Exploring the effect of primary tumor sidedness on therapeutic efficacy across treatment lines in patients with metastatic colorectal cancer: analysis of FIRE-3 (AIOKRK0306)

// Dominik Paul Modest 1, 2 , Sebastian Stintzing 1, 2 , Ludwig Fischer von Weikersthal 3 , Thomas Decker 4 , Alexander Kiani 5 , Ursula Vehling-Kaiser 6 , Salah-Eddin Al-Batran 7 , Tobias Heintges 8 , Christoph Kahl 9 , Gernot Seipelt 10 , Frank Kullmann 11 , Werner Scheithauer 12 , Markus Moehler 13, 14 , Julian Walter Holch 1, 2 , Jobst Christian von Einem 1, 2 , Swantje Held 15 and Volker Heinemann 1, 2 1 Department of Medicine III, University Hospital, LMU Munich, Munich, Germany 2 German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany 3 Gesundheitszentrum St. Marien, Amberg, Germany 4 Oncological Practice, Ravensburg, Germany 5 Medizinische Klinik IV, Klinikum Bayreuth, Bayreuth, Germany 6 Oncological Practice, Landshut, Germany 7 Department of Hematology and Oncology, Krankenhaus Nordwest Frankfurt/Main, Frankfurt, Germany 8 Department of Medicine II, Stadtisches Klinikum Neuss, Neuss, Germany 9 Haematology and Oncology, Staedtisches Klinikum Magdeburg, Magdeburg, Germany 10 Oncological Practice, Bad Soden, Germany 11 Department of Medicine I, Klinikum Weiden, Weiden in der Oberpfalz, Germany 12 Department of Internal Medicine I & Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria 13 Medical Department 1, Johannes-Gutenberg Universitat Mainz, Mainz, Germany 14 University Cancer Center Frankfurt/Mainz and German Cancer Consortium (DKTK), Heidelberg, Germany 15 ClinAssess GmbH, Leverkusen, Germany Correspondence to: Dominik Paul Modest, email: dominik.modest@med.uni-muenchen.de Keywords: colorectal cancer; tumor sidedness; EGFR antibody; bevacizumab; sequential therapy Received: July 31, 2017     Accepted: October 13, 2017     Published: November 11, 2017 ABSTRACT Purpose: To assess the impact of primary tumor sidedness on outcome of patients with metastatic colorectal cancer (mCRC) across treatment lines. Patients and Methods: Patients of the FIRE-3 trial (initial FOLFIRI plus either cetuximab or bevacizumab) were separately evaluated according to primary tumor site differentiating left-sided (LPT) from right-sided primary tumors (RPT). Efficacy (i.e. progression-free survival (PFS2nd) and overall survival (OS2nd) of second-line therapy) was evaluated by Kaplan-Meier method and compared by log rank test as well as Cox regression analyses. All analyses were also reported according to drug sequences. Results: 411 of 592 patients (69%) with KRAS exon 2 wild-type tumors received 2nd-line therapy has and had available information on primary tumor location, of those 309 patients (75%) presented with LPT. In patients with LPT, PFS2nd was markedly longer than in patients with RPT (6.0 months [95% CI 5.5-6.5] versus 3.8 months [95% CI 2.5-5.2], hazard ratio: 0.61 [95% CI 0.47-0.78], P<0.001). Differences in PFS2nd between study-arms were evident in patients with LPT, but not in patients with RPT (Cox model interaction test, P=0.12). Consistent observations were also made for OS2nd. Conclusion: This retrospective analysis of FIRE-3 indicates that efficacy of second-line therapy was significantly greater in patients with left-sided tumors as compared to right-sided tumors. This difference was driven by superior activity of second-line regimens of the initial cetuximab-arm as compared to the initial bevacizumab-arm in left-sided tumors. Our observations confirm the strong prognostic value of primary tumor location in second-line therapy of mCRC.