Randomized phase II study of nimotuzumab, an anti-EGFR antibody, plus irinotecan in patients with 5-fluorouracil–based regimen-refractory advanced or recurrent gastric cancer in Korea and Japan: Preliminary results.

Abstract

87 Background: Nimotuzumab is a humanized IgG1 anti-EGFR monoclonal antibody. In previous studies, nimotuzumab has demonstrated efficacy associated with an absence of severe skin toxicity, commonly caused by other EGFR-targeting therapies. Methods: This is a Korea and Japan collaborative, multi-center, randomized, open-label study of nimotuzumab (400 mg, IV q1 week) plus irinotecan (150 mg/m2 IV q2 weeks) (N+I) versus irinotecan (I) in patients with advanced or metastatic gastric cancer refractory to 5-fluorouracil-based regimen. The primary endpoint was PFS with an external review and the secondary endpoints included safety, ORR, OS, PK, and a biomarker. Results: Eighty-two eligible patients (ECOG PS 0-1, one prior regimen) were treated with N+I (n = 40) or I (n = 42). Baseline characteristics were balanced between both arms. Archival tumor tissues collected from 48 patients (N+I arm: 26, I arm: 22) were analyzed for EGFR and K-ras. EGFR status, 0/1+/2+/3+, examined by immunohistochemistry was 44%/25%/13%/17%, respectively. Two patients in N+I arm had a K-ras mutation in codon 12 or 13. The efficacy analysis was conducted 6 months after completion of randomization with median follow-up period of 197 days. Median PFS was 73.0 days in N+I arm compared with 85.0 days in I arm (HR 0.860; 95% CI, 0.516, 1.435). MST was 293.0 days in N+I arm compared with 227.0 days in I arm (HR 0.717; 95% CI, 0.420, 1.224). In the sub-analysis, the hazard ratio in PFS for patients with EGFR +1/2+/3+ was 0.463 (95%CI, 0.177, 1.212) and that of EGFR 2+/3+ was 0.341 (95% CI, 0.080, 1.457) and the hazard ratio in OS was 0.584 (95% CI, 0.242, 1.409) and 0.295 (95% CI, 0.077, 1.129), respectively. The incidence of adverse events was similar between both arms. No adverse events of grade 3 skin rash or grade 3 infusion-related reaction were reported. Conclusions: These results didn't demonstrate clear benefit at this sample size. However, EGFR-positive patients treated nimotuzumab showed a potential improvement of PFS and OS. This study supports the selection of gastric cancer patients by molecular status for future study of nimotuzumab. [Table: see text]

Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma

“…The ToGA (Trastuzumab for Gastric Cancer) trial has shown that trastuzumab improves the survival of patients with HER2 protein-overexpressing and/or HER2 geneamplifying advanced gastric cancer [5]. Although the addition of cetuximab or panitumumab to chemotherapy in non-molecularly selected gastric cancer patients did not improve survival [6,7], a phase 2 study has shown a possible improvement in the survival of the patient subset with high EGFR expression who were treated with nimotuzumab, a humanized monoclonal antibody to EGFR [8]. At present, a phase 3 nimotuzumab trial (ENRICH study) in patients with EGFR-overexpressing advanced gastric and gastroesophageal junction cancer is ongoing.…”

A systematic review and meta-analysis of randomized trials on the role of targeted therapy in the management of advanced gastric cancer: Evidence does not translate?

“…[22][23][24] Recently, RCTs investigated the efficacy of the targeted therapy alone or in combination with chemotherapy, but results were mostly unsatisfactory. [25][26][27][28][29][30][31][32][33][34][35][36][37][38] While several RCTs demonstrated an improvement in terms of response rate (RR), and progression free survival (PFS) only one study reported a significant increase in terms of OS in a selected subgroup of patients in front-line treatment. 25 In that trial, patients were selected according to HER2 status (resulted to be overexpressed in 16-34% of patients with intestinal type and 2-7% of diffuse aGC), and subsequently treated with trastuzumab plus standard chemotherapy with a significant 2.7 months advantage in OS.…”

“…[25][26][27][28][29][30][31][32][33][34][35][36][37]44,[51][52][53][54][55][56][57][58][59] The TYTAN trial missed data about PFS. One trial missed results about OS.…”

Gene copy number gain of EGFR is a poor prognostic biomarker in gastric cancer: evaluation of 855 patients with bright-field dual in situ hybridization (DISH) method

“…The results of a recent ToGA trial revealed that the anti-HER2 antibody trastuzumab improves the survival of patients with HER2-positive advanced gastric cancer [2]. The results of other studies suggest the potential efficacy of targeted therapy against gene alterations in gastric cancers [8][9][10], and several other therapeutic drugs against these RTKs, including EGFR, are currently under investigation [11].…”

“…The recent REAL3 (panitumumab) [19] and EXPAND (cetuximab) [20] randomized controlled phase III trials failed to demonstrate the efficacy of the anti-EGFR monoclonal antibodies for treating gastric cancer, presumably because precise patient inclusion criteria were not set for the trials. Several studies suggest that EGFR overexpression or gene amplification may serve as a potential biomarker for the efficacies of anti-EGFR therapies in gastric cancer [9,[21][22][23].…”