Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer.
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ABSTRACT: Background
Galunisertib is the first-in-class, first-in-human, oral small-molecule type I transforming growth factor-beta receptor (ALK5) serine/threonine kinase inhibitor to enter clinical development. The effect of galunisertib vs. placebo in patients with unresectable pancreatic cancer was determined.Methods
This was a two-part, multinational study: phase 1b was a non-randomised, open-label, multicentre, and dose-escalation study; phase 2 was a randomised, placebo- and Bayesian-augmented controlled, double-blind study in patients with locally advanced or metastatic pancreatic adenocarcinoma considered candidates for first-line chemotherapy with gemcitabine. Patients were randomised 2:1 to galunisertib-gemcitabine (N = 104) or placebo-gemcitabine (N = 52). Gemcitabine dose was 1000 mg/m2 QW. Primary endpoints for phases 1b and 2, respectively, were phase 2 dose and overall survival. Secondary objectives included tolerability and biomarkers.Results
Dose-escalation suggested a 300-mg/day dose. Primary objective was met: median survival times were 8.9 and 7.1 months for galunisertib and placebo, respectively (hazard ratio [HR] = 0.79 [95% credible interval: 0.59-1.09] and posterior probability HR < 1 = 0.93). Lower baseline biomarkers macrophage inflammatory protein-1-alpha and interferon-gamma-induced protein 10 were associated with galunisertib benefit.Conclusions
Galunisertib-gemcitabine combination improved overall survival vs. gemcitabine in patients with unresectable pancreatic cancer, with minimal added toxicity. Future exploration of galunisertib in pancreatic cancer is ongoing in combination with durvalumab.
SUBMITTER: Melisi D
PROVIDER: S-EPMC6251034 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC7905498 | biostudies-literature
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Project description:BackgroundThe clinical consequences of pancreatic exocrine insufficiency and its treatment in advanced pancreatic ductal adenocarcinoma (PDAC) are poorly investigated. This retrospective study aims at investigating the pancreatic enzyme replacement therapy (PERT) use and its impact on survival and maldigestion-related symptoms in advanced PDAC patients undergoing chemotherapy.MethodsA retrospective analysis was conducted on advanced PDAC patients, treated with first-line gemcitabine plus nab-paclitaxel at two academic institutions (March 2015-October 2018). Data were correlated with overall survival (OS) using Cox regression model. Kaplan-Meier curves were compared using Log-Rank test.ResultsData from 110 patients were gathered. PERT was administered in 55 patients (50%). No significant differences in baseline characteristics with those who did not receive PERT were found. Median OS for the entire group was 12 months (95% CI 9-15). At multivariate analysis, previous surgical resection of the primary tumor, (HR 2.67, p=0.11), weight gain after 3 months (HR 1.68, p=0.07) and PERT (HR 2.85, p ≤ 0.001) were independent predictors of OS. Patients who received PERT reported an improvement of maldigestion-related symptoms at 3 months more frequently than patients who did not (85.2% vs 14.8%, p ≤ 0.0001).ConclusionPERT is associated with significantly prolonged survival and maldigestion-related symptoms alleviation in advanced PDAC patients.
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Project description:BackgroundPancreatic cancer is mostly diagnosed in an advanced stage and treated with systemic therapy with palliative intent. Nowadays, the doublet chemotherapy of Gemcitabine and nab-paclitaxel (Gem-Nab) is one of the most frequently used regimens worldwide, but is not ubiquitarily available or reimbursed. Therefore, we compared the clinical efficacy of Gem-Nab to a historical control of patients treated with gemcitabine and oxaliplatin (Gem-Ox) at our tertiary cancer center, which was the standard treatment prior to the introduction of FOLFIRINOX.MethodsThis single-center retrospective real world study includes 121 patients diagnosed with locally advanced or primary metastatic pancreatic adenocarcinoma who were treated with chemotherapy doublet, with either Gem-Nab or Gem-Ox in palliative first-line. Survival rates were analyzed using the Kaplan-Meier method, and comparisons were made with log-rank tests. Gem-Ox was considered as standard first line therapy at our institution for patients who were deemed fit for doublet chemotherapy between the years 2006 to 2012. These patients were compared to a cohort of patients treated with the new standard first-line therapy of Gem-Nab between 2013 and 2020.ResultsA total of 554 patients with pancreatic cancer of all stages were screened, and 73 patients treated with Gem-Nab and 48 patients treated with Gem-Ox in the palliative first-line setting were identified and included in this analysis. Patients receiving Gem-Ox had a statistically significantly better performance score (ECOG PS) when compared to the Gem-Nab group (Odds ratio (OR) 0.28, 95% CI 0.12-0.65, p = 0.005), more often suffered from locally advanced than metastatic disease (OR 3.10, 95% CI 1.27-7.91, p = 0.019) and were younger in age (OR 0.95, 95% CI 0.91-0.99, p = 0.013). Median overall survival (OS) of the whole study cohort was 10.3 months (95% CI 8.5-11.6). No statistically significant difference in OS could be observed between the Gem-Nab and the Gem-Ox cohort (median OS: 8.9 months (95% CI 6.4-13.5) versus 10.9 months (95% CI 9.5-13.87, p = 0.794, HR 1.27, 95% CI 0.85-1.91)). Median progression-free survival (PFS) was 6.8 months in the entire cohort (95% CI 4.9-8.4). No statistically significant difference in PFS could be observed between the Gem-Nab and the Gem-Ox cohort (median PFS: 5.8 months (95% CI 4.3-8.2) versus 7.9 months (95% CI 5.4-9.5) p = 0.536, HR 1.11, 95% CI 0.74-1.67). Zero-truncated negative binomial regressions on OS and PFS adjusting for gender, age, performance status (ECOG PS), and CA19-9 levels yielded no significant difference between Gem-Nab or Gem-Ox.ConclusionFrom our analysis, we could evidence no difference in outcome parameters in this retrospective analysis despite the worse prognostic pattern for GemOX. Therefore, we suggest Gem-Ox as potential first line treatment option for inoperable locally advanced or metastatic pancreatic cancer, especially if Gem-Nab is not available.
| S-EPMC10501299 | biostudies-literature
Project description:ObjectiveGemcitabine plus nab-paclitaxel (GnP) is the standard first-line therapy for advanced pancreatic ductal adenocarcinoma (PDAC). S-1, an oral fluoropyrimidine derivative, as compared with gemcitabine, is non-inferior in terms of overall survival (OS) and is associated with lower hematologic toxicity. Accordingly, S-1 is a convenient oral alternative treatment for advanced PDAC. This study was aimed at comparing the efficacy and safety of gemcitabine plus S-1 (GS) vs. GnP as first-line chemotherapy for advanced PDAC.MethodsPatients with advanced PDAC who received first-line GS or GnP at the Peking Union Medical College Hospital between March 2011 and November 2022 were evaluated.ResultsA total of 300 patients were assessed, of whom 84 received GS and 216 received GnP. The chemotherapy completion rate was higher with GS than GnP (50.0% vs. 30.3%, P = 0.0028). The objective response rate (ORR) was slightly higher (14.3% vs. 9.7%, P = 0.35), and the median OS was significantly longer (17.9 months vs. 13.3 months, P = 0.0078), in the GS group than the GnP group. However, the median progression-free survival (PFS) did not significantly differ between groups. Leukopenia risk was significantly lower in the GS group than the GnP group (14.9% vs. 28.1%, P = 0.049).ConclusionsAs first-line chemotherapy for advanced PDAC, the GS regimen led to a significantly longer OS than the GnP regimen. The PFS, ORR, and incidence of severe adverse events were comparable between the GS and GnP groups.
| S-EPMC10618946 | biostudies-literature
Project description:BackgroundThe treatment paradigm of unresectable malignant pleural mesothelioma (MPM) has changed in recent years. Checkmate 743 demonstrate that nivolumab plus ipilimumab showed good clinical benefits compared with chemotherapy in the treatment of MPM. The study is aim to evaluate the cost-effectiveness of Nivolumab plus ipilimumab vs. platinum plus chemotherapy for the first-line treatment of unresectable MPM.MethodsA Markov model was developed to compare the cost and quality-adjusted life-year (QALY) of nivolumab plus ipilimumab and chemotherapy over a 10-year time horizon. Clinical efficacy and safety data were extracted from the CheckMate 743 trials. Health state utilities were obtained from published literature. Costs were collected from an US payer perspective. One-way and probabilistic sensitivity analyses were conducted to explore the impact of uncertainties on the cost-effectiveness's results.ResultsIn the base case analysis, the incremental healthcare costs and QALYs for Nivolumab plus Ipilimumab vs. chemotherapy are $196,604.22 and 0.53, respectively, resulting an incremental cost-effectiveness ratio (ICER) of $372,414.28/QALYs for the model cohort of patients with locally advanced or metastatic MPM. However, Probabilistic sensitivity analysis showed that there was no probability that Nivolumab plus ipilimumab was cost-effective within the fluctuation range of other model parameters in first-line in unresectable MPM. The results of one-way sensitivity analysis showed that the cost of Nivolumab was the most sensitive parameter.ConclusionsThe ICER of Nivolumab plus ipilimumab is above the theoretical willingness-to-pay threshold in the U.S, which suggests that first-line nivolumab plus ipilimumab for unresectable MPM may be not a cost-effective choice.
| S-EPMC9354521 | biostudies-literature
Project description:BackgroundThis exploratory analysis evaluated second-line (2L) therapy for metastatic pancreatic cancer in a large phase 3 trial (MPACT).MethodsPatients who received first-line (1L) nab-paclitaxel+gemcitabine (nab-P+Gem) or Gem were assessed for survival based on 2L treatment received. Multivariate analyses tested influence of treatment effect and prognostic factors on survival.ResultsThe majority of 2L treatments (267 out of 347, 77%) contained a fluoropyrimidine (5-fluorouracil or capecitabine). Median total survival (1L randomisation to death) for patients who received 2L treatment after 1L nab-P+Gem vs Gem alone was 12.8 vs 9.9 months (P=0.015). Median total survival for patients with a fluoropyrimidine-containing 2L therapy after nab-P+Gem vs Gem was 13.5 vs 9.5 months (P=0.012). Median 2L survival (duration from start of 2L therapy to death) was 5.3 vs 4.5 months for nab-P+Gem vs Gem, respectively (P=0.886). Factors significantly associated with longer post-1L survival by multivariate analyses included 1L nab-P+Gem, receiving 2L treatment, longer 1L progression-free survival, and Karnofsky performance status⩾70 and neutrophil-to-lymphocyte ratio⩽5 at the end of 1L treatment.ConclusionsThese findings support the use of 2L therapy for patients with metastatic pancreatic cancer. Fluoropyrimidine-containing treatment after 1L nab-P+Gem is an active regimen with significant clinical effect.
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