Pembrolizumab and ramucirumab neoadjuvant therapy for PD-L1-positive stage IB-IIIA lung cancer (EAST ENERGY).
Authors: Aokage Keiju , Shimada Yoshihisa , Yoh Kiyotaka , Wakabayashi Masashi , Fukutani Miki , Furuya Hideki , Nomura Kotaro , Miyoshi Tomohiro , Tane Kenta , Samejima Joji , Kumagai Shogo , Koyama Shohei , Nishikawa Hiroyoshi , Taki Tetsuro , Hayashi Takuo , Matsubayashi Jun , Ishii Genichiro , Ikeda Norihiko , Tsuboi Masahiro 
Published: June 2023

8509 Background: Neoadjuvant treatments for resectable non-small cell lung cancer (NSCLC) using novel combination therapies are being developed. Angiogenesis inhibitors have been reported to modify tumor immunity, and the efficacy and safety of treatments added to immune checkpoint inhibitors (ICIs) have been investigated in advanced NSCLC. In this multi-institutional phase II study, we evaluated the efficacy and feasibility of neoadjuvant therapy with pembrolizumab and ramucirumab, a direct vascular endothelial growth factor (VEGF) receptor-2 antagonist, followed by surgery, in patients with PD-L1 positive, clinical stage IB-IIIA NSCLC. Methods: Patients (aged ≥20) with pathologically proven NSCLC harboring PD-L1 expression ≥1% (22C3), resectable clinical stage IB-IIIA NSCLC, and performance status of 0 to 1 were eligible. Patients received two cycles of pembrolizumab (200 mg/body) and ramucirumab (10 mg/kg) every three weeks. Surgery was scheduled 4-8 weeks after the last dose. The primary endpoint was to determine the major pathologic response (MPR) rate. The sample size was calculated based on the exact binomial distribution, considering a threshold MPR rate of 20%, an expected MPR rate of 45%, a one-side alpha of 5%, and a desired power of 80%. Results: A total of 24 eligible patients, with a median age of 75 years (range 50-78), were enrolled between July 2019 and April 2022; 18 patients were male. The histological subtype was adenocarcinoma in 12 patients, and the clinical stage was IB, IIA, IIB, and IIIA in 1, 4, 9, and 10 patients, respectively. PD-L1 was ≥50% in nine patients (37.5%). The MPR rate by the blinded independent central review of three pathologists was 50.0% (90% confidence interval, 31.9-68.1%); therefore, the primary endpoint was met. Six of the 12 patients who achieved MPR showed pathological complete response. One patient developed pneumonia before neoadjuvant treatment and one patient showed progressed disease after neoadjuvant treatment. Grade 3 adverse events (AEs) occurred in nine of 24 patients (37.5%) during the protocol treatment. Postoperative complications of grade 3 AEs, including postoperative hematoma, pulmonary fistula, and intraoperative arterial injury, were observed in three patients. Immune-related AEs related to protocol treatment were thyroid dysfunction, acute tubulointerstitial nephritis, and hepatic dysfunction in three, two, and two patients, respectively; however, no grade 3 or high AEs were observed. Twenty-one patients achieved R0 resection and one patient underwent R1 resection. There were no wound-healing adverse events of concern due to the anti-VEGF action of ramucirumab. Conclusions: The results of this study demonstrated that this new neoadjuvant combination of ICI and anti-VEGF agent (pembrolizumab and ramucirumab) is feasible and showed encouraging results. Clinical trial information: NCT04040361 .