KRAS mutation status-stratified randomized phase II trial of GEMOX with and without cetuximab in advanced biliary tract cancer (ABTC): The TCOG T1210 trial.

Abstract

4018 Background: Gemcitabine/platinum combination is considered as globally acceptable standard care in patients with ABTC. Two recently published randomized trials showed adding EGFR antagonist, either erlotinib or cetuximab, does not further improve the clinical outcomes of gemcitabine/oxaliplatin (GEMOX)-treated ABTC patients. However, the impact of KRAS mutation status on the results of both studies was not properly addressed. Methods: A prospective, multicenter randomized, phase II trial to evaluate the therapeutic efficacies of adding cetuximab to GEMOX in patients with ABTC, in which eligible patients were stratified by status of KRAS mutation and ECOG PS, and tumor location then randomized to receive either GEMOX (gemcitabine 800 mg/m2, fixed-rate infusion and oxaliplatin 85 mg/m2, i.v., Q 2 weeks) or GEMOX plus cetuximab (500 mg/m2, i.v., Q 2 weeks, C-GEMOX). The primary endpoint was overall response rate (ORR). As an exploratory trial, 120 (60 per arm) patients was estimated to detect a two-tailed 10% difference in ORR (20% in GEMOX and 30% in C-GEMOX) with a significant level of a=0.2 and b=0.5. Results: Between Nov 2010 and May 2012, a total of 122 patients were accrued. The demography was male: 47.5%, median age: 60 y/o, ECOG PS 0/1: 28.7%/71.3%, IHCC/EHCC/GBC: 71.3%/16.4%/12.3%, KRAS mutation: 36.1%, with locally advanced/metastatic diseases: 32.0%/68.0%, and prior surgical resection: 41.8%. On intent-to-treat analysis, the ORR and DCR in the C-GEMOX (N=62) and GEMOX (N-60) arms was 27.3% vs 15.0% (p=0.1223) and 82.2% vs 60.0% (p=0.0090), respectively (Fisher’s exact test); while the median PFS was 7.1 vs 4.0 months (p= 0.0069) and median OS was 10.3 vs 8.8 months (p=0.4057), respectively (log-rank test). Planned subgroup analysis showed the 43 patients with KRAS mutated tumors benefited more from cetuximab therapy, with a DCR of 78.3% vs 38.1% (p=0.0132), median PFS of 7.0 vs 1.9 months (p=0.0351) and median OS of 10.3 vs 6.6 months (p=0.6924). Conclusions: Adding cetuximab significant improves the DCR and PFS of GEMOX in ABTC patients, notably in subpopulation with KRAS mutated tumors. Larger-scale phase III trial is warranted. Clinical trial information: NCT01267344.

Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial

“…Furthermore, our results did not differ in a predefined subset analysis according to the primary site of disease (ie, gallbladder vs non-gallbladder). Although we should be cautious when comparing trials, our results in both treatment groups are close to those reported with the combination of gemcitabine and cisplatin in the UKABC-02 trial 3 or the combination of gemcitabine and cisplatin with erlotinib 24 or cetuximab 25 in the two Asian trials (table 5). Indeed, our results did not confirm the promising efficacy data obtained with gemcitabine and oxaliplatin plus cetuximab in a phase 2 study.…”

“…Our negative results could be partly explained by the results noted in the chemotherapy alone group, which were better than in those reported in the two Asian randomised trials of chemotherapy plus erlotinib 24 or cetuximab 25 (table 5). Although overall survival was not statistically different between treatment groups in any of these trials, a marginally significant progression-free survival benefit was reported with the addition of erlotinib (p=0·087) 24 or cetuximab (p=0·064) 25 to chemotherapy (table 5). Differences in sensitivity to chemotherapy between Asian and European populations might explain these discrepancies.…”

“…EGFR mutations, amplification, or overexpression, and oncogenic mutations of key effectors of the EGFR pathway (eg, KRAS, BRAF ) have been consistently reported in biliary cancers. 27 However, the proportion of tumours with KRAS mutations varies widely across studies: 10% of patients in two studies 13,24 had KRAS mutations, but other studies 25 reported higher rates, as did our study (19%), and some have attained up to 50%. 27,28 Additionally, whether these mutations are predictive for inefficacy of EGFR inhibitors in patients with advanced biliary-tract cancers remains elusive.…”

“…Of the nine patients with KRAS mutations included in the two studies in which 10% of patients had KRAS mutations, 13,24 four had a partial response to chemotherapy plus EGFR inhibitor and three had stable disease. In the TCOG T1210 trial, 25 although only 14% of 44 patients with mutated KRAS tumours given chemotherapy alone had disease control for 16 weeks or longer compared with 48% of 78 patients with wild-type KRAS tumours (p=0·025), the presence of KRAS mutations did not preclude the potential benefit of adding cetuximab to chemotherapy. In our study, neither tumour KRAS or BRAF mutations nor EGFR overexpression were prognostic for patient outcomes.…”

“…In line with previously reported data, both gemcitabine and oxaliplatin, and gemcitabine and oxaliplatin plus cetuximab, were well tolerated in our study, with no unexpected adverse events. 4–7,13,24,25 Skin rash is associated with cetuximab, and was more frequent in the chemotherapy plus cetuximab group than in the chemotherapy alone group. However, no differences in peripheral neuropathy and febrile neutropenia were noted between the groups.…”