Evaluation of the Association of Perioperative <i>UGT1A1</i> Genotype–Dosed gFOLFIRINOX With Margin-Negative Resection Rates and Pathologic Response Grades Among Patients With Locally Advanced Gastroesophageal Adenocarcinoma
Authors: Daniel V. T. Catenacci, Leah Chase, Samantha Lomnicki, Theodore Karrison, Robert de Wilton Marsh, Murtuza M. Rampurwala, Sunil Narula, Lindsay Alpert, Namrata Setia, Shu-Yuan Xiao, John Hart, Uzma D. Siddiqui, Bryan Peterson, Kelly Moore, Kristin Kipping-Johnson, Ugne Markevicius, Barbara Gordon, Kenisha Allen, Christine Racette, Steven B. Maron, Chih-Yi Liao, Blase N. Polite, Hedy L. Kindler, Kiran Turaga, Vivek N. Prachand, Kevin K. Roggin, Mark K. Ferguson, Mitchell C. Posner
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Patients with locally advanced gastroesophageal adenocarcinoma (ie, stage ≥T3 and/or node positive) have high rates of recurrence despite surgery and adjunctive perioperative therapies, which also have high toxicity profiles. Evaluation of pharmacogenomically dosed perioperative gFOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and<i>UGT1A1</i>genotype–directed irinotecan) to optimize efficacy while limiting toxic effects may have value. <h3>Objective</h3> To evaluate the coprimary end points of margin-negative (R0) resection rates and pathologic response grades (PRGs) of gFOLFIRINOX therapy among patients with locally advanced gastroesophageal adenocarcinoma. <h3>Design, Setting, and Participants</h3> This single-group phase 2 trial, conducted at 2 academic medical centers from February 2014 to March 2019, enrolled 36 evaluable patients with locally advanced adenocarcinoma of the esophagus, gastroesophageal junction, and gastric body. Data analysis was conducted in May 2019. <h3>Interventions</h3> Patients received biweekly gFOLFIRINOX (fluorouracil, 2400 mg/m<sup>2</sup>over 46 hours; oxaliplatin, 85 mg/m<sup>2</sup>; irinotecan, 180 mg/m<sup>2</sup>for<i>UGT1A1</i>genotype 6/6, 135 mg/m<sup>2</sup>for<i>UGT1A1</i>genotype 6/7, or 90 mg/m<sup>2</sup>for<i>UGT1A1</i>genotype 7/7; and prophylactic peg-filgrastim, 6 mg) for 4 cycles before and after surgery. Patients with tumors positive for<i>ERBB2</i>also received trastuzumab (6-mg/kg loading dose, then 4 mg/kg). <h3>Main Outcomes and Measures</h3> Margin-negative resection rate and PRG. <h3>Results</h3> A total of 36 evaluable patients (27 [78%] men; median [range] age, 66 [27-85] years; 10 [28%] with gastric body cancer; 24 [67%] with intestinal-type tumors; 6 [17%] with<i>ERBB2</i>-positive tumors; 19 [53%] with<i>UGT1A1 </i>genotype 6/6; 16 [44%] with genotype 6/7; and 1 [3%] with genotype 7/7) were enrolled. Of these, 35 (97%) underwent surgery; 1 patient (3%) died after completing neoadjuvant chemotherapy while awaiting surgery. Overall, R0 resection was achieved in 33 of 36 patients (92%); 2 patients (6%) with linitis plastica achieved R1 resection. Pathologic response grades 1, 2, and 3 occurred in 13 patients (36%), 9 patients (25%), and 14 patients (39%), respectively, and PRG 1 was observed in 11 of 24 intestinal-type tumors (46%). Median disease-free survival was 30.1 months (95% CI, 15.0 months to not reached), and median overall survival was not reached (95% CI, 8.3 months to not reached). There were no differences in outcomes by<i>UGT1A1</i>genotype group. A total of 38 patients, including 2 (5%) with antral tumors, were evaluable for toxic effects. Grade 3 or higher adverse events occurring in 5% or more of patients during the perioperative cycles included diarrhea (7 patients [18%]; 3 of 19 patients [16%] with genotype 6/6; 2 of 16 patients [13%] with genotype 6/7; 2 of 3 patients [67%] with genotype 7/7), anemia (2 patients [5%]), vomiting (2 patients [5%]), and nausea (2 patients [5%]). <h3>Conclusions and Relevance</h3> In this study, perioperative pharmacogenomically dosed gFOLFIRINOX was feasible, providing downstaging with PRG 1 in more than one-third of patients and an R0 resection rate in 92% of patients. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02366819