Primary tumor location and efficacy of second-line therapy after initial treatment with FOLFIRI in combination with cetuximab or bevacizumab in patients with metastatic colorectal cancer- FIRE-3 (AIOKRK0306).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3525-3525 ◽  
Author(s):  
Dominik Paul Modest ◽  
Sebastian Stintzing ◽  
Ludwig Fischer von Weikersthal ◽  
Thomas Decker ◽  
Alexander Kiani ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Primary Tumor ◽  
Treatment Duration ◽  
Tumor Location ◽  
Second Line ◽  
Wild Type ◽  
Second Line Therapy ◽  
Primary Tumor Location ◽  
Line Therapy

3525 Background: FIRE3 compared 1st-line therapy with FOLFIRI plus either cetuximab (arm A) or bevacizumab (arm B) in 592 patients (pts) with KRAS exon 2 wild-type metastatic colorectal cancer (mCRC). Second-line therapies appeared more successful in arm A compared to arm B. The impact of primary tumor location on this observation is unclear. Methods: Pts. were stratified for primary tumor site (left- vs. right-sided). Duration of 2nd-line therapy was calculated as time from first to last application. Progression-free survival (PFS2nd) and overall survival (OS2nd) of second-line therapy) were evaluated by Kaplan-Meier method and compared by log rank test as well as Cox regression. All analyses were performed in the RAS wild-type population of the trial and reported according to drug sequences. Results: 272 of 400 pts. (68%) received 2nd-line therapy, of those 206 (109 in arm A, 97 in arm B) pts. presented left-sided, whereas 66 (26 in arm A, 40 in arm B) pts. presented right-sided primaries. PFS2nd was markedly longer in pts. with left-sided as compared to right-sided primary tumors (6.0 (95% CI: 5.5-6.7) vs. 3.4 (95% CI: 3.0-5.8) months, hazard ratio (HR): 0.64 (95% CI: 0.47-0.87), P = 0.005). Differences in PFS2nd between study-arms were evident in pts. with left-sided primaries (arm A: 7.3 (95% CI: 6.4-7.7) vs. arm B: 5.3 (95% CI: 4.3-5.9) months, HR: 0.61 (95% CI: 0.44-0.84), P = 0.002), but not in pts. with right-sided primaries (arm A: 4.0 (95% CI: 3.0-6.3) vs. arm B: 3.3 (95% CI: 2.6-5.8) months, HR: 1.09 (95% CI: 0.62-1.90). Consistent observations were also made for treatment duration and OS2nd. Conclusions: This retrospective analysis indicates that treatment duration and efficacy of second-line therapy are associated with primary tumor location. Efficacy of second-line therapy was significantly greater in pts. with left-sided tumors as compared to right sided tumors. This difference was driven by superior activity of second-line regimens of arm A compared to arm B in left-sided tumors. Our observations confirm the strong prognostic value of primary tumor location in mCRC across treatment lines. Clinical trial information: NCT00433927.

A phase Ib/II study of second-line therapy with panitumumab, irinotecan, and everolimus (PIE) in metastatic colorectal cancer with KRAS wild type (WT).

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. TPS162-TPS162 ◽  
Author(s):  
A. R. Townsend ◽  
L. Pirc ◽  
J. Hardingham ◽  
C. S. Karapetis ◽  
N. C. Tebbutt ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Second Line ◽  
Wild Type ◽  
Second Line Therapy ◽  
Phase Ib ◽  
Line Therapy

scholarly journals Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal Cancer

JAMA Oncology ◽  
2017 ◽  
Vol 3 (2) ◽  
pp. 194 ◽  
Author(s):  
Sabine Tejpar ◽  
Sebastian Stintzing ◽  
Fortunato Ciardiello ◽  
Josep Tabernero ◽  
Eric Van Cutsem ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Primary Tumor ◽  
Tumor Location ◽  
Wild Type ◽  
Primary Tumor Location

scholarly journals Optimal Sequence and Second-Line Systemic Treatment of Patients with RAS Wild-Type Metastatic Colorectal Cancer: A Meta-Analysis

2021 ◽  
Vol 10 (21) ◽  
pp. 5166
Author(s):  
Chih-Chien Wu ◽  
Chao-Wen Hsu ◽  
Meng-Che Hsieh ◽  
Jui-Ho Wang ◽  
Min-Chi Chang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Meta Analysis ◽  
Second Line ◽  
Wild Type ◽  
First Line ◽  
Second Line Therapy ◽  
Optimal Sequence ◽  
First Line Therapy ◽  
Line Therapy

Although several sequential therapy options are available for treating patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), the optimal sequence of these therapies is not well established. A systematic review and meta-analysis of 13 randomized controlled trials and 4 observational studies were performed, resulting from a search of the Cochrane Library, PubMed, and Embase databases. Overall survival (OS) did not differ significantly in patients with RAS-WT failure who were administered a second-line regimen of changed chemotherapy (CT) plus anti-epidermal growth factor receptor (EGFR) versus only changed CT, changed CT plus bevacizumab versus changed CT plus anti-EGFR, or changed CT versus maintaining CT plus anti-EGFR after first-line therapy with CT, plus bevacizumab. However, OS was significantly different with a second-line regimen that included changed CT plus bevacizumab, versus only changing CT. Analysis of first-line therapy with CT plus anti-EGFR for treatment of RAS-WT mCRC indicated that second-line therapy of changed CT plus an anti-EGFR agent resulted in better outcomes than changing CT without targeted agents. The pooled data study demonstrated that the optimal choice of second-line treatment for improved OS was an altered CT regimen with retention of bevacizumab after first-line bevacizumab failure. The best sequence for first-to-second-line therapy of patients with RAS-WT mCRC was cetuximab-based therapy, followed by a bevacizumab-based regimen.

Impact of Subsequent Therapies on Outcome of the FIRE-3/AIO KRK0306 Trial: First-Line Therapy With FOLFIRI Plus Cetuximab or Bevacizumab in Patients With KRAS Wild-Type Tumors in Metastatic Colorectal Cancer

2015 ◽  
Vol 33 (32) ◽  
pp. 3718-3726 ◽  
Author(s):  
Dominik P. Modest ◽  
Sebastian Stintzing ◽  
Ludwig Fischer von Weikersthal ◽  
Thomas Decker ◽  
Alexander Kiani ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Subsequent Treatment ◽  
Hazard Ratio ◽  
Second Line ◽  
Wild Type ◽  
First Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
The Impact

Purpose We investigated choice and efficacy of subsequent treatment, with special focus on second-line therapy, in the FIRE-3 trial (FOLFIRI plus cetuximab [arm A] or bevacizumab [arm B]) for patients with KRAS wild-type metastatic colorectal cancer. Patients and Methods Start of subsequent-line (second or third) therapy was defined as use of an antitumor drug that was not part of the previous regimen. We evaluated choice, duration, and efficacy of subsequent therapy and determined the impact of subsequent-line treatment on outcome of patients in FIRE-3. Results Of 592 patients in the intent-to-treat population, 414 (69.9%) received second-line and 256 (43.2%) received third-line therapy. In subsequent treatment lines, 47.1% of patients originally assigned to arm A received bevacizumab, and 52.2% originally assigned to arm B received either cetuximab or panitumumab. Oxaliplatin was subsequently used in 55.9% (arm A) and 53.2% (arm B) of patients. Second-line therapy was administered for a median duration of 5.0 versus 3.2 months (P < .001) in study arm A versus B. Progression-free (6.5 v 4.7 months; hazard ratio, 0.68; 95% CI, 0.54 to 0.85; P < .001) and overall survival (16.3 v 13.2 months; hazard ratio, 0.70; 95% CI, 0.55 to 0.88; P = .0021) from start of second-line therapy were longer in patients in arm A compared with arm B. Conclusion Our data suggest that the sequence of drug application might be more important than exposure to single agents. In patients with RAS wild-type tumors, first-line application of anti–epidermal growth factor receptor–directed therapy may represent a favorable condition for promoting effective subsequent therapy including antiangiogenic agents.

scholarly journals Impact of exact segment by segment primary tumor location status on anti-EGFR antibody first-line treatment efficacy in RAS/BRAF wild-type and BRAF mutant metastatic colorectal cancer. A pooled analysis of AIO studies FIRE-1, CIOX, FIRE-3, XELAVIRI, and VOLFI.

2021 ◽  
Author(s):  
Annabel Helga Sophie Alig ◽  
Volker Heinemann ◽  
Michael Geissler ◽  
Ludwig Fischer von Weikersthal ◽  
Thomas Decker ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Primary Tumor ◽  
Tumor Location ◽  
Pooled Analysis ◽  
Trial Registration ◽  
Wild Type ◽  
First Line ◽  
Primary Tumor Location ◽  
Braf Mutant

Abstract BackgroundPrimary tumor location (left vs. right) has prognostic and predictive impact on the therapeutic management of metastatic colorectal cancer (mCRC) in particular in the context of anti-epithelial growth factor receptor (anti-EGFR) antibodies. This analysis evaluates the relevance of exact segment-by-segment tumor location in patients with metastatic colorectal cancer on outcome and efficacy of anti-EGFR-antibodies.MethodsThis is a retrospective, pooled analysis of five randomized clinical trials (FIRE-1, CIOX, FIRE-3, XELAVIRI and VOLFI) treating metastatic colorectal cancer patients in a first-line setting, published between 2011-2019. Each trial was a multicentre, phase 2 or phase 3 trial in which patients with untreated metastatic colorectal cancer received chemotherapy regimens with or without monoclonal antibodies (anti-VEGF, anti-EGFR). Eligible were patients with histologically confirmed metastatic colorectal cancer in good performance status who were at least 18 years old. Individual data of 1809 patients with available exact primary tumor location were included into this analysis. Prognostic and predictive effects of primary tumor location were evaluated in uni- and multivariate analyses using the Kaplan Meier method, log rank tests, Cox regressions and logistic regressionsResults Exact primary tumor location is an important determinant of overall survival (OS) in mCRC patients (P<0.001). Multivariate analysis of RAS/BRAF wild-type metastatic colorectal cancer indicate that efficacy of anti-EGFR agents in terms of OS increases continuously from primary tumors located in the caecum (HR 2.63), ascending colon (HR 1.24), right flexure/transverse colon (HR 0.99), left flexure/descending colon (HR 0.91) to the sigmoid (HR 0.71) and rectum (HR 0.58), demonstrating significant benefit in sigmoid and rectal metastatic colorectal cancer, as well as clear detriment in caecum mCRC. Patients with BRAF V600E mutant disease arising from left-sided segments of the colorectum benefitted from EGFR-antibody treatment survival: hazard ratio for death in left-sided tumors: 0.42 (95% CI 0.19-0.92).Conclusions Primary tumor location of metastatic colorectal cancer affects prognosis. Anti-EGFR efficacy increases continuously from proximal to distal segments of the colorectum in metastatic colorectal cancer patients with RAS/BRAF wild-type and BRAF mutant tumors. Therefore, patients with BRAF mutant tumors of the distal segments may benefit from first-line Anti-EGFR-based therapy.Trial registrationFIRE1 trial registration ID n/aCIOX trial registration ID NCT00254137FIRE3 trial registration ID NCT00433927XELAVIRI trial registration ID NCT01249638VOLFI trial registration ID NCT01328171

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