Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104)

Abstract

Objective AIO-PK0104 investigated two treatment strategies in advanced pancreatic cancer (PC): a reference sequence of gemcitabine/erlotinib followed by 2nd-line capecitabine was compared with a reverse experimental sequence of capecitabine/erlotinib followed by gemcitabine. Methods 281 patients with PC were randomly assigned to 1st-line treatment with either gemcitabine plus erlotinib or capecitabine plus erlotinib. In case of treatment failure (eg, disease progression or toxicity), patients were allocated to 2nd-line treatment with the comparator cytostatic drug without erlotinib. The primary study endpoint was time to treatment failure (TTF) after 1st-and 2nd-line therapy (TTF2; non-inferiority design). KRAS exon 2 mutations were analysed in archival tumour tissue from 173 of the randomised patients. Results Of the 274 eligible patients, 43 had locally advanced and 231 had metastatic disease; 140 (51%) received 2nd-line chemotherapy. Median TTF2 was estimated with 4.2 months in both arms; median overall survival was 6.2 months with gemcitabine/erlotinib followed by capecitabine and 6.9 months with capecitabine/erlotinib followed by gemcitabine, respectively (HR 1.02, p¼0.90). TTF for 1st-line therapy (TTF1) was significantly prolonged with gemcitabine/ erlotinib compared to capecitabine/erlotinib (3.2 vs 2.2 months; HR 0.69, p¼0.0034). Skin rash was associated with both TTF2 (rash grade 0/1/2e4:2.9/4.3/ 6.7 months, p<0.0001) and survival (3.4/7.0/ 9.6 months, p<0.0001). Each arm showed a safe and manageable toxicity profile during 1st-and 2nd-line therapy. A KRAS wild-type status (52/173 patients, 30%) was associated with an improved overall survival (HR 1.68, p¼0.005). Conclusion Both treatment strategies are feasible and demonstrated comparable efficacy; KRAS may serve as biomarker in patients with advanced PC treated with erlotinib.

Current Standards of Chemotherapy for Pancreatic Cancer

“…This was in contrast to the modest improvement in overall survival of 0.33 months with the gemcitabine/erlotinib combination, the only regimen prior to FOLFIRINOX that improved survival compared to gemcitabine (median overall survival of 6.24 months with gemcitabine/erlotinib and 5.91 months with gemcitabine). 16,17 Analysis indicated that the survival benefit of FOLFIRINOX was not due to use of subsequent second-line therapy. All subgroups favored FOLFIRINOX for improved survival, except for those with metachronous metastases, 3 or more metastatic sites or a biliary stent, who favored gemcitabine monotherapy.…”

Therapeutic Approaches for Metastatic Pancreatic Adenocarcinoma

“…41,42 To assess whether KRAS mutations conferred resistance to erlotinib therapy in pancreatic cancer, posthoc analyses were performed of the PA.3 trial and a second trial involving erlotinib, known as AIO-PK0104 (Arbeitsgemeinschaft Internistische Onkologie -PK0104). 38,43 The latter trial compared gemcitabine followed by capecitabine at disease progression with capecitabine followed by gemcitabine at disease progression, with erlotinib administered in the first-line regimen in both arms. Unfortunately, these subgroup analyses had modest power and failed to show statistically significant interactions between somatic KRAS mutations and patient survival while receiving erlotinib.…”

Current Standard and Future Perspectives in First- and Second-Line Treatment of Metastatic Pancreatic Adenocarcinoma

“…capecitabine, oxaliplatin, irinotecan and cisplatin), small molecule inhibitors or monoclonal antibodies against receptor tyrosine kinases or oncogenic growth factors. Unfortunately, despite promising results in preclinical approaches, none of these combinations were able to significantly prolong progression free or overall survival when compared with gemcitabine monotherapy [2,3,4,5,6]. …”