects, costs and cost-effectiveness of our MetAction PCM study with corresponding data from comparator populations given best supportive care (BSC) in two external randomised controlled trials. Methods We designed three partitioned survival models to evaluate the healthcare costs and quality-adjusted life years (QALYs) as the main outcomes. Cost-effectiveness was calculated as the incremental cost-effectiveness ratio (ICER) of PCM relative to BSC with an annual willingness-to-pay (WTP) threshold of EUR 56,384 (NOK 605,000). One-way and probabilistic sensitivity analyses addressed uncertainty. Results We estimated total healthcare costs (relating to next-generation sequencing (NGS) equipment and personnel wages, molecularly matched medications to the patients with an actionable tumour target and follow-up of the responding patients) and the health outcomes for the MetAction patients versus costs (relating to estimated hospital admission) and outcomes for the BSC cases. The ICERs for incremental QALYs were twice or more as high as the WTP threshold and relatively insensitive to cost decrease of the NGS procedures, while reduction of medication prices would contribute significantly towards a cost-effective PCM strategy. Conclusions The models suggested that the high ICERs of PCM were driven by costs of the NGS diagnostics and molecularly matched medications, with a likelihood for the strategy to be cost-effective defying WTP constraints. Reducing drug expenses to half the list price would likely result in an ICER at the WTP threshold. This can be an incentive for a public-private partnership for sharing drug costs in PCM, exemplified by ongoing European initiatives. ClinicalTrials.gov, identifier NCT02142036

Erstlinientherapie des metastasierten Urothelkarzinoms: ein Update

BackgroundUrothelial carcinoma (UC) of the bladder is considered to be a tumor sensitive to chemotherapy. Nevertheless, the 5‑year survival rate in stage IV is < 5%. Approximately half of the patients receive only first-line treatment due to rapid disease progression and/or poor general condition.ObjectiveNarrative review of the first-line treatment of advanced UC.Material and methodsEvaluation of treatment recommendations of national and international guidelines as well as a literature search in PubMed and congress abstracts.ResultsCrucial for the choice of first-line treatment is the (cis)platinum eligibility. If possible, a chemotherapy combination containing cisplatin should be carried out. In cases of contraindications, cisplatin can be replaced by carboplatin but at the cost of a loss of efficacy. If at least stable disease is achieved after 4–6 cycles of treatment containing platinum, immune maintenance therapy with avelumab should be subsequently applied. The programmed cell death 1 ligand 1 (PD-L1) inhibitor showed a survival benefit compared with best supportive care (BSC) regardless of prior platinum treatment or cycle number. Patients with (cis)platinum ineligibility and positive PD-L1 status can receive immuno-monotherapy with atezolizumab or pembrolizumab. For the remaining patients, an individual decision has to be made whether and which systemic treatment should be considered or whether a BSC approach should be favored.ConclusionThe course of the disease is set early, before initiation of first-line treatment, with the determination of (cis)platinum eligibility. Avelumab is the first immune maintenance treatment available with significant survival benefit.

Cost-effectiveness analysis of prolonged-release fampridine to treat walking disability of multiple sclerosis in China.

Objectives: This study evaluates the cost-effectiveness of adding prolonged-release (PR)-fampridine to best supportive care (BSC) versus BSC alone in adult multiple sclerosis patients with walking disability in China. Materials & methods: A hybrid decision tree and Markov model from both the societal and healthcare perspectives were constructed. Parameters were derived from clinical trials of PR-fampridine, published sources and clinical expert interviews. Results: Over a 10-year time horizon, adding PR-fampridine to BSC led to 0.15 quality-adjusted life year (QALY) gain and lower costs, with incremental cost-effectiveness ratios of -238,806 Chinese Yuan/QALY and -113,488 Chinese Yuan/QALY from the societal and healthcare perspectives, respectively. Conclusion: Compared with BSC alone, PR-fampridine plus BSC is considered an economically dominant strategy for the treatment of multiple sclerosis-related walking disability in China.

PS1-5 IMpower010: results from Asian patients in a phase 3 study of adjuvant atezolizumab in resected stage IB-IIIA NSCLC

The Ph 3 IMpower010 study (NCT02486718) met its primary endpoint, showing significant disease-free survival (DFS) benefit with atezo vs best supportive care (BSC) after adjuvant chemo in patients (pts) with completely resected stage II-IIIA NSCLC (HR 0.79 95% CI 0.64, 0.96), with pronounced benefit in PD-L1 TC≥1% stage II-IIIA pts (HR 0.66 95% CI 0.50, 0.88). We report data from the Asian population (pts recruited from Japan, mainland China, Taiwan, Korea and Hong Kong).

Influence of the SARS-CoV-2 outbreak on management and prognosis of new lung cancer cases, a retrospective multicentre real-life cohort study

IntroductionThe SARS-CoV-2 pandemic has impacted the care of cancer patients. This study sought to assess the pandemic’s impact on the clinical presentations and outcomes of newly referred patients with lung cancer from the Greater Paris area. MethodsWe retrospectively retrieved the electronic health records and administrative data of 11.4 million patients pertaining to Greater Paris University Hospital (AP-HP). We compared indicators for the 2018–2019 period to those of 2020 in regard to newly referred lung cancer cases. We assessed the initial tumour stage, the delay between the first multidisciplinary tumour board (MTB) and anticancer treatment initiation, and 6-month overall survival (OS) rates depending on the anticancer treatment, including surgery, palliative systemic treatment, and best supportive care (BSC). ResultAmong 6240 patients with lung cancer, 2179 (35%) underwent tumour resection, 2069 (33%) systemic anticancer therapy, 775 (12%) BSC, whereas 1217 (20%) did not receive any treatment. During the first lockdown, the rate of new diagnoses decreased by 32% compared with that recorded in 2018–2019. Initial tumour stage, repartition of patients among treatment categories, and MTB-related delays remained unchanged. The 6-month OS rates of patients diagnosed in 2018–2019 who underwent tumour resection were 98% versus 97% (HR = 1.2; 95% CI: 0.7–2.0) for those diagnosed in 2020; the respective rates for patients who underwent systemic anticancer therapy were 78% versus 79% (HR = 1.0; 95% CI: 0.8–1.2); these rates were 20% versus 13% (HR = 1.3; 95% CI: 1.1–1.6) for those who received BSC. COVID-19 was associated with poorer OS rates (HR = 2.1; 95% CI: 1.6–3.0) for patients who received systemic anticancer therapy. ConclusionsThe SARS-CoV-2 pandemic has not exerted any deleterious impact on 6-month OS of new lung cancer patients that underwent active anticancer therapy in Greater Paris University hospitals.

MSR6 Modeling Survival of People with Cystic Fibrosis (PWCF) Aged ≥6 Years Heterozygous for the F508DEL Mutation with a Minimal Function Mutation (F/MF) in Brazil Treated with Elexacaftor/Tezacaftor/Ivacaftor and Ivacaftor (ELX/TEZ/IVA)

ELX/TEZ/IVA is a breakthrough therapy targeting the underlying cause of cystic fibrosis that is currently not available in Brazil. ELX/TEZ/IVA has been shown to substantially improve lung function and nutritional outcomes. Although survival projections are available in non-Brazilian settings, the potential long-term impact of ELX/TEZ/IVA on Brazilian pwCF is of interest given regional variation in survival. Here we estimate survival in Brazilian F/MF pwCF aged ≥6 years receiving ELX/TEZ/IVA+best supportive care (BSC) versus BSC-alone.

EE400 Cost-Effectiveness Analysis of Fampridine for Multiple Sclerosis Treatment in China

Fampridine is the only approved symptomatic drug to improve multiple sclerosis (MS) related walking disability globally. This study aims to evaluate the cost-effectiveness of adding fampridine to best supportive care (BSC) versus BSC alone for the improvement of walking ability in adult MS patients with Expanded Disability Status Scale (EDSS) score 4-7 in China.

Cost-effectiveness analysis of durvalumab as a maintenance treatment for patients with locally advanced, unresectable, stage Ⅲ nsclc in china.

The aim of this study was to evaluate the cost-effectiveness of durvalumab compared with Best supportive care (BSC) after chemoradiotherapy in patients with stage III non-small cell lung cancer from healthcare system perspective in China. A dynamic state transition model was adopted to simulate life time, direct medical costs and QALYs. In the base case scenario, for patients with unresectable, stage Ⅲ non-small cell lung cancer whose disease has not progressed after platinum-based chemoradiation therapy, the treatment group would use durvalumab whereas the control group would use BSC. Clinical data and health utility were derived from the patient-level data of Asian ethnicity in the PACIFIC trial. Cost of drug acquisition, follow-up, medical service, inspection, terminal care and adverse event treatment were considered in this model. The cost of durvalumab was calculated based on retail prices and Patient Assistance Program. In the base case, the durvalumab group yielded an additional 2.60 LYs and 2.37QALYs (discounted), causing an additional cost of 0.459 million RMB and 0.109 million RMB without and with PAP, so the ICER was 193,898 RMB/QALY and 46,093.12 RMB/QALY respectively. This study demonstrated that durvalumab can improve the survival of patients with unresectable, stage Ⅲ non-small cell lung cancer whose disease has not progressed after platinum-based chemoradiation therapy and would be a cost-effective option compared with BSC at a willingness to pay (WTP) threshold of 212676 RMB (three times GDP per capita of China in 2019).

P561: VIALE-T: A RANDOMIZED, OPEN-LABEL, PHASE 3 STUDY OF VENETOCLAX IN COMBINATION WITH AZACITIDINE AFTER ALLOGENEIC STEM CELL TRANSPLANTATION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA

Background: Acute myeloid leukemia (AML) is an aggressive malignancy and is the most common and second most common form of acute leukemia in adults and children, respectively. The combination of the highly selective BCL-2 inhibitor venetoclax and the hypomethylating agent azacitidine was shown to be safe and effective in clinical trials (DiNardo et al. Blood. 2019;133:7-17; DiNardo et al. N Engl J Med. 2020;383:617-629) and is approved by the United States Food and Drug Administration and European Medicines Agency for the treatment of patients with AML who are not eligible to receive intensive chemotherapy. Following allogeneic stem cell transplantation (alloSCT), most patients do not receive antileukemic therapy; however, an unmet need remains as disease relapse and graft-versus-host disease (GvHD) commonly occur posttransplant. In addition to the antileukemic effect of venetoclax shown in clinical studies, preclinical studies suggest venetoclax may mitigate the risk of GvHD. VIALE-T is a Phase 3, randomized, open-label trial in progress (NCT04161885) evaluating the safety and efficacy of venetoclax in combination with azacitidine versus best supportive care (BSC) as maintenance therapy following alloSCT in patients with AML. Aims: N/A Methods: This Phase 3 study consists of 2 parts (Figure). Key inclusion criteria include diagnosis of AML; plans to receive alloSCT or have received alloSCT within the past 30 days; bone marrow blasts <10% before pretransplant conditioning and <5% posttransplant; have received myeloablative, or reduced intensity, or nonmyeloablative pretransplant conditioning protocols. Grafts are allowed from various sources (bone marrow, peripheral blood stem cells, cord blood cells). Patients must be ≥18 years old for Part 1 and ≥12 years old for Part 2. Additionally, patients must meet key laboratory values for absolute neutrophil count (Part 1, ≥1500/µL; Part 2, ≥1000/µL), platelet count (Part 1, ≥80,000/µL; Part 2, ≥50,000/µL), bilirubin ≤3 times the upper limit of normal, and creatinine clearance >30 mL/min. Patients who have received venetoclax and had no history of disease progression while receiving venetoclax are eligible. Part 1 evaluates dose levels of venetoclax combined with azacitidine to determine the recommended Phase 3 dose (RP3D), which will be confirmed in approximately 12 additional patients enrolled in the Safety Expansion Cohort. Part 2 will be a randomized, open-label evaluation of the RP3D of venetoclax combined with azacitidine and BSC versus BSC only in adults and children aged 12 years or older. All venetoclax-treated patients will receive antibiotic prophylaxis during Cycle 1. The primary endpoint for Part 1 is the frequency of dose-limiting toxicities. The primary endpoint for Part 2 is relapse-free survival as assessed by an independent review committee. Key secondary endpoints for Part 2 include overall survival, GvHD-free relapse-free survival, and the rate of patients without higher grade GvHD at 90 days after randomization. Enrollment into the Safety Expansion Cohort will be completed in 2021. Part 2 will enroll approximately 400 patients across approximately 175 participating study sites in 17 countries, with recruitment beginning in 2022. Results: N/A Image:Summary/Conclusion: N/A

P768: GUADECITABINE (SGI-110) VS. TREATMENT CHOICE (TC) IN RELAPSED/REFRACTORY(R/R) MYELODYSPLASTIC SYNDROME (MDS), RESULTS OF A GLOBAL, RANDOMIZED, PHASE 3 STUDY.

Background: Guadecitabine (G) is a next-generation hypomethylating agent (HMA), administered as a small-volume subcutaneous (SC) injection, designed with the potential to overcome pharmacokinetic resistance to first-generation HMAs (decitabine and azacitidine). Preliminary guadecitabine phase 2 data in r/r MDS showed an overall survival of almost 12 months (Garcia-Manero,G, et al; Lancet Haematol http://dx.doi.org/10.1016/S2352-3026 [19]30029-8) leading to the ASTRAL-3 study. Aims: Compare overall survival of guadecitabine to that of TC consisting of low-dose cytarabine (LDAC), intensive chemotherapy (IC), or best supportive care (BSC). Secondary objectives included multiple standard assessments of response and safety. Methods: Subjects with r/r MDS or Chronic Myelomonocytic Leukemia (CMML) who had progressed or failed to respond after 6 full cycles of standard HMA therapy were randomized 2:1 between guadecitabine (60 mg/m2) SC Days 1-5 every 28 days vs. a pre-selected TC (BSC, IC, or LDAC). Stratification was by disease, disease burden (>10% bone marrow blasts or not, geography, and pre-selected TC option). Primary endpoint was overall survival (OS) and the study was designed with ~90% power to detect a hazard ratio of 0.68 (approximately 2.8 month difference in median survival). Results: 417 MDS/CMML subjects were randomized to G or TC (G:277, TC: 140). Demographics and disease status were reasonably balanced across the groups (see Table 1 below) as was percentage of commonly associated genetic mutations (TET2, DNMT3A, SF3Baa, RUNX1, and TP53). Median guadecitabine exposure was 4 cycles and 3 cycles for TC. Neither overall survival (G: median 9.1 months, TC: median 8.3 months, p=0.61, HR:0.94 with 95% CI: [0.74-1.19]) nor leukemia-free survival (LFS) (G: median 5.7 months, TC: median 5.9 months; p=0.38) demonstrated a significant difference between the two groups and subgroup analyses did not suggest a difference between guadecitabine and any of the different TC options or different genetic mutations. Transfusion dependence for 8 weeks was similar with 32.1% and 22.4% of the G group and 37.9% and 20.0% of the TC group being platelet transfusion or red blood cell transfusion independent, respectively. Safety was consistent with known profiles of the respective agents with the G group having a slightly higher overall incidence of adverse events (AE) (99.3% vs 92.6% for TC) and grade 3 or higher AE (92.2% vs 70.5% for TC). The AEs with the highest incidence in subjects who received guadecitabine were febrile neutropenia (38.5 vs 18.9% for TC), pneumonia (34.4% vs 18.9% for TC), neutropenia (34.1% vs 15.6% for TC), and thrombocytopenia (32.2% vs 21.3% for TC). Image:Summary/Conclusion: This large, global, randomized phase 3 study did not demonstrate superiority of guadecitabine over Standard TC in MDS/CMML patients who were refractory or relapsed following full course of prior HMA treatment.

Assessment of face validity of a disease model of nonsense mutation Duchenne muscular dystrophy: a multi-national Delphi panel study

Objective The objective of this study was to assess the face validity of a disease model evaluating the cost-effectiveness of ataluren for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD). Methods This was a Delphi panel study comprising of physicians with first-hand experience of ataluren for the treatment of nmDMD. Consensus was sought for previously unvalidated model data, including patient health status and quality of life measured using the Health Utility Index (HUI), mortality, informal caregiving, and the expected benefit of early ataluren treatment across four states: (1) ambulatory, (2) non-ambulatory, not yet requiring ventilation support, (3) non-ambulatory, night-time ventilation support, and (4) non-ambulatory, full-time ventilation support. Results Nine experts from five countries participated in the Delphi panel. Consensus was obtained for all questions after three panel rounds (except for two HUI-questions concerning hand function [dexterity]). Consensus HUI-derived utilities for state (1) were 1.0000 for ataluren on top of best supportive care (BSC) and 0.7337 for BSC alone. Corresponding estimates for state (2) were 0.3179 and 0.2672, for state (3) 0.1643 and 0.0913, and for state (4) −0.0732 and −0.1163. Consensus mortality rates for states (1), (2), and (3) were 4%, 13%, and 33%, and life expectancy in state (4) was agreed to be 3 years. Panelists further agreed that two informal caregivers typically provide day-to-day care/support to patients with nmDMD, and that starting treatment with ataluren at 2 versus 5 years of age would be expected to delay loss of ambulation by an additional 2 years, and initiation of night-time and full-time ventilation support by an additional 3 years, respectively. Limitations The main limitation concerns the size of the Delphi panel, govern primarily by the rarity of the disease. Conclusion This study confirms the face validity of key clinical parameters and assumptions underlying the ataluren cost-effectiveness model.