Afatinib and Gemcitabine/Nab-paclitaxel in Metastatic Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) remains an almost uniformly lethal disease. Although there has been significant progress in understanding of the underlying molecular biology of pancreatic cancer, this progress has not translated into substantially better treatments. Alarmingly, the number of pancreatic cancer cases is constantly rising and pancreatic cancer will be the second most frequent cause of cancer related death by 2030. Accordingly, novel therapeutic strategies for patients with pancreatic cancer are desperately needed. Recently, the combination of gemcitabine and nab-paclitaxel proofed to be superior when compared to single agent gemcitabine (overall survival \[OS\] 8.7 months in the nab-paclitaxel/gemcitabine group versus 6.6 months in the gemcitabine group; hazard ratio for death, 0.72; 95% confidence interval \[CI\], 0.62 to 0.83; P\<0.001). Consequently, this combination therapy is now regarded as a novel treatment option for patient with metastatic pancreatic cancer and should therefore serve as a backbone for future clinical studies. Preclinical studies suggest a significant role for ErbB signaling in the pathogenesis of pancreatic cancer. Accordingly, targeting the family of ErbB receptor tyrosine kinases seems to be a viable option to improve the outcome of patients with pancreatic cancer. Addition of the selective reversible EGFR tyrosine kinase inhibitor erlotinib to gemcitabine significantly improved progression-free survival and overall survival in metastatic pancreatic cancer patients. However, the effect on median survival time in absolute values between the two arms (erlotinib and gemcitabine versus gemcitabine alone) accounted for less than a half month. Afatinib is a selective, potent and irreversible ErbB family blocker. Unlike erlotinib, afatinib covalently binds to and irreversibly blocks signalling from all homo- and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. Afatinib is applied orally once daily. Preclinical studies suggest that application of afatinib should result in greater efficacy against tumor growth than application of erlotinib. Afatinib as monotherapy has a marketing authorization for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation/mutations for daily doses up to 50 mg once daily. In a Phase I trial for safety and tolerability of afatinib in combination with gemcitabine in patients with advanced solid tumors the maximum tolerated dose (MTD) was 40 mg afatinib (given continuously once daily) plus 1000 mg/m2 gemcitabine on D1 and D8 of a 21-day cycle, with no dose-limiting toxicity in the respective cohort. Accordingly, in another current Phase II trial of the sponsor for treatment of metastatic pancreatic cancer the dose of 40 mg continuously orally once daily given afatinib in combination with 1000 mg/m2 gemcitabine given on Day1, Day 8, and Day 15 of a 28-day cycle against monotherapy with gemcitabine 1000 mg/m2 is used. The investigators hypothesize that addition of afatinib to gemcitabine/nab-paclitaxel might result in better anti-tumor activity. Accordingly, the aim of this trial is to establish the MTD for afatinib in combination with gemcitabine/nab-paclitaxel in order to proceed into Phase II trials.