NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial

Gemcitabine; Metastatic pancreatic ductal adenocarcinomaGemcitabina; Adenocarcinoma ductal de pàncrees metastàticGemcitabina; Adenocarcinoma ductal de páncreas metastásicoBackground Pancreatic ductal adenocarcinoma remains one of the most lethal malignancies, with few treatment options. NAPOLI 3 aimed to compare the efficacy and safety of NALIRIFOX versus nab-paclitaxel and gemcitabine as first-line therapy for metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods NAPOLI 3 was a randomised, open-label, phase 3 study conducted at 187 community and academic sites in 18 countries worldwide across Europe, North America, South America, Asia, and Australia. Patients with mPDAC and Eastern Cooperative Oncology Group performance status score 0 or 1 were randomly assigned (1:1) to receive NALIRIFOX (liposomal irinotecan 50 mg/m2, oxaliplatin 60 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2, administered sequentially as a continuous intravenous infusion over 46 h) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2, administered intravenously, on days 1, 8, and 15 of a 28-day cycle. Balanced block randomisation was stratified by geographical region, performance status, and liver metastases, managed through an interactive web response system. The primary endpoint was overall survival in the intention-to-treat population, evaluated when at least 543 events were observed across the two treatment groups. Safety was evaluated in all patients who received at least one dose of study treatment. This completed trial is registered with ClinicalTrials.gov, NCT04083235. Findings Between Feb 19, 2020 and Aug 17, 2021, 770 patients were randomly assigned (NALIRIFOX, 383; nab-paclitaxel–gemcitabine, 387; median follow-up 16·1 months [IQR 13·4–19·1]). Median overall survival was 11·1 months (95% CI 10·0–12·1) with NALIRIFOX versus 9·2 months (8·3–10·6) with nab-paclitaxel–gemcitabine (hazard ratio 0·83; 95% CI 0·70–0·99; p=0·036). Grade 3 or higher treatment-emergent adverse events occurred in 322 (87%) of 370 patients receiving NALIRIFOX and 326 (86%) of 379 patients receiving nab-paclitaxel–gemcitabine; treatment-related deaths occurred in six (2%) patients in the NALIRIFOX group and eight (2%) patients in the nab-paclitaxel–gemcitabine group. Interpretation Our findings support use of the NALIRIFOX regimen as a possible reference regimen for first-line treatment of mPDAC.Ipsen

Pembrolizumab in Asian patients with microsatellite-instability-high/mismatch-repair-deficient colorectal cancer

The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n =?22; chemotherapy, n =?26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1?57.8) months with pembrolizumab and 43.9 (range 36.6?55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months?NR) with pembrolizumab versus 10.4 (95% CI 6.3?22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26?1.20). Median OS was NR (range 13.8 months?NR) versus 30.0 (14.7?NR) months (HR 0.65, 95% CI 0.27?1.55) and ORR was 50% (95% CI 28?72) versus 46% (95% CI 27?67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002.FUNDING INFORMATION: The study was designed under the responsibility of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, in conjunction with the steering committee. The study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Pembrolizumab was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication. ACKNOWLEDGMENTS: This work was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. We thank the patients and their families and caregivers for participating in this trial, and all investigators and site personnel. Medical writing and editorial assistance were provided by Jemimah Walker, PhD, Mehak Aggarwal, PharmD, and Doyel Mitra, PhD, CMPP, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA

A Randomized Study of Lenvatinib 18 mg vs 24 mg in Patients With Radioiodine-Refractory Differentiated Thyroid Cancer

Background: Lenvatinib is a multikinase inhibitor approved to treat radioiodine-refractory differentiated thyroid cancer (RR-DTC) at a starting dose of 24 mg/day. This study explored, in a double-blinded fashion, whether a starting dose of 18 mg/day would provide comparable efficacy with reduced toxicity. Methods: Patients with RR-DTC were randomized to lenvatinib 24 mg/day or 18 mg/day. The primary efficacy endpoint was objective response rate as of week 24 (ORRwk24); the odds ratio noninferiority margin was 0.4. The primary safety endpoint was frequency of grade ≥3 treatment-emergent adverse events (TEAEs) as of week 24. Tumors were assessed using RECIST v1.1. TEAEs were monitored and recorded. Results: The ORRwk24 was 57.3% (95% CI 46.1, 68.5) in the lenvatinib 24-mg arm and 40.3% (95% CI 29.3, 51.2) in the lenvatinib 18-mg arm, with an odds ratio (18/24 mg) of 0.50 (95% CI 0.26, 0.96). As of week 24, the rates of TEAEs grade ≥3 were 61.3% in the lenvatinib 24-mg arm and 57.1% in the lenvatinib 18-mg arm, a difference of -4.2% (95% CI -19.8, 11.4). Conclusion: A starting dose of lenvatinib 18 mg/day did not demonstrate noninferiority compared to a starting dose of 24 mg/day as assessed by ORRwk24 in patients with RR-DTC. The results represent a clinically meaningful difference in ORRwk24. The safety profile was comparable, with no clinically relevant difference between arms. These results support the continued use of the approved starting dose of lenvatinib 24 mg/day in patients with RR-DTC and adjusting the dose as necessary. Trial registration: ClinicalTrials.gov NCT02702388

Principes d'un essai thérapeutique en oncogériatrie (élaboration d'un protocole d'idarubicine en administration orale dans le cancer de prostate hormonorésistant du sujet âgé)

MONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUM (751062103) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

Irinotecan associated with cetuximab given every 2 weeks versus cetuximab weekly in metastatic colorectal cancer

Aim: The aim of the present study was to compare the efficacy and safety of weekly versus an every 2-week administration of cetuximab in association with irinotecan in patients with metastatic colorectal cancer (MCRC). Methods: We reviewed the clinical records of 50 patients with MCRC who began treatment with cetuximab from February 2004 to January 2007. Two different treatment schedules were used. In the first group (N = 32), cetuximab was given at an initial dose of 400 mg/m 2 , followed by weekly infusions of 250 mg/m 2 . In the second group (N = 18), cetuximab was administered every 2 weeks at a dose of 500 mg/m 2 . The two groups were compared for tumor response, time to progression (TTP), overall survival (OS), and toxicity. Results: All patients had received irinotecan and 5-fluorouracil; a majority had previously received oxaliplatin. Disease control (partial response + stable disease) was achieved in 56.3% of patients receiving weekly cetuximab versus 77.8% in the other group (P = 0.21). The median follow-up for all patients was 34.2 months. TTP (Group 1: 28% vs. Group 2: 18%, P = 0.9356) and OS (Group 1: 75% vs. Group 2: 72%, P = 0.6748) rates at 7 months were similar in the two groups. Skin toxicity was the most relevant adverse event: 78.1% of the patients had acne-like rash in the first group and 61% in the second group. However, only one patient in each group had a grade 3 toxic reaction. Conclusion: There is no major difference of efficacy and safety between cetuximab given every 2 weeks and a weekly dosing regimen, in association with irinotecan

Irinotecan associated with cetuximab given every 2 weeks versus cetuximab weekly in metastatic colorectal cancer

Aim: The aim of the present study was to compare the efficacy and safety of weekly versus an every 2-week administration of cetuximab in association with irinotecan in patients with metastatic colorectal cancer (MCRC). Methods: We reviewed the clinical records of 50 patients with MCRC who began treatment with cetuximab from February 2004 to January 2007. Two different treatment schedules were used. In the first group (N = 32), cetuximab was given at an initial dose of 400 mg/m 2 , followed by weekly infusions of 250 mg/m 2 . In the second group (N = 18), cetuximab was administered every 2 weeks at a dose of 500 mg/m 2 . The two groups were compared for tumor response, time to progression (TTP), overall survival (OS), and toxicity. Results: All patients had received irinotecan and 5-fluorouracil; a majority had previously received oxaliplatin. Disease control (partial response + stable disease) was achieved in 56.3% of patients receiving weekly cetuximab versus 77.8% in the other group (P = 0.21). The median follow-up for all patients was 34.2 months. TTP (Group 1: 28% vs. Group 2: 18%, P = 0.9356) and OS (Group 1: 75% vs. Group 2: 72%, P = 0.6748) rates at 7 months were similar in the two groups. Skin toxicity was the most relevant adverse event: 78.1% of the patients had acne-like rash in the first group and 61% in the second group. However, only one patient in each group had a grade 3 toxic reaction. Conclusion: There is no major difference of efficacy and safety between cetuximab given every 2 weeks and a weekly dosing regimen, in association with irinotecan

Irinotecan associated with cetuximab given every 2 weeks versus cetuximab weekly in metastatic colorectal cancer

Aim: The aim of the present study was to compare the efficacy and safety of weekly versus an every 2-week administration of cetuximab in association with irinotecan in patients with metastatic colorectal cancer (MCRC). Methods: We reviewed the clinical records of 50 patients with MCRC who began treatment with cetuximab from February 2004 to January 2007. Two different treatment schedules were used. In the first group (N = 32), cetuximab was given at an initial dose of 400 mg/m 2 , followed by weekly infusions of 250 mg/m 2 . In the second group (N = 18), cetuximab was administered every 2 weeks at a dose of 500 mg/m 2 . The two groups were compared for tumor response, time to progression (TTP), overall survival (OS), and toxicity. Results: All patients had received irinotecan and 5-fluorouracil; a majority had previously received oxaliplatin. Disease control (partial response + stable disease) was achieved in 56.3% of patients receiving weekly cetuximab versus 77.8% in the other group (P = 0.21). The median follow-up for all patients was 34.2 months. TTP (Group 1: 28% vs. Group 2: 18%, P = 0.9356) and OS (Group 1: 75% vs. Group 2: 72%, P = 0.6748) rates at 7 months were similar in the two groups. Skin toxicity was the most relevant adverse event: 78.1% of the patients had acne-like rash in the first group and 61% in the second group. However, only one patient in each group had a grade 3 toxic reaction. Conclusion: There is no major difference of efficacy and safety between cetuximab given every 2 weeks and a weekly dosing regimen, in association with irinotecan