Dataset Information

Safety and tolerability of first-line durvalumab with tremelimumab and chemotherapy in esophageal squamous cell carcinoma.

ABSTRACT:

Background

Advanced or metastatic esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis; new first-line systemic treatment options are needed. Combining immuno-oncology therapies with standard chemotherapy may represent a promising approach for the treatment of solid tumors. Results from a Phase Ib study evaluating durvalumab with tremelimumab and chemotherapy in patients with advanced or metastatic ESCC are reported.

Methods

Adults with advanced or metastatic ESCC who were candidates for first-line platinum-based chemotherapy received durvalumab 1500 mg (Day 1), tremelimumab 75 mg (Day 1), cisplatin 80 mg/m² (Day 1) and 5-fluorouracil (5-FU) 800 mg/m² (Days 1-5) in 28-day cycles until disease progression or discontinuation due to toxicity. The study consisted of safety run-in (Part A) and expansion (Part B) periods. The primary endpoint was safety. Antitumor activity was an exploratory endpoint.

Results

Sixteen patients were enrolled, 6 in Part A and 10 in Part B, and received a median of 4.0 treatment cycles. All patients were Asian; median age was 65.0 years. All patients experienced adverse events (AEs) related to cisplatin and 5-FU, and 8 (50.0%) patients experienced AEs related to durvalumab and tremelimumab. Grade ≥3 treatment-related AEs occurred in 7 (43.8%) patients. There were no deaths associated with AEs. Six (37.5%) patients achieved an objective response. Median progression-free survival was 3.75 months, and median overall survival was 9.69 months.

Conclusions

Durvalumab with tremelimumab and chemotherapy demonstrated manageable safety and antitumor activity in patients with advanced or metastatic ESCC, warranting further investigation in randomized trials. Registered with ClinicalTrials.gov: NCT02658214.

SUBMITTER: Lee DH

PROVIDER: S-EPMC10469840 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

Safety and tolerability of first-line durvalumab with tremelimumab and chemotherapy in esophageal squamous cell carcinoma.

Lee Dae Ho DH Kim Hye Ryun HR Keam Bhumsuk B Kato Ken K Kuboki Yasutoshi Y Gao Haiyan H Yovine Alejandro A Robbins Scott H SH Ahn Myung-Ju MJ

Cancer medicine 20230725 15

<h4>Background</h4>Advanced or metastatic esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis; new first-line systemic treatment options are needed. Combining immuno-oncology therapies with standard chemotherapy may represent a promising approach for the treatment of solid tumors. Results from a Phase Ib study evaluating durvalumab with tremelimumab and chemotherapy in patients with advanced or metastatic ESCC are reported.<h4>Methods</h4>Adults with advanced or metastati ...[more]

PMID: 37489066

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Project description:BackgroundWhile the tremelimumab plus durvalumab combined with chemotherapy (T + D + CT) has shown promise in treating epidermal growth factor receptor/anaplastic lymphoma kinase (EGFR/ALK) wild-type metastatic non-small cell lung cancer (mNSCLC), particularly in patients with low or no programmed cell death ligand 1 (PD-L1) expression, the economic implications of its high cost remain poorly understood. This study fills a critical gap in knowledge by evaluating the cost-effectiveness of T + D + CT from a US health care perspective, offering valuable insights for clinical and policy decision-making.MethodsA 10-year Markov model was crafted to track the disease progression, survival, and treatment-related toxicities of a patient cohort with EGFR/ALK wild-type mNSCLC. Transition probabilities were derived from the POSEIDON trial, while health state utilities were obtained from the literature. Cost data, including drug acquisition and administration, subsequent anticancer therapies, and adverse event management were estimated using the Centers for Medicare and Medicaid Services and the Healthcare Cost and Utilization Project databases, with additional costs sourced from current literature. All cost and effectiveness measures were discounted at an annual rate of 3%. The model's robustness was assessed through deterministic sensitivity analysis (DSA), probabilistic sensitivity analysis (PSA), and scenario analysis.ResultsT + D + CT compared to chemotherapy alone yielded incremental cost-effectiveness ratios (ICERs) of $370,208 to $691,960 per quality-adjusted life-year (QALY) gained, exceeding the standard willingness-to-pay (WTP) threshold of $100,000 to $150,000 per QALY. Against durvalumab plus chemotherapy, T + D + CT was only cost-effective in all subgroups. DSA results for patients with PD-L1 expression <1% showed that the ICER for first-line T + D + CT remained above the WTP threshold range, even with substantial changes to model inputs. PSA revealed a higher likelihood of T + D + CT being cost-effective as WTP thresholds increased. Scenario analysis confirmed the study's primary findings, with the exception of a scenario where durvalumab was offered at no cost.ConclusionsThe findings suggests that T + D + CT may not be a cost-effectiveness first-line treatment for EGFR/ALK wild-type mNSCLC in the US, given its high ICERs and limited cost-effectiveness in the majority of PD-L1 expression subgroups.

Project description:Importance: In the open-label phase III POSEIDON randomized clinical trial (RCT), a limited course of tremelimumab plus durvalumab and chemotherapy (T + D + CT) indicated in the first-line treatment of metastatic non-small cell lung cancer (mNSCLC), progression-free survival, and overall survival (OS) were substantially improved without significant additional tolerance burden compared to chemotherapy (CT). However, given the high cost of T + D + CT, its value needs to be evaluated in terms of both potency and cost. Objective: To evaluate the cost-effectiveness of T + D + CT versus CT in individuals with previously untreated mNSCLC from a U.S. payer perspective. Design, setting, and participants: A three-state Markov model was adopted to weigh the lifetime costs and effectiveness of T + D + CT versus CT for the treatment of first-line mNSCLC, according to the results of the POSEIDON phase III RCT involving 675 individuals with mNSCLC. Individuals were simulated to undergo either T + D + CT for up to four 21-day cycles, followed by durvalumab once every 4 weeks until disease progression or unacceptable toxic effects and one additional tremelimumab dose, or CT for up to six 21-day cycles (with or without pemetrexed maintenance; all groups) in the analysis. Main outcomes and measures: Lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were evaluated with a willingness-to-pay (WTP) threshold of $ 100,000 to $ 150,000 per QALY. The uncertainty of the model was investigated using univariate and probabilistic sensitivity analysis. Results: T + D + CT produced additional 0.36 QALYs with additional costs of $ 217,694, compared to CT, giving rise to ICERs of $ 608,667.86/QALY. The univariate sensitivity analysis demonstrated that the outcomes were most sensitive to the cost of durvalumab. Other variables with a large or moderate influence were the utility of progression-free survival state, utility of progressive disease state, and cost of tremelimumab. Probability sensitivity analysis revealed that T + D + CT had a 0% probability of cost-effectiveness in individuals with mNSCLC at a willingness-to-pay threshold of $ 100,000 to $ 150,000 per QALY. Conclusion and relevance: In this model, T + D + CT was estimated to be less cost-effective than CT for patients with mNSCLC at a WTP threshold of $ 100,000 to $ 150,000 per QALY in the United States. When new combination therapies with remarkable effect become pivotal in the first-line treatment, the price reduction of durvalumab and tremelimumab may be necessary to achieve cost-effectiveness in future possible context.

Dataset Information

Safety and tolerability of first-line durvalumab with tremelimumab and chemotherapy in esophageal squamous cell carcinoma.

Background

Methods

Results

Conclusions

Publications

Safety and tolerability of first-line durvalumab with tremelimumab and chemotherapy in esophageal squamous cell carcinoma.

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