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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

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.
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):4866–4875CrossRefPubMed
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):1041–1047CrossRefPubMed
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):23–30CrossRefPubMed
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):905–914CrossRefPubMed
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):229–237CrossRefPubMed
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):780–787CrossRefPubMedPubMedCentral
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):499–508CrossRefPubMed
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):3977–3986CrossRefPubMed
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):558–564CrossRefPubMed
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):429–437CrossRefPubMedPubMedCentral
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):160–166CrossRefPubMed
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):946–954CrossRefPubMed
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):3499–3506CrossRefPubMed
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):132–140CrossRefPubMed
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):29–31CrossRef
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):669–680CrossRefPubMedPubMedCentral
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):980–988CrossRefPubMed
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):334–345PubMedPubMedCentral
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):2013–2019CrossRefPubMed
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):1842–1847CrossRefPubMed
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):92–98CrossRefPubMed
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):692–700CrossRefPubMed
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):245–255CrossRefPubMed
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):167–180CrossRefPubMed
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):1537–1545CrossRefPubMed
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):779–786CrossRef
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):357–371CrossRefPubMed
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):813–823CrossRef
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):1056–1063CrossRefPubMedPubMedCentral