Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial

Author(s): Margaret A. Tempero, MD¹; Uwe Pelzer, MD²; Eileen M. O’Reilly, MD³; Jordan Winter, MD⁴; Do-Youn Oh, MD^5,6; Chung-Pin Li, MD, PhD^7,8,9; Giampaolo Tortora, MD^10,11; Heung-Moon Chang, MD¹²; Charles D. Lopez, MD, PhD¹³; Tanios Bekaii-Saab, MD¹⁴; Andrew H. Ko, MD¹; Armando Santoro, MD^15,16; Joon Oh Park, MD, PhD¹⁷; Marcus S. Noel, MD¹⁸; Giovanni Luca Frassineti, MD¹⁹; Yan-Shen Shan, MD, PhD²⁰; Andrew Dean, MD²¹; Hanno Riess, MD²; Eric Van Cutsem, MD, PhD²²; Jordan Berlin, MD²³; Philip Philip, MD^24,25; Malcolm Moore, MD²⁶; David Goldstein, MD²⁷; Josep Tabernero, MD, PhD²⁸; Mingyu Li, PhD²⁹; Stefano Ferrara, PharmD³⁰; Yvan Le Bruchec, MS³⁰; George Zhang, PhD²⁹; Brian Lu, MD, PhD²⁹; Andrew V. Biankin, MD, PhD^31,32,33; and Michele Reni, MD³⁴

Source: DOI: 10.1200/JCO.22.01134 Journal of Clinical Oncology 41, no. 11 (April 10, 2023) 2007-2019.

Dr. Maen Hussein's Thoughts

Somewhat disappointing as this was a negative study, however it is still an option for patients who are not candidates for mFOLFIRINOX.

PURPOSE

This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430).

METHODS

We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety.

RESULTS

Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 (nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 (nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent (nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events.

CONCLUSION

The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

Author Affiliations

¹University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA²Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany³Memorial Sloan Kettering Cancer Center, New York, NY⁴Thomas Jefferson University Hospital, Philadelphia, PA⁵Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea⁶Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, South Korea⁷Division of Clinical Skills Training, Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan⁸Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan⁹School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan¹⁰Azienda Ospedaliera Universitaria, Verona, Italy¹¹Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy¹²Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea¹³Oregon Health & Science University, Knight Cancer Institute, Portland, OR¹⁴Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, AZ¹⁵Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy¹⁶IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Rozzano, Milan, Italy¹⁷Division of Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea¹⁸Division of Hematology/Oncology, Georgetown Lombardi Cancer Center, Washington, DC¹⁹Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy²⁰Department of Surgery, Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan²¹Department of Medical Oncology, St John of God Subiaco Hospital, Subiaco, Western Australia, Australia²²University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium²³Vanderbilt-Ingram Cancer Center, Nashville, TN²⁴Karmanos Cancer Institute, Detroit, MI²⁵Henry Ford Cancer Institute, Detroit, MI²⁶Princess Margaret Hospital, Toronto, Ontario, Canada²⁷Nelune Cancer Center, Prince of Wales Hospital, University of New South Wales, Randwick, New South Wales, Australia²⁸Vall d’Hebron Hospital Campus and Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona, Spain²⁹Bristol Myers Squibb, Princeton, NJ³⁰Celgene Research SLU, a Bristol Myers Squibb Company, Boudry, Switzerland³¹Wolfson Wohl Cancer Research Center, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom³²West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom³³South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales, Australia³⁴IRCCS Ospedale San Raffaele Vita e Salute University, Milan, Italyon behalf of the APACT Investigators

Safety and Efficacy of CT041 in Patients With Refractory Metastatic Pancreatic Cancer: A Pooled Analysis of Two Early-Phase Trials

CAR-T agent for refractory met-pancreas showing a median duration of response of 9.5 months. These treatments are far from widely available, but the proof of principle is nice to see in a disease that otherwise has not had responses to immunotherapy. Hopefully more agents to come.

Nimotuzumab Plus Gemcitabine for K-Ras Wild-Type Locally Advanced or Metastatic Pancreatic Cancer

Asian study of nimotuzumab (humanized EGFR-inhibitor) + gemcitabine (gem) vs. gem alone. The overall survival (OS) was 10.9 vs. 8.5 months in favor of the combination arm. While the OS difference is small, recall that the OS in the NALIRIFOX and FOLFIRINOX studies are similar. The safety profile of nimotuzumab + gemcitabine is superior to a triplet or double cytotoxic chemotherapy combination regimen. This drug is currently not available in the USA but is approved for nasopharyngeal carcinoma in China.

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

You may have enrolled a patient in this trial, but it seems we may have a new first line regimen. Surprisingly toxicity simar in both arms, but there was improvement in PFS and OS (17% reduction in death) although it wasn’t statistically significant in OS.
More diarrhea with nalirifox, but more neutropenia with gem abraxane.

Randomized Study of Temozolomide or Temozolomide and Capecitabine in Patients With Advanced Pancreatic Neuroendocrine Tumors (ECOG-ACRIN E2211)

Positive study for the combo of TMZ + cape vs. TMZ alone in met-pNET, confirming a regimen that is already widely used. Patients were first-line, and those with MGMT-def had a better response.

NAPOLI-3: A randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).

The NAPOLI-3 study assessed FOLFOX+ liposomal irinotecan vs. gemcitabine + nab-paclitaxel. NALIRIFOX was superior, with an OS of 11.1 vs. 9.2 months. Criticisms of modern gem trials are often that of rigid dosing requirements that differ from modern clinical practice. Additionally, it is unclear whether NALIRIFOX provides any meaningful benefit over FOLFIRINOX, and the cost is always a consideration.