The combination of HLA-B*15:01 and DRB1*15:01 is associated with gemcitabine plus erlotinib-induced interstitial lung disease in patients with advanced pancreatic cancer.

Meiko Nishimura,Takeshi Kotake,Toru Mukohara,Yoshiro Saito,Masanori Toyoda,Yoshinori Imamura,Naoko Chayahara,Naomi Kiyota,Akihito Tsuji,Kosuke Saito,Kei Takenaka,Hironobu Minami

doi:10.1007/s00280-016-3026-6

Abstract

PurposeIn a phase III study of gemcitabine plus erlotinib for advanced pancreatic cancer conducted in Canada, the incidence of interstitial lung disease (ILD) was 3.5 %. However, the incidence of ILD was reported as high as 8.5 % in a Japanese phase II study. These results suggest the influence of ethnic factors in the association of the use of gemcitabine plus erlotinib with the incidence of ILD. Here, we conducted a prospective study to analyze the relationship between human leukocyte antigen (HLA) alleles and ILD in Japanese patients with advanced pancreatic cancer receiving gemcitabine plus erlotinib.MethodsPatients were treated with gemcitabine (1000 mg/m2; administered by intravenous infusion on days 1, 8, and 15 every 4 weeks) and erlotinib (given orally at 100 mg/day). We compared the frequencies of HLA alleles in patients who did and did not develop ILD.ResultsA total of 57 patients were treated, and 4 patients (7.0 %) developed ILD. The combination of HLA-B*15:01 and DRB1*15:01 was observed in 2 of 4 patients (50 %) with ILD and in only 1 of 53 patients without ILD (2 %) resulting in odds ratio of 52.0 (95 % CI 3.2–842.5; p = 0.011).ConclusionThese results suggest that the combination of HLA-B*15:01 and DRB1*15:01 is associated with ILD in Japanese patients with advanced pancreatic cancer receiving gemcitabine plus erlotinib.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-016-3026-6) contains supplementary material, which is available to authorized users.

Highlights

In a phase III study, gemcitabine plus erlotinib improved overall survival significantly compared with gemcitabine alone in patients with advanced pancreatic cancer [1]
Our results demonstrate that the combination of HLAB*15:01 and DRB1*15:01 is over-represented significantly in Japanese patients with advanced pancreatic cancer who developed interstitial lung disease (ILD) after the treatment with gemcitabine plus erlotinib
The number of patients was small, the odds ratio (OR) of 52.0 was much higher than the OR (2.2–4.2) of previously reported risk factors for ILD caused by gemcitabine and erlotinib [6]

Summary

Introduction

In a phase III study, gemcitabine plus erlotinib improved overall survival significantly compared with gemcitabine alone in patients with advanced pancreatic cancer [1]. A higher incidence of ILD was reported in Japanese patients compared to white patients treated with either erlotinib or gemcitabine. In patients with non-small cell lung cancer, erlotinib treatment resulted in ILD in 4.3 % of Japanese patients and 2.7 % of white patients [2, 3]. The incidence of ILD in patients treated with gemcitabine for pancreatic cancer was 2.1 % of Japanese patients and 0.4 % of white patients [1, 4]. In a phase III study of combination chemotherapy with gemcitabine and erlotinib for pancreatic cancer conducted in Canada, the incidence of ILD was 3.5 %, while a higher incidence of 8.5 % was reported

Methods

Results

Conclusion