A multi-center phase II study and biomarker analysis of combined cetuximab and modified FOLFIRI as second-line treatment in patients with metastatic gastric cancer

To evaluate the efficacy of cetuximab combined with modified FOLFIRI (mFOLFIRI) as a second-line treatment in metastatic gastric cancer patients and to identify potential biomarkers of clinical outcomes

Liu et al BMC Cancer (2017) 17:188 DOI 10.1186/s12885-017-3174-z RESEARCH ARTICLE Open Access A multi-center phase II study and biomarker analysis of combined cetuximab and modified FOLFIRI as second-line treatment in patients with metastatic gastric cancer Xin Liu1†, Weijian Guo1†, Wen Zhang1, Jiliang Yin1, Jun Zhang2, Xiaodong Zhu1, Tianshu Liu3, Zhiyu Chen1, Biyun Wang1, Jianhua Chang1, Fangfang Lv1, Xiaonan Hong1, Huijie Wang1, Jialei Wang1, Xinmin Zhao1, Xianghua Wu1 and Jin Li1* Abstracts Background: To evaluate the efficacy of cetuximab combined with modified FOLFIRI (mFOLFIRI) as a second-line treatment in metastatic gastric cancer patients and to identify potential biomarkers of clinical outcomes Methods: All 61 patients received an initial intravenous (IV) dose of cetuximab (400 mg/m2) and weekly doses (250 mg/ m2) thereafter, starting on day On day of each 14-day period, patients received IV irinotecan (180 mg/m2), leucovorin (200 mg/m2), and an IV bolus dose of 5-FU (400 mg/m2) followed by a continuous infusion of 5-FU (2400 mg/m2) for 46 h The primary endpoint was time-to-progression (TTP) Results: The response rate (RR) was 33.3% among 54 evaluable patients In the intention-to-treat analysis, median TTP was 4.6 months (95% confidential interval [CI]: 3.6-5.6 months) and median overall survival (OS) was 8.6 months (95% CI: 3-9.9 months) In univariate analyses, plasma vascular endothelial growth factor (VEGF) levels were correlated with clinical outcome In patients with low (≤12.6 pg/ml) and high (>12.6 pg/ml) baseline plasma VEGF levels, RR values were 55.0% and 5.3%, respectively (P = 0.001); median TTP values were 6.9 months and 2.8 months, respectively (P = 0.0005); and median OS values were 12 months and months, respectively (P 59 17 28 17 28 44 72 Gender Age, years ECOG PS Table Overall responses Number Percentage (%) Assessable patients 54 100 Overall response 18 33.3 CR 1.9 PR 17 31.5 SD 27 50.0 PD 16.7 DCR (CR + PR + SD) 45 83.3 Abbreviations: CR complete response, PR partial response, SD stable disease, PD progressive disease, DCR disease control rate complete remission and 17 partial responses, resulting in a RR of 33.3% (18/54) patients (95% CI, 20.7% to 45.9%) Stable disease (SD) was observed in 50% (27/54) of patients (95% CI 43.3%–56.7%) and PD in 16.7% (9/54) of patients (95% CI 6.8%–26.6%) The DCR (CR + PR + SD) was 83.3% (95% CI 73.4%–93.2%) The median follow-up time was 16 months At the time of analysis, 97% (59/61) of enrolled patients presented with progressive disease and 15% (9/61) remained alive In the ITT population, median TTP was 4.6 months (95% CI, 3.6 to 5.6 months; Fig 1a) and the median OS was 8.6 months (95% CI, 7.3-9.9 months; Fig 1b) In an analysis of TTP Primary tumor site Stomach 47 77 Gastroesophageal junction 14 23 Yes 40 66 No 21 34 Abdominal lymph node 34 56 Liver 27 44 Primary 14 23 Lung 11 18 Ovarian 10 16 Distant lymph node 10 16 Peritoneum 15 Others 11 18 13 21 Prior surgery of primary tumor Sites of metastatic disease First-line chemotherapy 5-FU/capecitabine + oxaliplatin ECF/EOF/EOX 34 56 5-FU plus TXT/PTX 13 21 Capecitabine Abbreviations: ECOG Eastern Cooperative Oncology Group, PS performance status, 5-FU 5- fluorouracil, ECF epirubicin, cisplatin, 5-FU, EOF epirubicin, oxaliplatin, 5-FU, EOX epirubicin, capecitabine, oxaliplatin, TXT, docetaxel, PTX, paclitaxel Fig Kaplan–Meier estimates of (a) time-to-progression (TTP) and (b) overall survival (OS) among patients with metastatic gastric cancer treated with cetuximab, irinotecan, folinic acid and 5-fluorouracil (FOLFIRI) Liu et al BMC Cancer (2017) 17:188 Page of 10 and OS in relation to tumor response, patients with a CR or PR had longer TTP times (median: 8.6 months vs 4.0 months, P = 0.006) and OS times (median: 13.7 months vs 7.0 months, P = 0.0016) compared with patients with SD or PD median TTP values were 6.9 months and 2.8 months, respectively (P = 0.0005); and median OS values were 12 months and months, respectively (P 12.6 pg/ml) baseline plasma VEGF levels, RR values were 55.0 and 5.3%, respectively (P = 0.001); Table Grade or Adverse Events (National Cancer Institute Common Toxicity Criteria, Version 3.0) Number (n = 61) Percentage (%) Neutropenia 32 52.5 Febrile neutropenia 13.1 Anemia 18 29.5 Thrombocytopenia 8.2 Hematological toxicity Non-hematological toxicity Nausea 8.2 Vomiting 6.6 Stomatitis 1.6 Diarrhea 6.6 Infection 4.9 Asthenia 4.9 Intestinal obstruction 6.6 Elevated aminotransferase 1.6 Allergic reaction 1.6 Rash 9.8 Protein expression analysis Fifty-one tumor samples were available for protein expression analysis pEGFR expression was detected in 27.5% (14/ 51) of patients In pEGFR-negative and pEGFR-positive patients, RR were 32.4 and 28.6%, respectively (P = 0.791); median TTP were 5.3 months and 4.3 months, respectively (P = 0.503); and median OS were 7.8 months and 9.1 months, respectively (P = 0.520) pAKT expression was detected in 47.1% (24/51) of patients (47.1%) In pAKTnegative and pEGFR-positive patients, RR were 29.6% and 33.3%, respectively (P = 0.776); median TTP were 5.2 months and 4.0 months, respectively (P = 0.497); and median OS were 8.1 months and 9.1 months, respectively (P = 0.394) We have also detected protein expression of P27 and mTOR in the tumors, which located in EGFR downstream signally pathways and protein expression of PTEN, which located in upstream of PI3K/AKT However, no correlations were identified among P27, m-TOR and PTEN expression and RR, median TTP or OS (Table 4) Discussion This phase II study was conducted to assess the efficacy and safety of cetuximab combined with mFOLFIRI as a second-line therapy in patients with metastatic gastric cancer following the failure of first-line chemotherapy The median TTP observed in this study was 4.6 months, which exceeded the pre-specified criteria of months, with a RR of 33.3%, a DCR of 83.3% and a median OS of 8.6 months Treatment was generally well tolerated and the predominant grade 3/4 treatment-related toxic effects were neutropenia (52.5%), anemia (29.5%), and thrombocytopenia (8.2%) It seems that the median TTP observed in our study was better than in previously reported studies In WJOG4007 study, median PFS was 3.6 months in the paclitaxel group and 2.3 months in the irinotecan group for the second-line treatment of MGC [5] Moreover, the median TTP in our study was similar with that of ramucirumab plus paclitaxel in RAINBOW study (median PFS was 4.4 months), which was the only successfully developed target drug combined with chemotherapy in second-line setting with the best effects [6] So the preliminary results of our study are exciting Liu et al BMC Cancer (2017) 17:188 Page of 10 Fig Kaplan–Meier curves of time-to-progression (a) and overall survival (b) according to serum protein level of vascular endothelial growth factor (VEGF) P-value by log-rank test Table Univariate analyses of biomarker and treatment outcomes RR (%) P-value Median TTP (mo) P-value Median OS (mo) P-value 32.4 0.79 5.3 0.50 7.8 0.52 Tumor expression (IHC) pEGFR negative positive 28.6 pAKT negative 29.6 positive 33.3 P27 negative 23.1 positive 40.9 5.6 9.2 positive 34.3 5.1 9.2 negative 31.1 positive 35.2 PTEN 4.3 0.78 5.2 0.22 4.9 9.1 0.50 8.1 0.25 7.3 4.0 0.56 4.4 0.39 9.1 0.28 4.9 8.2 0.33 0.39 9.0 Serum protein level (ELISA) (pg/ml) VEGF ≤12.6 >12.6 5.3 EGF ≤0.70 31.8 >0.70 29.4 55.0 0.001 6.9 0.0005 2.8 1.00 4.7 4.0 12