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. 2022 Feb 24;14(5):1168.
doi: 10.3390/cancers14051168.

Evaluating Alternative Ramucirumab Doses as a Single Agent or with Paclitaxel in Second-Line Treatment of Locally Advanced or Metastatic Gastric/Gastroesophageal Junction Adenocarcinoma: Results from Two Randomized, Open-Label, Phase II Studies

Manish A Shah  1 , Anghel Adrian Udrea  2 , Igor Bondarenko  3 , Was Mansoor  4 , Raquel Guardeño Sánchez  5 , Tomasz Sarosiek  6 , Silvia Bozzarelli  7 , Michael Schenker  8   9 , Carlos Gomez-Martin  10 , Carys Morgan  11 , Mustafa Özgüroğlu  12 , Joanna Pikiel  13 , Haralabos P Kalofonos  14 , Elzbieta Wojcik  15 , Tomas Buchler  16 , Daniel Swinson  17 , Irfan Cicin  18 , Mano Joseph  19 , Ihor Vynnychenko  20 , Alexander Valerievich Luft  21 , Peter C Enzinger  22 , Tomas Salek  23 , Christos Papandreou  24 , Christophe Tournigand  25 , Evaristo Maiello  26 , Ran Wei  27 , David Ferry  28 , Ling Gao  28 , Joana M Oliveira  28 , Jaffer A Ajani  29
Affiliations

Evaluating Alternative Ramucirumab Doses as a Single Agent or with Paclitaxel in Second-Line Treatment of Locally Advanced or Metastatic Gastric/Gastroesophageal Junction Adenocarcinoma: Results from Two Randomized, Open-Label, Phase II Studies

Manish A Shah et al. Cancers (Basel). .

Abstract

Studies JVDB and JVCZ examined alternative ramucirumab dosing regimens as monotherapy or combined with paclitaxel, respectively, in patients with advanced/metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. For JVDB, randomized patients (N = 164) received ramucirumab monotherapy at four doses: 8 mg/kg every 2 weeks (Q2W) (registered dose), 12 mg/kg Q2W, 6 mg/kg weekly (QW), or 8 mg/kg on days 1 and 8 (D1D8) every 3 weeks (Q3W). The primary objectives were the safety and pharmacokinetics of ramucirumab monotherapy. For JVCZ, randomized patients (N = 245) received paclitaxel (80 mg/m2-D1D8D15) plus ramucirumab (8 mg/kg- or 12 mg/kg-Q2W). The primary objective was progression-free survival (PFS) of 12 mg/kg-Q2W arm versus placebo from RAINBOW using meta-analysis. Relative to the registered dose, exploratory dosing regimens (EDRs) led to higher ramucirumab serum concentrations in both studies. EDR safety profiles were consistent with previous studies. In JVDB, serious adverse events occurred more frequently in the 8 mg/kg-D1D8-Q3W arm versus the registered dose; 6 mg/kg-QW EDR had a higher incidence of bleeding/hemorrhage. In JVCZ, PFS was improved with the 12 mg/kg plus paclitaxel combination versus placebo in RAINBOW; however, no significant PFS improvement was observed between the 12 mg/kg and 8 mg/kg arms. The lack of a dose/exposure-response relationship in these studies supports the standard dose of ramucirumab 8 mg/kg-Q2W as monotherapy or in combination with paclitaxel as second-line treatment for advanced/metastatic gastric/GEJ adenocarcinoma.

Keywords: angiogenesis; gastric adenocarcinoma; ramucirumab; vascular endothelial growth factor receptor.

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Conflict of interest statement

M.A.S. reports grants from Eli Lilly and Company. A.A.U. reports travel and accommodation fees from Amgen, Angelini, Janssen, Merck Sharp & Dohme, Pfizer, and Roche. M.S. reports grants for clinical trials from Eli Lilly and Company, Roche, MSD, Merck, Astra Zeneca, Tesaro, Regeneron Pharmaceuticals, Astellas, Novartis, Bristol Myers Squibb, Pfizer, AbbVie, GlaxoSmithKline, Mylan, Samsung Pharmaceuticals, Bioven, BeiGene, PharmaMar, Clovis, Bayer, Gilead, and Amgen. C.G.-M. reports personal fees from Eli Lilly and Company, Roche, BMS, and Eisai-MSD. H.K. reports research funding from Roche, Pfizer, Novartis, Amgen, Bayer, Genesis, Eli Lilly and Company, MSD, Janssen Pharmaceuticals, and Merck-Serono; consulting/advisory fee from Roche, Novartis, MSD, Genesis, Pfizer, Eli Lilly and Company, LEO Pharma, Amgen, and Merck-Serono; and travel/accommodations fees from Roche, Novartis, Enorasis, and Pfizer. TB reports personal fees and institutional payments for clinical studies from Eli Lilly and Company, Roche, Bristol Myers Squibb, Bayer, Merck, Eisai, Exelixis, AstraZeneca, and Sanofi; personal fees from Astellas, Janssen, Ipsen, and Servier; non-financial support from Bristol Myers Squibb and Ipsen; grants from Servier. P.E. reports honoraria and advisory/consultancy fees from ALX Oncology, Arcus Biosciences, Astellas, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Five Prime Therapeutics, Ideaya Biosciences, Istari Oncology, Legend Biotech, Eli Lilly and Company, Loxo Oncology, Merck, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical Company, Turning Point Therapeutics, Xencor, and Zymeworks. L.G. is a former employee of Eli Lilly and Company. R.W., D.F., L.G., and J.M.O. are full-time employees of Eli Lilly and Company. All other authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1
(A) JVDB ramucirumab trough and peak serum concentrations (mean ± SD) before and after administration of indicated doses of ramucirumab monotherapy (n = 160 patients). (B) JVCZ ramucirumab trough and peak serum concentrations before and after administration of ramucirumab 8 or 12 mg/kg in combination with paclitaxel (n = 232 patients). Abbreviations: Conc—concentration; D—day; Q2W—every 2 weeks; Q3W—every 3 weeks; QW—weekly; SD—standard deviation; w—weeks.
Figure 2
Figure 2
Six-week PFS and objective responses (A), PFS (B), and OS (C) for the standard regimen (Arm 1) and the 3 EDRs (Arms 2, 3 and 4) of ramucirumab monotherapy (JVDB). Abbreviations: EDRs—exploratory dosing regimens; OS—overall survival; PFS—progression-free survival.
Figure 3
Figure 3
PFS and OS analysis of ramucirumab 12 mg/kg plus paclitaxel in JVCZ versus placebo plus paclitaxel in RAINBOW (Analysis 1) and 12 mg/kg versus 8 mg/kg within JVCZ (Analysis 2) (A), PFS (B), and OS (C). Abbreviations: OS—overall survival; PFS—progression-free survival.
Figure 4
Figure 4
PFS (A) and OS (B) of JVCZ safety population by ramucirumab Cmin,1 quartiles. Abbreviations: Cmin,1—serum minimum concentration; OS—overall survival; PFS—progression-free survival.
See this image and copyright information in PMC

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