Skip to main content
Latest news
Browse specialties
Breast cancer Genitourinary cancers Lung & thoracic cancers
In focus
Next-generation sequencing: Emerging biomarkers in thyroid and NSCLCs ctDNA and bladder cancer: Current understanding and beyond ROS1 fusion-positive NSCLC NSCLC driver mutations: Discussing the importance of RET, ALK and ROS1 alterations in NSCLC Early-stage NSCLC management: Surgery, targeted treatment and immunotherapy ALK fusion-positive NSCLC: International approaches to management RET fusion-positive NSCLC: Informing on the use of pralsetinib for patients with RET fusion-positive, advanced NSCLC COVID-19 & cancer
Conferences
SABCS 2022 ESMO 2022 2022 ASCO Annual Meeting
About us
Medicine Matters Oncology
EXTENDED SEARCH
Top

25-07-2017 | Colorectal cancer | Article

Exposure–response relationship of ramucirumab in patients with advanced second-line colorectal cancer: exploratory analysis of the RAISE trial

Journal: Cancer Chemotherapy and Pharmacology

Authors: Allen Lee Cohn, Takayuki Yoshino, Volker Heinemann, Radka Obermannova, György Bodoky, Jana Prausová, Rocio Garcia-Carbonero, Tudor Ciuleanu, Pilar Garcia-Alfonso, David C. Portnoy, Eric Van Cutsem, Kentaro Yamazaki, Philip R. Clingan, Jonathon Polikoff, Sara Lonardi, Lisa M. O’Brien, Ling Gao, Ling Yang, David Ferry, Federico Nasroulah, Josep Tabernero

Publisher: Springer Berlin Heidelberg

Login to get access

Abstract

Purpose

To characterize ramucirumab exposure–response relationships for efficacy and safety in patients with metastatic colorectal cancer (mCRC) using data from the RAISE study.

Methods

Sparse pharmacokinetic samples were collected; a population pharmacokinetic analysis was conducted. Univariate and multivariate Cox proportional hazards models analyzed the relationship between predicted ramucirumab minimum trough concentration at steady state (C min,ss) and survival. Kaplan–Meier analysis was used to evaluate survival from patients in the ramucirumab plus folinic acid, 5-fluorouracil, and irinotecan (FOLFIRI) treatment arm stratified by C min,ss quartiles (Q). An ordered categorical model analyzed the relationship between C min,ss and safety outcomes.

Results

Pharmacokinetic samples from 906 patients were included in exposure–efficacy analyses; samples from 905 patients were included in exposure–safety analyses. A significant association was identified between C min,ss and overall survival (OS) and progression-free survival (PFS) (p < 0.0001 for both). This association remained significant after adjusting for baseline factors associated with OS or PFS (p < 0.0001 for both). Median OS was 11.5, 12.9, 16.4, and 16.7, and 12.4 months for ramucirumab C min,ss Q1, Q2, Q3, Q4, and placebo group, respectively. Median PFS was 5.4, 4.6, 6.8, 8.5, and 5.2 months for ramucirumab C min,ss Q1, Q2, Q3, Q4, and placebo group, respectively. The risk of Grade ≥3 neutropenia was associated with an increase in ramucirumab exposure.

Conclusions

Exploratory exposure–response analyses suggested a positive relationship between efficacy and ramucirumab exposure with manageable toxicities in patients from the RAISE study with mCRC over the ranges of exposures achieved by a dose of 8 mg/kg every 2 weeks in combination with FOLFIRI.

DOI: 10.1007/s00280-017-3380-z

Literature
  1. World Health Organization (2012) GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence Worldwide in 2012. http://​globocan.​iarc.​fr/​Pages/​fact_​sheets_​cancer.​aspx. Accessed 8 June 2014
  2. World Health Organization (2015) Cancer Fact sheet No. 297, updated February 2014. http://​www.​who.​int/​mediacentre/​factsheets/​fs297/​en/​. Accessed 8 June 2015
  3. Colucci G, Gebbia V, Paoletti G et al (2005) Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol 23(22):4866–4875View ArticlePubMed
  4. Douillard JY, Cunningham D, Roth AD et al (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355(9209):1041–1047View ArticlePubMed
  5. Goldberg RM, Sargent DJ, Morton RF et al (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22(1):23–30View ArticlePubMed
  6. Saltz LB, Cox JV, Blanke C et al (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343(13):905–914View ArticlePubMed
  7. Tournigand C, Andre T, Achille E et al (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22(2):229–237View ArticlePubMed
  8. Spratlin JL, Cohen RB, Eadens M et al (2010) Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol 28(5):780–787View ArticlePubMedPubMed Central
  9. Tabernero J, Yoshino T, Cohn AL et al (2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16(5):499–508View ArticlePubMed
  10. Feng Y, Roy A, Masson E, Chen TT, Humphrey R, Weber JS (2013) Exposure-response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma. Clin Cancer Res 19(14):3977–3986View ArticlePubMed
  11. Wang J, Song P, Schrieber S et al (2014) Exposure-response relationship of T-DM1: insight into dose optimization for patients with HER2-positive metastatic breast cancer. Clin Pharmacol Ther 95(5):558–564View ArticlePubMed
  12. Zhu M, Tang R, Doshi S et al (2015) Exposure-response analysis of rilotumumab in gastric cancer: the role of tumour MET expression. Br J Cancer 112(3):429–437View ArticlePubMedPubMed Central
  13. Tabernero J, Ohtsu A, Muro K et al (2016) Exposure-response (E–R) relationship of ramucirumab (RAM) from two global, randomized, double-blind, phase 3 studies of patients (Pts) with advanced second-line gastric cancer. J Clin Oncol 33[(suppl 3):abstr 121]
  14. Smit EF, Perol M, Reck M et al (2015) Exposure-response relationship for ramucirumab (RAM) from the randomized, double-blind, phase III REVEL trial (docetaxel [DOC] vs DOC plus RAM) in second-line treatment of metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 33(suppl):8053
  15. O’Brien L, Westwood P, Gao L, Heathman M (2015) Population pharmacokinetic meta-analysis of Ramucirumab in cancer patients. J Pharmacokinet Pharmacodyn 42(Supplement 1):S11–S107
  16. U.S. Department of Health and Human Services (2003) Guidance for industry, exposure-response relationships-study design, data analysis, and regulatory applications. https://​www.​fda.​gov/​downloads/​drugs/​guidancecomplian​ceregulatoryinfo​rmation/​guidances/​ucm072109.​pdf. Accessed 8 June 2015
  17. Yang J, Zhao H, Garnett C et al (2013) The combination of exposure-response and case-control analyses in regulatory decision making. J Clin Pharmacol 53(2):160–166View ArticlePubMed
  18. Shigeta K, Hasegawa H, Okabayashi K et al (2016) Randomized phase II trial of TEGAFIRI (tegafur/uracil, oral leucovorin, irinotecan) compared with FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) in patients with unresectable/recurrent colorectal cancer. Int J Cancer 139(4):946–954View ArticlePubMed
  19. Van Cutsem E, Tabernero J, Lakomy R et al (2012) Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30(28):3499–3506View ArticlePubMed
  20. Elez E, Kocakova I, Hohler T et al (2015) Abituzumab combined with cetuximab plus irinotecan versus cetuximab plus irinotecan alone for patients with KRAS wild-type metastatic colorectal cancer: the randomised phase I/II POSEIDON trial. Ann Oncol 26(1):132–140View ArticlePubMed
  21. Gibson TB, Ranganathan A, Grothey A (2006) Randomized phase III trial results of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, in metastatic colorectal cancer. Clin Colorectal Cancer 6(1):29–31View Article
  22. Grothey A, George S, van Cutsem E, Blay JY, Sobrero A, Demetri GD (2014) Optimizing treatment outcomes with regorafenib: personalized dosing and other strategies to support patient care. Oncologist 19(6):669–680View ArticlePubMedPubMed Central
  23. Grothey A (2015) Regorafenib in metastatic colorectal cancer: optimal dosing and patient selection recommendations. Clin Adv Hematol Oncol 13(8):514–517PubMed
  24. Hecht JR, Patnaik A, Berlin J et al (2007) Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 110(5):980–988View ArticlePubMed
  25. Lv Y, Yang Z, Zhao L, Zhao S, Han J, Zheng L (2015) The efficacy and safety of adding bevacizumab to cetuximab- or panitumumab-based therapy in the treatment of patients with metastatic colorectal cancer (mCRC): a meta-analysis from randomized control trials. Int J Clin Exp Med 8(1):334–345PubMedPubMed Central
  26. Saltz LB, Clarke S, Diaz-Rubio E et al (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26(12):2013–2019View ArticlePubMed
  27. Van Cutsem E, Rivera F, Berry S et al (2009) Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol 20(11):1842–1847View ArticlePubMed
  28. Van Cutsem E, Siena S, Humblet Y et al (2008) An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy. Ann Oncol 19(1):92–98View ArticlePubMed
  29. Van Cutsem E, Lenz HJ, Kohne CH et al (2015) Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 33(7):692–700View ArticlePubMed
  30. Wilhelm SM, Dumas J, Adnane L et al (2011) Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 129(1):245–255View ArticlePubMed
  31. Thai HT, Veyrat-Follet C, Mentre F, Comets E (2013) Population pharmacokinetic analysis of free and bound aflibercept in patients with advanced solid tumors. Cancer Chemother Pharmacol 72(1):167–180View ArticlePubMed
  32. Tabernero J, Ciardiello F, Rivera F et al (2010) Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/pharmacodynamic phase I dose-escalation study. Ann Oncol 21(7):1537–1545View ArticlePubMed
  33. Lu JF, Bruno R, Eppler S, Novotny W, Lum B, Gaudreault J (2008) Clinical pharmacokinetics of bevacizumab in patients with solid tumors. Cancer Chemother Pharmacol 62(5):779–786View Article
  34. Houk BE, Bello CL, Poland B, Rosen LS, Demetri GD, Motzer RJ (2010) Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol 66(2):357–371View ArticlePubMed
  35. Giles FJ, Yin OQ, Sallas WM et al (2013) Nilotinib population pharmacokinetics and exposure-response analysis in patients with imatinib-resistant or -intolerant chronic myeloid leukemia. Eur J Clin Pharmacol 69(4):813–823View Article
  36. Han K, Jin J, Maia M, Lowe J, Sersch MA, Allison DE (2014) Lower exposure and faster clearance of bevacizumab in gastric cancer and the impact of patient variables: analysis of individual data from AVAGAST phase III trial. AAPS J 16(5):1056–1063View ArticlePubMedPubMed Central