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Clinical Trial
. 2024 Aug 1;10(8):1027-1035.
doi: 10.1001/jamaoncol.2024.1575.

Perioperative Modified FOLFIRINOX for Resectable Pancreatic Cancer: A Nonrandomized Controlled Trial

Michael Cecchini  1 , Ronald R Salem  2 , Marie Robert  3 , Suzanne Czerniak  4 , Ondrej Blaha  5 , Daniel Zelterman  5 , Moein Rajaei  5 , Jeffrey P Townsend  5 , Guoping Cai  3 , Sumedha Chowdhury  6 , Deanne Yugawa  3   6 , Robert Tseng  6 , Carlos Mejia Arbelaez  3   6 , Jingjing Jiao  3 , Kenneth Shroyer  7 , Jaykumar Thumar  1 , Jeremy Kortmansky  1 , Wajih Zaheer  1 , Neal Fischbach  1 , Justin Persico  1 , Stacey Stein  1 , Sajid A Khan  2 , Charles Cha  2 , Kevin G Billingsley  2 , John W Kunstman  2 , Kimberly L Johung  6 , Christina Wiess  8 , Mandar D Muzumdar  1 , Erik Spickard  9 , Vasily N Aushev  9 , George Laliotis  9 , Adham Jurdi  9 , Minetta C Liu  9 , Luisa Escobar-Hoyos  6   8 , Jill Lacy  1
Affiliations
Clinical Trial

Perioperative Modified FOLFIRINOX for Resectable Pancreatic Cancer: A Nonrandomized Controlled Trial

Michael Cecchini et al. JAMA Oncol. .

Abstract

Importance: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection.

Objective: To assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival.

Design, setting, and participants: This open-label, single-arm, phase 2 nonrandomized controlled trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analyzed from January to July 2023.

Interventions: Patients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumors were evaluated for treatment response and keratin 17 (K17) expression.

Main outcomes and measures: The primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumor molecular features, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimator.

Results: Of 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had nonsignificantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07).

Conclusions and relevance: This nonrandomized controlled trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies.

Trial registration: ClinicalTrials.gov Identifier: NCT02047474.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cecchini reported nonfinancial support from Natera during the conduct of the study; grants from National Institute of Health; and personal fees from DAVA Oncology, Taiho, Seattle Genetics, Macrogenics, Daiichi-Sankyo, AstraZeneca, and Parthenon Therapeutics outside the submitted work. Dr Robert reported personal fees from Takeda and Bristol Myers Squibb outside the submitted work. Dr Czerniak reported stock ownership in Merck, Johnson & Johnson, Bristol Myers Squibb, Abbott, and Amgen outside the submitted work. Dr Shroyer reported personal fees from KDx outside the submitted work; in addition, Dr Shroyer had patent 20180340935 issued. Dr Stein reported personal fees from AbbVie, AstraZeneca, Genentech, Eisai, and Merck outside the submitted work. Dr Muzumdar reported personal fees from Nested Therapeutics and grants from Genentech outside the submitted work; in addition, Dr Muzumdar had a patent for WO-2023097244-A1 issued to Yale University. Dr Spickard reported stock ownership in Natera outside the submitted work. Dr Laliotis reported stock ownership in Natera during the conduct of the study; nonfinancial support from Docus ai; and personal fees from Sirius Therapeutics and Tegus outside the submitted work. Dr Liu reported stock ownership in Natera during the conduct of the study; research support from Eisai, Exact Sciences, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, and Tesaro; and personal fees paid to her institution from AstraZeneca, Celgene, Roche/Genentech, Genomic Health, GRAIL, Ionis, Merck, Pfizer, Seattle Genetics, and Syndax outside the submitted work. Dr Escobar-Hoyos has a patent for WO2017075174A1 issued and a patent for WO2016141269A1 issued to the Yale School of Medicine. Dr Lacy reported personal fees from Genentech, Ipsen, Novartis, Deciphera, Aptitude Health, Techspert, First World Group, KeyQuest, Guidepoint, and FirstThought outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Trial Profile
aOne patient discontinued modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) to receive gemcitabine + nab-paclitaxel prior to surgery, 2 patients went to surgery after 1 cycle of mFOLFIRINOX, 1 patient went to surgery after 3 cycles of mFOLFIRINOX, and 1 patient underwent 12 total cycles of neoadjuvant mFOLFIRINOX and radiation prior to surgery. Three patients did not complete per-protocol therapy due to biliary tract complications, and all 3 ultimately underwent R0 surgical resection. bAfter all 6 cycles of neoadjuvant mFOLFIRINOX; 2 patients received gemcitabine + nab-paclitaxel prior to surgery, 2 patients received additional mFOLFIRINOX, and 1 patient received additional mFOLFIRINOX, radiation, and gemcitabine + nab-paclitaxel prior to surgery. cA total of 27 patients underwent surgery per protocol and 5 patients did not start adjuvant mFOLFIRINOX; 1 developed rapid progression, 1 pursued radiation for positive surgical margin, and 3 did not sufficiently recover from surgery to receive adjuvant therapy. dThree patients prematurely discontinued adjuvant therapy, including 1 patient who discontinued mFOLFIRINOX after 1 cycle to pursue radiation for positive margin, 1 patient who discontinued to pursue adjuvant gemcitabine for improved tolerability, and 1 patient who progressed after 1 cycle of mFOLFIRINOX.
Figure 2.
Figure 2.. Survival Curves
Progression-free survival (PFS) and overall survival (OS) curves for the intention-to-treat population.
Figure 3.
Figure 3.. Circulating Tumor DNA (ctDNA) Results
A, ctDNA results for patients with available results at 5 time points: baseline (pretreatment), preoperative (after 6 cycles of modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan [mFOLFIRINOX]), postoperative (after surgical resection), end of treatment (after 6 cycles of adjuvant mFOLFIRINOX), and at the time of disease recurrence or progression. B, The progression-free survival for patients with detectable postoperative ctDNA levels. C, The overall survival for patients with detectable postoperative ctDNA levels. One patient who started postoperative FOLFIRINOX prior to postoperative ctDNA blood draw was excluded from postoperative ctDNA survival analysis. F indicates female; HR, hazard ratio; ID, identifier; M, male; OS, overall survival; PFS, progression-free survival.
Figure 4.
Figure 4.. Keratin 17 (K17) Signatures
A and B, Overall survival (OS) and progression-free survival (PFS) curves using diagnostic needle aspirate samples. C and D, Overall survival and progression-free survival curves using surgical specimen cases. Insets, Representative immunohistochemical stains for K17. HR indicates hazard ratio.
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