Dataset Information

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study.

ABSTRACT:

Purpose

The open-label, phase III POSEIDON study evaluated tremelimumab plus durvalumab and chemotherapy (T + D + CT) and durvalumab plus chemotherapy (D + CT) versus chemotherapy alone (CT) in first-line metastatic non-small-cell lung cancer (mNSCLC).

Methods

Patients (n = 1,013) with EGFR/ALK wild-type mNSCLC were randomly assigned (1:1:1) to tremelimumab 75 mg plus durvalumab 1,500 mg and platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression and one additional tremelimumab dose; durvalumab plus chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression; or chemotherapy for up to six 21-day cycles (with or without maintenance pemetrexed; all arms). Primary end points were progression-free survival (PFS) and overall survival (OS) for D + CT versus CT. Key alpha-controlled secondary end points were PFS and OS for T + D + CT versus CT.

Results

PFS was significantly improved with D + CT versus CT (hazard ratio [HR], 0.74; 95% CI, 0.62 to 0.89; P = .0009; median, 5.5 v 4.8 months); a trend for improved OS did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.02; P = .0758; median, 13.3 v 11.7 months; 24-month OS, 29.6% v 22.1%). PFS (HR, 0.72; 95% CI, 0.60 to 0.86; P = .0003; median, 6.2 v 4.8 months) and OS (HR, 0.77; 95% CI, 0.65 to 0.92; P = .0030; median, 14.0 v 11.7 months; 24-month OS, 32.9% v 22.1%) were significantly improved with T + D + CT versus CT. Treatment-related adverse events were maximum grade 3/4 in 51.8%, 44.6%, and 44.4% of patients receiving T + D + CT, D + CT, and CT, respectively; 15.5%, 14.1%, and 9.9%, respectively, discontinued treatment because of treatment-related adverse events.

Conclusion

D + CT significantly improved PFS versus CT. A limited course of tremelimumab added to durvalumab and chemotherapy significantly improved OS and PFS versus CT, without meaningful additional tolerability burden, representing a potential new option in first-line mNSCLC.

SUBMITTER: Johnson ML

PROVIDER: S-EPMC9937097 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study.

Johnson Melissa L ML Cho Byoung Chul BC Luft Alexander A Alatorre-Alexander Jorge J Geater Sarayut Lucien SL Laktionov Konstantin K Kim Sang-We SW Ursol Grygorii G Hussein Maen M Lim Farah Louise FL Yang Cheng-Ta CT Araujo Luiz Henrique LH Saito Haruhiro H Reinmuth Niels N Shi Xiaojin X Poole Lynne L Peters Solange S Garon Edward B EB Mok Tony T

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20221103 6

<h4>Purpose</h4>The open-label, phase III POSEIDON study evaluated tremelimumab plus durvalumab and chemotherapy (T + D + CT) and durvalumab plus chemotherapy (D + CT) versus chemotherapy alone (CT) in first-line metastatic non-small-cell lung cancer (mNSCLC).<h4>Methods</h4>Patients (n = 1,013) with <i>EGFR</i>/<i>ALK</i> wild-type mNSCLC were randomly assigned (1:1:1) to tremelimumab 75 mg plus durvalumab 1,500 mg and platinum-based chemotherapy for up to four 21-day cycles, followed by durval ...[more]

PMID: 36327426

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Project description:ImportanceCheckpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic non-small cell lung cancer.ObjectiveTo compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer.Design, setting, and participantsThis open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non-small cell lung cancer who had no sensitizing EGFR or ALK genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018.InterventionsPatients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy.Main outcomes and measuresThe primary end points, assessed in patients with ≥25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory.ResultsBetween July 21, 2015, and June 8, 2016, 1118 patients were randomized. Baseline demographic and disease characteristics were balanced between treatment groups. Among 488 patients with ≥25% of tumor cells expressing PD-L1, median OS was 16.3 months (95% CI, 12.2-20.8) with durvalumab vs 12.9 months (95% CI, 10.5-15.0) with chemotherapy (hazard ratio [HR], 0.76; 97.54% CI, 0.56-1.02; P = .04 [nonsignificant]). Median OS was 11.9 months (95% CI, 9.0-17.7) with durvalumab plus tremelimumab (HR vs chemotherapy, 0.85; 98.77% CI, 0.61-1.17; P = .20). Median PFS was 3.9 months (95% CI, 2.8-5.0) with durvalumab plus tremelimumab vs 5.4 months (95% CI, 4.6-5.8) with chemotherapy (HR, 1.05; 99.5% CI, 0.72-1.53; P = .71). Among 809 patients with evaluable bTMB, those with a bTMB ≥20 mutations per megabase showed improved OS for durvalumab plus tremelimumab vs chemotherapy (median OS, 21.9 months [95% CI, 11.4-32.8] vs 10.0 months [95% CI, 8.1-11.7]; HR, 0.49; 95% CI, 0.32-0.74). Treatment-related adverse events of grade 3 or higher occurred in 55 (14.9%) of 369 patients who received treatment with durvalumab, 85 (22.9%) of 371 patients who received treatment with durvalumab plus tremelimumab, and 119 (33.8%) of 352 patients who received treatment with chemotherapy. These adverse events led to death in 2 (0.5%), 6 (1.6%), and 3 (0.9%) patients, respectively.Conclusions and relevanceThe phase 3 MYSTIC study did not meet its primary end points of improved OS with durvalumab vs chemotherapy or improved OS or PFS with durvalumab plus tremelimumab vs chemotherapy in patients with ≥25% of tumor cells expressing PD-L1. Exploratory analyses identified a bTMB threshold of ≥20 mutations per megabase for optimal OS benefit with durvalumab plus tremelimumab.Trial registrationClinicalT rials.gov Identifier: NCT02453282.

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.

Project description:BackgroundAngiogenesis is critical to gastroesophageal adenocarcinoma growth and metastasis. Regorafenib is a multikinase inhibitor targeting angiogenic and stromal receptor tyrosine kinases. We evaluated whether regorafenib augments the antitumor effect of first-line chemotherapy in metastatic esophagogastric cancer.Materials and methodsPatients with previously untreated metastatic gastroesophageal adenocarcinoma received 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) every 14 days and regorafenib 160 mg daily on days 4 to 10 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS). To identify predictive biomarkers of outcome, we examined correlations between genomic characteristics of sequenced pretreatment tumors and PFS.ResultsBetween August 2013 and November 2014, 36 patients with metastatic esophagogastric cancer were accrued to this single-center phase II study (NCT01913639). The most common grade 3-4 treatment-related adverse events were neutropenia (36%), leucopenia (11%) and hypertension (8%). The 6-month PFS was 53% (95% confidence interval [CI], 38%-71%), the objective response rate was 54% (95% CI, 37%-70%), and the disease control rate was 77% (95% CI, 67%-94%). Next-generation sequencing did not identify any genomic alterations significantly correlated with response, and there was no association between homologous recombination deficiency and PFS with platinum-based chemotherapy.ConclusionRegorafenib (one week on-one week off schedule) is well tolerated in combination with first-line FOLFOX but does not improve 6-month PFS relative to historical control.Implications for practicePrognosis for metastatic esophagogastric cancer remains poor despite modern systemic therapy regimens. This phase II trial indicates that the combination of regorafenib and FOLFOX is well tolerated but does not add to the efficacy of first-line chemotherapy in metastatic esophagogastric cancer. Notably, recently reported data suggest potential synergy between regorafenib and the PD-1 inhibitor nivolumab. As this study demonstrates that regorafenib plus FOLFOX is safe, and combined chemotherapy and immunotherapy show favorable toxicity profiles, future studies combining immunotherapy with regorafenib and chemotherapy may be feasible.

Dataset Information

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study.

Purpose

Methods

Results

Conclusion

Publications

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study.

Similar Datasets

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