Exposure-response (E-R) relationship of Ramucirumab (RAM) from a global, randomized, double-blind, Phase 3 study of patients (Pts) with advanced 2nd line colorectal cancer

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

Kategorie: Kolorektální karcinom

Téma: Postery

Číslo abstraktu: P113/2123

Autoři: Allen Lee Cohn, M.D.; Takayuki Yoshino; MUDr. Radka Obermannová; 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.; Eric Van Cutsem; Kentaro Yamazaki; Prof. Philip Clingan; Jonathan Polikoff, M.D.; Sara Lonardi; Ling Gao; Ling Yang; M.D. Shao-Chun Chang, Ph.D.; Prof. M.D. David R. Ferry, Ph.D.; Federico Nasroulah; Josep Tabernero, MD

Background: Previously, the E-R relationship of RAM in pts with gastric cancer in the second line setting has been reported. The subject of this report is the E-R relationship of RAM in pts with advanced colorectal cancer from the RAISE trial.

Methods: Pts received RAM (8mg/kg) q2w plus FOLFIRI or placebo (PL) q2w plus FOLFIRI in RAISE. Nine-hundred and six pts (85% of the ITT population) were evaluable for E-R analysis. Pharmacokinetic (PK) samples were collected; a population PK analysis was conducted. A model-predicted minimum concentration at steady state (Cmin,ss) was used for correlation with efficacy and safety variables. RAM treated pts were categorized into 4 quartiles according to the Cmin,ss level. Kaplan–Meier analysis, Cox regression, ordered categorical and logistic regression analyses were performed to evaluate E-R relationships.

Results: Analyses included 425 RAM+FOLFIRI and 481 PL+ FOLFIRI pts from RAISE.

Conclusions: RAM was safe and effective at 8mg/kg q2w in combination with FOLFIRI. Exposure-response analyses based on pK data suggest higher RAM exposures were associated with longer PFS and OS, smaller hazard ratios, and potentially increased neutropenia. Similar findings have been reported in the gastric cancer trials with RAM (Tabernero J et al. J Clin Oncol 33, 2015, suppl 3; abstr 121).

Conflict of interest: Ownership: NA. 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. Joseph Tabernero – Amgen, Eli Lilly and Company, Merck kGaA, Millennium, Novartis, Roche, Sanofi, Celgene, Chugai, Taiho. Board of Directors: NA. 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, Joseph Tabernero – Eli Lilly and Company. Other Substantive Relationships: Ling Gao, Ling Yang, Shao-Chun Chang, David Ferry and Federico Nasroulah – Employee and shareholder, Eli Lilly and Company.

Summary of Efficacy (OS and PFS)
  RAISEb Median (months) Hazard ratio (95%CI)a
OS          
 PL+FOLFIRI 12.4  
 Cmin,ss Q1 11.5 1.311 (1.024, 1.678)
  Q2 12.9 0.954 (0.736, 1.238)
  Q3 16.4 0.604 (0.459, 0.795)
  Q4 16.7 0.657 (0.500, 0.865)
PFS          
 PL+FOLFIRI 5.2  
 Cmin,ss Q1 5.4 0.932 (0.739, 1.175)
  Q2 4.6 0.957 (0.763, 1.200)
  Q3 6.8 0.684 (0.542, 0.864)
  Q4 8.5 0.546 (0.434, 0.688)
Adverse Events, Grade ≥3 AE, %
  Hypertension Neutropenia Fatigue Diarrhea
 PL+FOLFIRI 2.92 23.3 7.92 10.0
 Cmin,ss Q1 11.3 39.6 6.6 8.49
  Q2 16.0 34.9 11.3 12.3
  Q3 9.43 41.5 8.49 12.3
  Q4 14.0 48.6 15.0 7.48

 

aAdjusted for significant prognostic factors; relative to PL+FOLFIRI in RAISE. bRAM+FOLFIRI pts divided into Cmin,ss quartiles (in µg/mL): Q1: <49.7 (n=106); Q2: 49.7–<62.6 (n=106); Q3: 62.6–<81.1 (n=106); Q4: ≥81.1 (n=107); each compared to PL+FOLFIRI pts (n=481).

Keywords:
colorectal
Exposure-response
Gastrointestinal
 

Datum přednesení příspěvku: 27. 9. 2015