• Adjuvant/Neoadjuvant Therapy
• Oncology Clinical Trials
• Cancers of the Accessory Digestive Organs
• Gastrointestinal Cancers

• Adjuvant/Neoadjuvant Therapy
• Oncology
• Oncology Clinical Trials
• Cancers of the Accessory Digestive Organs
• Gastrointestinal Cancers

Adding sorafenib (SOR) to gemcitabine (GEM) as adjuvant therapy for patients after R1 resection for pancreatic cancer does not improve disease-free survival (DFS) or overall survival (OS) compared with GEM alone. Marianne Sinn, Charité-Universitätsmedizin, Berlin, Germany, presented results from the phase 2b CONKO-006 study.

Even after successful surgery intended as curative, up to 90% of patients with pancreatic cancer suffer a relapse. Adjuvant chemotherapy with GEM can improve DFS and OS, and more importantly, the rate of cure [Oettle H et al. JAMA. 2013]. In the CONKO-001 study [ISRCTN34802808], which compared 6 months of postoperative GEM with observation only, 5-year survival was improved from 10.4% to 20.7% with the addition of GEM. R1-resected patients seem to benefit just as well from adjuvant treatment, she said, but because the benefits were discovered in subgroup analysis in CONKO-001, evidence for the benefit remains limited.

On the basis of these results, the multicenter German CONKO-006 trial was designed to investigate the utility of prolonged postoperative therapy with 12 months of the combination of GEM and SOR in patients after R1 resection. The study included 122 patients with R1 resection of pancreatic adenocarcinoma who were randomized in a double-blind fashion to 48 weeks of either GEM 1000 mg/m² IV on days 1, 8, and 15, and repeated on day 29, plus continuous SOR 200 mg PO BID, or GEM plus placebo (PBO), for a planned 12 cycles. The definition of R1 resection margin was standardized and documented in the study protocol, including multicolor margin staining and axial slicing and an obligatory analysis of the retro-peritoneal resection margin.

SOR was chosen as an adjuvant add-on because it interrupts tumor proliferation by inhibiting Raf kinases and the Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway, said Prof Sinn, and because of its tumor-specific angiogenesis through inhibition of the vascular endothelial growth factor receptor, epidermal growth factor receptor, and platelet-derived growth factor receptor [Siu LL et al. Clin Cancer Res. 2006].

Patient characteristics were well balanced between the SOR + GEM and the GEM + PBO groups, including median age (63 years for both), tumor stage T3 and + T4 (97% for both), and the percentage of patients with positive nodes (86% for SOR; 85% for GEM).

Toxicities and side effects, although not severe, were similar to those observed in other studies of GEM and SOR, and included diarrhea, skin reactions in the hands and feet, hypertension, tiredness and fatigue, hematology (leukocytopenia, neutropenia, and thrombocytopenia), and elevated gamma glutamyl transferase.

There was no relevant difference in median treatment duration (26.6 weeks in the SOR + GEM arm vs 25.1 weeks in the GEM + PBO arm). Thirty-three percent of patients in the SOR + GEM arm and 22% in the GEM + PBO arm completed the planned 12 cycles. Thirty-five percent of patients in the SOR + GEM arm and 46% in the GEM + PBO arm discontinued treatment due to disease recurrence.

The primary end point of median DFS from surgery was not significantly different at 9.6 vs 10.7 months in the SOR + GEM and the GEM + PBO arms, respectively (P = .89). Median DFS from randomization was 8.7 vs 9.5 months in the 2 groups, respectively. The relapse rate after 18 months was 50% with SOR + GEM and 49% with GEM + PBO. The secondary end point of OS was also not significantly different between the 2 groups. Median OS from surgery was 18.2 months in the SOR + GEM arm and 17.1 months in the GEM + PBO arm (P = .94). Median OS from randomization was 17.6 and 15.6 months, respectively, and 1-year survival was 68% and 70%, respectively.

The study data confirm that R1-resected patients must still be considered a high-risk cohort, concluded Prof Sinn.

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