Phase II study of neoadjuvant NALIRIFOX followed by chemoradiation with paclitaxel and carboplatin in locally advanced gastroesophageal cancer.
Authors: Wo Jennifer Yon-Li , Strickland Matthew , Yeap Beow Y. , Guan Zoe , Keane Florence , Roberts Hannah Johnson , Morse Christopher , Lanuti Michael , Mullen John Thomas , Sachdeva Uma , Auchincloss Hugh G. , Mendel Bailey , Drapek Lorraine C. , Meurer Jessica , Blaszkowsky Lawrence Scott , clark jeffrey William , Hong Theodore S. , Klempner Samuel J. 
Published: January 2025

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Background:
We performed a single-arm phase II study of neoadjuvant NALIRIFOX and chemoradiation (CRT) with concurrent carboplatin/taxol (C/T) followed by surgery in patients with locally advanced gastroesophageal (GE) cancer.
Methods:
Patients were enrolled on an NCI sponsored, prospective, single arm study (NCT04656041). Key eligibility criteria included: histologically confirmed T3/4 or lymph node (LN) positive GE junction or esophageal cancer, ECOG PS ≤1, age 18+, and life expectancy > 3 months. Exclusion criteria included: metastatic disease, prior chemotherapy or RT, or prior targeted therapy for diagnosis. Extensive LN disease beyond the surgical field (supraclavicular or para-aortic) was permitted if deemed feasible to be encompassed within a RT field. Laparoscopy was not required. Pts were treated with neoadjuvant NALIRIFOX x 4-8 cycles pending patient tolerance and physician discretion, restaging, CRT (50.4 Gy in 28 fractions) with concurrent C/T, restaging, followed by surgical resection. Dose reductions were at discretion of the treating physician. The primary study endpoint was the pathologic complete response rate following neoadjuvant treatment with NALIRIFOX and CRT with concurrent C/T. Major pathologic response (mPR) was defined as Tumor Regression Grade 0 and 1. Secondary endpoints included: 1) acute toxicity; 2) clinical response per RECIST criteria; 3) PFS and 4) OS.
Results:
From June 2021 to October 2023, 40 patients were enrolled. Median age was 64 (range: 47-82), and 31 patients were male (78%). All patients started NALIRIFOX, and the median number of NALIRIFOX received was 5 (range: 1-8). Reasons for discontinuation of NALIRIFOX were: physician discretion (n=29), subject withdrew from treatment (n=2), progressive disease (n=1), death (n=1). Rates of grade 3+ toxicity for overall, gastrointestinal, and hematologic attributed to NALIRIFOX were 55%, 35%, and 13% respectively. 35 patients started chemoRT (88%) and 33 patients completed chemoRT (83%). Rates of grade 3+ toxicity for overall, gastrointestinal, and hematologic attributed to chemoRT were 86%, 11%, and 9% respectively. Of 33 who completed chemoRT, two patients declined surgery (including 1 with clinical CR), and 31 (78%) patients went for surgical exploration. No patients were found with intraoperative metastases. Therefore, 31 (78%) patients underwent surgical resection. In total, 9 patients had pCR (29% in resected cohort, 23% in ITT cohort) and 15 had a major PR (48% in resected cohort, 38% in ITT cohort). In total, 10 (25% in ITT) patients had pCR or clinically CR at 1 year.
Conclusions:
Neoadjuvant NALIRIFOX followed by CRT is feasible with acceptable rates of treatment completion and grade 3+ toxicity. In our phase II trial, the rate of pCR is promising and further studies incorporating this regimen should be considered.
Clinical trial information: NCT04656041
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