Subgroup analysis by KRAS status in RAISE: A randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression during or following first-line combination therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine

Konference: 2015 40th Congress ESMO a 18th ECCO - účast ČR

Kategorie: Kolorektální karcinom

Téma: Postery

Číslo abstraktu: P098/2108

Autoři: Eric Van Cutsem; MUDr. Radka Obermannová, Ph.D.; M.D. György Bodoky, Ph.D.; Doc. MUDr. Jana Prausová, Ph.D., MBA; Rocio García-Carbonero; Tudor Ciuleanu; Pilar Garcia Alfonso; David Portnoy, M.D.; Allen Lee Cohn, M.D.; Kentaro Yamazaki; Prof. Philip Clingan; Takayuki Yoshino; Jonathan Polikoff, M.D.; Sara Lonardi; Teresa Macarulla, MD; Ling Yang; Federico Nasroulah

Background: Ramucirumab (RAM) is a recombinant human IgG1 monoclonal antibody that binds to the extracellular domain of VEGFR-2, preventing ligand binding and receptor activation. In the completed phase 3 RAISE trial (NCT01183780, sponsor Eli Lilly and Company), adding RAM to FOLFIRI demonstrated a survival benefit for patients with metastatic colorectal carcinoma (mCRC) with progression on or after first-line combination therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. KRAS mutations occur in 40–50% of CRC tumors and may contribute to tumorigenesis and upregulate angiogenesis. This analysis evaluates the efficacy and safety of RAM+FOLFIRI in RAISE by KRAS subgroup.

Materials and Methods: Patients enrolled in RAISE were stratified by KRAS status (wild-type vs. mutant), geography, and time to first-line PD, and then randomized 1:1 to RAM 8mg/kg IV+FOLFIRI every 2 weeks (Q2W) or placebo (PBO)+FOLFIRI Q2W. Overall survival (OS) and progression-free survival (PFS) of KRAS subgroups were evaluated by Kaplan–Meier. Hazard ratio (HR) was calculated by unstratified Cox proportional hazards model; P-value was calculated by unstratified log rank test. The interaction was tested to determine if treatment effect was consistent between KRAS subgroups. Treatment-emergent adverse events (TEAEs) were compared between treatment arms by KRAS subgroup.


KRAS Wild-type

KRAS Mutant






Overall survival (OS)

OS median










Hazard ratio, unstratified






Log rank p-value, unstratified



Interaction p-value


Progression-free survival (PFS)

PFS median










Hazard ratio, unstratified






Log rank p-value, unstratified



Interaction p-value


Safety Population





Patients with ≥1 TEAE





 Any grade, n (%)

260 (98.9)

264 (98.1)

262 (98.5)

255 (98.5)

 Grade ≥3, n (%)

204 (77.6)*

170 (63.2)

214 (80.5)*

159 (61.4)

*p<0.05 between treatment group comparison, Fisher's exact test.

Results: Within each KRAS subgroup, baseline patient and tumor characteristics were well balanced between treatment groups. Median OS and PFS were greater for patients receiving RAM+FOLFIRI in both KRAS subgroups, compared with patients receiving PBO+FOLFIRI (Table). OS and PFS treatment benefit was not statistically different between patient groups defined by KRAS status, demonstrated by lack of treatment-by-subgroup interaction. RAM+FOLFIRI was well tolerated in KRAS wild-type and mutant subgroups.

Conclusions: Median OS was greater for patients receiving RAM+FOLFIRI vs PBO+FOLFIRI overall, with a consistent treatment effect irrespective of tumor KRAS status. Safety results were similar between KRAS subgroups in the RAISE population.

Conflict of interest: Advisory Board: Gyorgy Bodoky – Eli Lilly and Company. Rocio Garcia-Carbonero – Eli Lilly and Company, Roche, Sanofi, Merck, Amgen, Novartis, Bayer, Ipsen. Tudor Ciuleanu – Eli Lilly and Company, Pfizer, Roche, Merck, MSD, BMS, Sandoz, Janssen, Astellas, Amgen, Novartis, Astra Zeneca. Radka Obermannova – Eli Lilly and Company. Corporate-sponsored Research: Eric Van Cutsem – Eli Lilly and Company, Amgen, Bayer, Boehringer, Celgene, Merckserono, Novartis, Roche, Sanofi. Radka Obermannova, Gyorgy Bodoky, Jana Prausova, Rocio Garcia-Carbonero, Tudor Ciuleanu, Pilar Garcia Alfonso, David Portnoy, Allen Cohn, Kentaro Yamazaki, Phil Clingan, Takayuki Yoshino, Jonathon Polikoff, Sara Lonardi, Teresa Macarulla – Eli Lilly and Company. Other Substantive Relationships: Ling Yang and Federico Nasroulah – Employee and shareholder, Eli Lilly and Company.

colorectal carcinoma

Datum přednesení příspěvku: 27. 9. 2015