Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study

T. Yoshino, D. C. Portnoy, R. Obermannová, G. Bodoky, J. Prausová, R. Garcia-Carbonero, T. Ciuleanu, P. García-Alfonso, A. L. Cohn, E. Van Cutsem, K. Yamazaki, S. Lonardi, K. Muro, T. W. Kim, K. Yamaguchi, A. Grothey, J. O'Connor, J. Taieb, S. R. Wijayawardana, R. R. Hozak & 2 others F. Nasroulah, J. Tabernero

Research output: Contribution to journalArticle

Abstract

Background: : Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC) [hazard ratio (HR)=0.84, 95% CI 0.73-0.98, P = 0.022]. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters. Patients and methods: Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum. Results: RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI 0.71-1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI 0.64-1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI 0.25-1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P = 0.523, PFS P = 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI 0.68-0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI 0.75-1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P = 0.276). Conclusions: In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the P-values were not statistically significant. ClinicalTrials.gov number: NCT01183780.

LanguageEnglish
Pages124-131
Number of pages8
JournalAnnals of oncology : official journal of the European Society for Medical Oncology
Volume30
Issue number1
DOIs
Publication statusPublished - Jan 1 2019

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Colorectal Neoplasms
Biomarkers
Mutation
Neoplasms
Survival
Transverse Colon
Placebos
Disease-Free Survival
ramucirumab
Descending Colon
Therapeutics
Ascending Colon
Cecum
Patient Rights
Sigmoid Colon
Rectum
Sample Size

ASJC Scopus subject areas

  • Hematology
  • Oncology

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Biomarker analysis beyond angiogenesis : RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study. / Yoshino, T.; Portnoy, D. C.; Obermannová, R.; Bodoky, G.; Prausová, J.; Garcia-Carbonero, R.; Ciuleanu, T.; García-Alfonso, P.; Cohn, A. L.; Van Cutsem, E.; Yamazaki, K.; Lonardi, S.; Muro, K.; Kim, T. W.; Yamaguchi, K.; Grothey, A.; O'Connor, J.; Taieb, J.; Wijayawardana, S. R.; Hozak, R. R.; Nasroulah, F.; Tabernero, J.

In: Annals of oncology : official journal of the European Society for Medical Oncology, Vol. 30, No. 1, 01.01.2019, p. 124-131.

Research output: Contribution to journalArticle

Yoshino, T, Portnoy, DC, Obermannová, R, Bodoky, G, Prausová, J, Garcia-Carbonero, R, Ciuleanu, T, García-Alfonso, P, Cohn, AL, Van Cutsem, E, Yamazaki, K, Lonardi, S, Muro, K, Kim, TW, Yamaguchi, K, Grothey, A, O'Connor, J, Taieb, J, Wijayawardana, SR, Hozak, RR, Nasroulah, F & Tabernero, J 2019, 'Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study', Annals of oncology : official journal of the European Society for Medical Oncology, vol. 30, no. 1, pp. 124-131. https://doi.org/10.1093/annonc/mdy461
Yoshino, T. ; Portnoy, D. C. ; Obermannová, R. ; Bodoky, G. ; Prausová, J. ; Garcia-Carbonero, R. ; Ciuleanu, T. ; García-Alfonso, P. ; Cohn, A. L. ; Van Cutsem, E. ; Yamazaki, K. ; Lonardi, S. ; Muro, K. ; Kim, T. W. ; Yamaguchi, K. ; Grothey, A. ; O'Connor, J. ; Taieb, J. ; Wijayawardana, S. R. ; Hozak, R. R. ; Nasroulah, F. ; Tabernero, J. / Biomarker analysis beyond angiogenesis : RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study. In: Annals of oncology : official journal of the European Society for Medical Oncology. 2019 ; Vol. 30, No. 1. pp. 124-131.
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title = "Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study",
abstract = "Background: : Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC) [hazard ratio (HR)=0.84, 95{\%} CI 0.73-0.98, P = 0.022]. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters. Patients and methods: Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum. Results: RAS/RAF mutation status was available for 85{\%} of patients (912/1072) and primary tumour location was known for 94.4{\%} of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95{\%} CI 0.71-1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95{\%} CI 0.64-1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95{\%} CI 0.25-1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P = 0.523, PFS P = 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95{\%} CI 0.68-0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95{\%} CI 0.75-1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P = 0.276). Conclusions: In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the P-values were not statistically significant. ClinicalTrials.gov number: NCT01183780.",
author = "T. Yoshino and Portnoy, {D. C.} and R. Obermannov{\'a} and G. Bodoky and J. Prausov{\'a} and R. Garcia-Carbonero and T. Ciuleanu and P. Garc{\'i}a-Alfonso and Cohn, {A. L.} and {Van Cutsem}, E. and K. Yamazaki and S. Lonardi and K. Muro and Kim, {T. W.} and K. Yamaguchi and A. Grothey and J. O'Connor and J. Taieb and Wijayawardana, {S. R.} and Hozak, {R. R.} and F. Nasroulah and J. Tabernero",
year = "2019",
month = "1",
day = "1",
doi = "10.1093/annonc/mdy461",
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TY - JOUR

T1 - Biomarker analysis beyond angiogenesis

T2 - Annals of Oncology

AU - Yoshino, T.

AU - Portnoy, D. C.

AU - Obermannová, R.

AU - Bodoky, G.

AU - Prausová, J.

AU - Garcia-Carbonero, R.

AU - Ciuleanu, T.

AU - García-Alfonso, P.

AU - Cohn, A. L.

AU - Van Cutsem, E.

AU - Yamazaki, K.

AU - Lonardi, S.

AU - Muro, K.

AU - Kim, T. W.

AU - Yamaguchi, K.

AU - Grothey, A.

AU - O'Connor, J.

AU - Taieb, J.

AU - Wijayawardana, S. R.

AU - Hozak, R. R.

AU - Nasroulah, F.

AU - Tabernero, J.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: : Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC) [hazard ratio (HR)=0.84, 95% CI 0.73-0.98, P = 0.022]. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters. Patients and methods: Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum. Results: RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI 0.71-1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI 0.64-1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI 0.25-1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P = 0.523, PFS P = 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI 0.68-0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI 0.75-1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P = 0.276). Conclusions: In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the P-values were not statistically significant. ClinicalTrials.gov number: NCT01183780.

AB - Background: : Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC) [hazard ratio (HR)=0.84, 95% CI 0.73-0.98, P = 0.022]. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters. Patients and methods: Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum. Results: RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI 0.71-1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI 0.64-1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI 0.25-1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P = 0.523, PFS P = 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI 0.68-0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI 0.75-1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P = 0.276). Conclusions: In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the P-values were not statistically significant. ClinicalTrials.gov number: NCT01183780.

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