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. 2017 Nov 11;8(62):105749-105760.
doi: 10.18632/oncotarget.22396. eCollection 2017 Dec 1.

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 , Volker Heinemann  1   2
Affiliations

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 et al. Oncotarget. .

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.

Keywords: EGFR antibody; bevacizumab; colorectal cancer; sequential therapy; tumor sidedness.

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Conflict of interest statement

CONFLICTS OF INTEREST DPM: Honoraria: Merck, Amgen, Bayer, Servier, Roche, MSD, SIRTEX. Travel Support: Merck, Roche, Amgen, Bayer, Sanofi, Servier. SS: Honoraria (Talks & Advisory boards): Amgen, Merck, Roche, Lilly, Bayer, Sanofi. LFvW: none. TD: none. AK: Honoraria: Merck, Roche. UVK: Honoraria: Gilead, MSD, Abbvie, Roche Pharma, Lilly, Amgen. SEAB: Advisory boards: Merck, Roche. Research grant: Roche. TH: none. CK:none. GS:none. FK: Honoraria/advisory boards: BMS, Celgene, Merck, Lilly, Merck, Sanofi, TevaWS. MM: Honoraria/travel support: Lilly, Amgen, Roche, Merck, MSD, BMS, Pfizer, AstraZeneca. JWH: honoraria for advisory board and speaker from Roche and travel support from Novartis. JCvE: Travel support: Apceth. SH: none. VH: Honoraria: Merck, Amgen, Roche, Sanofi, SIRTEX. Consulting or Advisory Board: Merck, Amgen, Roche, Sanofi, SIRTEX. Research funding: Merck, Amgen, Roche, SanofiTravel Accommodation expenses: Merck, Roche.

Figures

Figure 1
Figure 1. Proportion of patients in subsequent treatment line
LPT= left-sided primary tumor; RPT=right-sided primary tumor.
Figure 2
Figure 2. Deaths according to treatment lines in FIRE-3
LPT= left-sided primary tumor; RPT=right-sided primary tumor.
Figure 3
Figure 3. Kaplan-Meier estimates of PFS2nd and OS2nd in the FIRE-3 KRAS exon 2 wild-type population according to initial study arm and primary tumor location
(A) PFS2nd according to tumor location; (B) PFS2nd in patients with left-sided primary tumor according to initial study arm; (C) PFS2nd in patients with right-sided primary tumor according to initial study arm; (D) OS2nd according to tumor location; (E) OS2nd in patients with left-sided primary tumor according to initial study arm; (F) PFS2nd in patients with right-sided primary tumor according to initial study arm. arm A= initial FOLFIRI plus cetuximab. arm B= initial FOLFIRI plus bevacizumab.
Figure 4
Figure 4. Kaplan-Meier estimates of PFS2nd and OS2nd in the FIRE-3 KRAS exon 2 wild-type population according to antibody-crossover sequences by initial study arm and primary tumor location
(A) PFS2nd according to tumor location and antibody-sequence; (B) OS2nd according to tumor location and antibody-sequence. LPT= left-sided primary tumor, RPT= right-sided primary tumor. A= arm A= initial cetuximab. B= arm B= initial bevacizumab.
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