Alternating gemcitabine plus nab-paclitaxel and gemcitabine alone versus continuous gemcitabine plus nab-paclitaxel after induction treatment of metastatic pancreatic cancer (ALPACA): a multicentre, randomised, open-label, phase 2 trial.

Autor:	Dorman K; Department of Medicine III and Comprehensive Cancer Center, University Hospital, LMU Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany., Boeck S; Department of Medicine III and Comprehensive Cancer Center, University Hospital, LMU Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany; Department of Hematology and Oncology, Munich Municipal Hospital Neuperlach, Munich, Germany., Caca K; Department of Internal Medicine I, Hospital Ludwigsburg, Ludwigsburg, Germany., Reichert M; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany; Department of Internal Medicine II, University Hospital rechts der Isar, Technical University Munich, Munich, Germany., Ettrich TJ; Department of Internal Medicine I, University of Ulm, Ulm, Germany., Oettle H; Dayclinic for Oncology and Hematology, Outpatient Department of Medical Oncology, Friedrichshafen, Germany., Waidmann O; Center for Hematology and Oncology Bethanien, Frankfurt, Germany., Modest DP; Department of Hematology, Oncology, and Cancer Immunology, Charité University Hospital Berlin, Berlin, Germany., Müller L; Oncological Practice UnterEms, Leer, Germany., Michl P; Department of Gastroenterology, Hepatology, and Infectious Diseases, Medical University Hospital, Heidelberg, Germany., Kanzler S; Department of Internal Medicine II, Leopoldina Hospital Schweinfurt, Schweinfurt, Germany., Pink D; Department of Medical Oncology, Helios Hospital Bad Saarow, Bad Saarow, Germany; Clinic for Internal Medicine C, University Medicine Greifswald, Greifswald, Germany., Reinacher-Schick A; Department of Haematology and Oncology, St Josef Hospital, Ruhr University, Bochum, Germany., Geißler M; Department of Internal Medicine, Oncology/Hematology, Gastroenterology, Hospital Esslingen, Esslingen, Germany., Pelz H; Center for Hematology and Oncology Offenburg, Offenburg, Germany., Kunzmann V; Department of Medical Oncology, University Hospital of Wuerzburg, Wuerzburg, Germany., Held S; ClinAssess, Leverkusen, Germany., Schichtl T; MVZ Oncology, Hospitals Nordoberpfalz, Weiden, Germany., Heinemann V; Department of Medicine III and Comprehensive Cancer Center, University Hospital, LMU Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany., Kullmann F; Department of Medicine I, Hospital Weiden, Weiden, Germany. Electronic address: frank.kullmann@kno.ag.
Jazyk:	angličtina
Zdroj:	The lancet. Gastroenterology & hepatology [Lancet Gastroenterol Hepatol] 2024 Oct; Vol. 9 (10), pp. 935-943. Date of Electronic Publication: 2024 Aug 16.
DOI:	10.1016/S2468-1253(24)00197-3
Abstrakt:	Background: A standardised dose-reduction strategy has not been established for the widely used gemcitabine plus nab-paclitaxel regimen in patients with metastatic pancreatic ductal adenocarcinoma. We aimed to investigate the efficacy and tolerability of alternating treatment cycles of nab-paclitaxel-gemcitabine combination therapy and gemcitabine alone versus continuous treatment with the nab-paclitaxel-gemcitabine combination. Methods: ALPACA was a randomised, open-label, phase 2 trial conducted at 29 study centres across Germany. Patients aged 18 years or older with a histologically or cytologically confirmed diagnosis of metastatic pancreatic ductal adenocarcinoma who had not been previously treated for advanced disease were enrolled. After an induction phase with three cycles of nab-paclitaxel-gemcitabine combination therapy (nab-paclitaxel 125 mg/m 2 and gemcitabine 1000 mg/m 2 administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients were randomly assigned (1:1) by stratified permuted block randomisation either to continue treatment with standard nab-paclitaxel-gemcitabine or to receive alternating cycles of nab-paclitaxel-gemcitabine and gemcitabine alone. Patients and investigators were not masked to treatment allocation. Randomisation was done centrally by the study statistician using a computer-generated randomisation list, and was stratified by Karnofsky Performance Status and presence of liver metastases. The primary endpoint was the derivation of an unbiased point estimate and an associated confidence interval with a confidence coefficient of 80% for the hazard ratio (HR) for overall survival after randomisation, without testing a specific hypothesis, analysed by intention to treat in all patients who started randomised treatment. Safety was analysed according to treatment received. This trial is registered with ClinicalTrials.gov, NCT02564146, and is completed. Findings: Between May 27, 2016, and May 27, 2021, 325 patients were enrolled. Following three cycles of induction treatment, 174 patients were randomly assigned: 85 to continue receiving standard nab-paclitaxel-gemcitabine, of whom 79 started treatment, and 89 to the alternating treatment schedule, of whom 88 started treatment. Of the 167 patients who started randomised treatment, 88 (53%) were female and 79 (47%) were male. Median overall survival after randomisation was 10·4 months (80% CI 9·2-12·0) in the group that received standard treatment and 10·5 months (10·2-11·1) in the group that received alternating treatment (HR 0·90, 80% CI 0·72-1·13; p=0·56). The most common adverse events of any grade were peripheral neuropathy (59 [74%] of 80 patients in the continuous treatment group vs 53 [62%] of 85 patients in the alternating treatment group) and fatigue (43 [54%] vs 44 [52%]). Treatment-emergent serious adverse events after randomisation occurred in 40 (50%) patients in the continuous treatment group and in 28 (33%) in the alternating treatment group. Fewer treatment-emergent adverse events of grade 3 or higher occurred in patients treated with alternating cycles compared with those receiving standard therapy, especially for peripheral neuropathy (17 [21%] patients in the continuous treatment group vs 12 [14%] in the alternating treatment group) and infections (16 [20%] vs nine [11%]). There were two treatment-related deaths after randomisation, both in the continuous treatment group (one multiple organ dysfunction syndrome, not treated after randomisation, and one interstitial lung disease). Interpretation: Our findings suggest that a dose-reduced regimen with alternating cycles of nab-paclitaxel-gemcitabine and gemcitabine alone after three induction cycles is associated with similar overall survival to that for standard treatment with nab-paclitaxel-gemcitabine, but with improved tolerability. We therefore propose that a switch to the alternating schedule could be considered in a clinical setting for patients with metastatic pancreatic cancer who have at least stable disease after three cycles of nab-paclitaxel-gemcitabine treatment. Funding: Celgene/Bristol Myers Squibb. Competing Interests: Declaration of interests KD reports honoraria from AstraZeneca and support for travel, accommodation, and expenses from Servier, GSK, Bristol Myers Squibb, and AstraZeneca. SB reports honoraria for scientific presentations from Celgene, Servier, and MSD, fees for consultancy or advisory roles from Celgene, Servier, Incyte, Janssen-Cilag, AstraZeneca, MSD, and Bristol Myers Squibb, and support for travel, accommodation, and expenses from Lilly. MR reports honoraria for speakers' bureaus from Roche, Falk, and Servier and approved patents (EP18783030.2-1109, combination treatment of pancreatic cancer targeting PI3K signalling; EP20206259.2, analysis of tissue samples using quantitative phase-contrast microscopy). TJE reports research funding from Baxalta/Shire, support for travel, accommodation, and expenses from Ipsen, fees for consultancy or advisory roles from Eisai, MSD, Bayer, Roche, Sanofi, Bristol Myers Squibb, Incyte, AstraZeneca, Merck Serono, Pierre Fabre, Servier, Lilly, Ipsen, and Daiichi Sankyo Europe. OW reports honoraria from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Merck, MSD, Novartis, Roche, and Zentiva, consultancy fees from Amgen, Bayer, Bristol Myers Squibb, Celgene, Eisai, Incyte, Ipsen, Merck, MSD, Novartis, Roche, and Servier, and support for travel, accommodation, and expenses from Abbvie, Bayer, Bristol Myers Squibb, Gilead, Ipsen, Medac, Merck, Pierre Fabre, and Roche. DPM reports research funding to his institution from Amgen and Servier, honoraria from Merck Serono, Amgen, Servier, Bristol Myers Squibb, Taiho Pharmaceutical, MSD, Pierre Fabre, Onkowissen, Sanofi, Lilly, Institut für klinische Krebsforschung, AstraZeneca/MedImmune, Incyte, and Takeda, and fees for consultancy or advisory roles from Merck Serono, Amgen, MSD, Roche, Servier, Incyte, Bristol Myers Squibb, Pierre Fabre, Lilly, Cor2Ed, IQvia, and Onkowissen. PM reports grants from Lilly, royalties and licenses from Elsevier, consultancy fees from Lilly and Ipsen, honoraria for speakers' bureaus from Falk, Amgen, and Roche, and support for travel, accommodation, and expenses from Galapagos. DP reports consultancy fees and honoraria paid to his institution from Boehringer Ingelheim, Deciphera, and PharmaMar, support for travel, accommodation, and expenses paid to his institution from PharmaMar, fees for consultancy or advisory roles paid to his institution from Boehringer Ingelheim, Deciphera, PharmaMar, and Thermosome, and research funding paid to his institution from Bristol Myers Squibb, PharmaMar, Roche, EUSA Pharma, and Boehringer Ingelheim. AR-S reports honoraria from Amgen, Roche, Merck Serono, Bristol Myers Squibb, MSD, MCI Group, and AstraZeneca, support for travel, accommodation, and expenses from Roche, Amgen, Pierre Fabre, and MSD, fees for consultancy or advisory roles from Abbvie, Amgen, Boehringer Ingelheim, Roche, Merck Serono, Bristol Myers Squibb, MSD, AstraZeneca, Pierre Fabre, Daiichi Sankyo, Janssen-Cilag, and Servier, and research funding paid to her institution from Roche, Celgene, Ipsen, Amgen, Alexion Pharmaceuticals, AstraZeneca, Lilly, Servier, AIO-Studien, Rafael Pharmaceuticals, Erytech Pharma, and BioNTech. HP reports honoraria from Bristol Myers Squibb and AstraZeneca, support for travel, accommodation, and expenses from Abbvie, iOMEDICO, and Merck, fees for consultancy or advisory roles from Roche, Bristol Myers Squibb, Pfizer, Bayer, Novartis, Takeda, Janssen-Cilag, Gilead, Amgen, Abbvie, GSK, BeiGene, Oncopeptides, Incyte, Seagen, and Kedrion, and leadership and fiduciary roles for PiTri Studien. VH reports research funding paid to his institution from Merck, Amgen, and Roche, fees for consultancy and advisory roles from Merck, Amgen, Roche, MSD, Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre, TERUMO, GSK, Servier/Pfizer, AstraZeneca, Oncosil, and Nordic Bioscience, honoraria from Roche, Amgen, Sanofi, Merck, Servier, Pfizer, Pierre Fabre, AstraZeneca, MSD, and Seagen, and support for travel, accommodation, and expenses from Merck. FK reports research funding from Celgene and consultancy fees from Bayer and Novartis. All other authors declare no competing interests. (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu