The safety and efficacy of ramucirumab for the treatment of metastatic colorectal cancer

Introduction: Ramucirumab (IMC-1121B, LY3009806) is a fully humanized monoclonal antibody that targets the extracellular domain of vascular endothelial growth factor receptor 2 (VEGFR2), the principal mediator of VEGF-A downstream effects in cancer angiogenesis. Ramucirumab has been recently approved for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen. This approval was based on the results of the RAISE phase III placebo-controlled trial. This study demonstrated that the addition of ramucirumab to irinotecan-based chemotherapy significantly improved progression-free and overall survival of patients with mCRC, with manageable toxicity.

Areas covered: The aim of this drug profile is to briefly summarize the pharmacology, clinical efficacy, safety and tolerability of ramucirumab in the context of metastatic colorectal cancer, and to provide some perspective regarding the role of the drug in clinical practice.

Expert commentary: Pending issues that shall be addressed in the upcoming years include the optimization of ramucirumab dosing schedule, assessment of its role with other chemotherapy regimens or in other treatment settings, comparative evaluation of this agent with other antiangiogenics, and identification of predictive biomarkers to improve the therapeutic index and cost-effectiveness of this drug.     

Transient vocal fold lesion and hoarseness associated with the use of ramucirumab: Case report

IntroductionGastric cancer (GC) is among the leading neoplasms with highest morbidity and mortality in the world. Tumor angiogenesis represents one of important targets of antineoplastic treatment, as it has an important role in cell development and growth.Case reportRamucirumab, an IgG1 monoclonal antibody (MoAb), inhibits the angiogenesis pathway by blocking the VEGFR-2 activation. The most common adverse events associated with angiogenic inhibitors are cardiovascular and healing disorders, such as systemic arterial hypertension (HTN), thromboembolism, bleeding, wound healing delay and fistulas. We report a case of vocal fold lesion associated with ramucirumab in a patient with metastatic gastric cancer. The patient presented with transient hoarseness that was related to the exposure to ramucirumab.DiscussionLaryngeal toxicity due to anti-angiogenic agents is rare. Despite the fact that this adverse event is not a life-threatening complication, it can significantly impair quality of life and should be promptly recognized.     

A randomised non-comparative phase II trial of cixutumumab (IMC-A12) or ramucirumab (IMC-1121B) plus mitoxantrone and prednisone in men with metastatic docetaxel-pretreated castration-resistant prostate cancer

BackgroundCixutumumab, a human monoclonal antibody (HuMAb), targets the insulin-like growth factor receptor. Ramucirumab is a recombinant HuMAb that binds to vascular endothelial growth factor receptor-2. A non-comparative randomised phase II study evaluated cixutumumab or ramucirumab plus mitoxantrone and prednisone (MP) in metastatic castration-resistant prostate cancer (mCRPC).Patients and methodsMen with progressive mCRPC during or after docetaxel therapy received mitoxantrone 12 mg/m² on day 1 and prednisone 5 mg twice daily and were randomised 1:1 to receive either cixutumumab or ramucirumab 6 mg/kg intravenously weekly in a 21-day cycle. Primary end-point was composite progression-free survival (cPFS). Secondary end-points included safety, response, radiographic progression-free survival (PFS) and overall survival (OS). Sample size was based on a 50% increase in median cPFS from 2.6 (MP) to 3.9 months (either combination).Results132 men were treated (66 per arm). Median cPFS was 4.1 months (95% confidence interval (CI), 2.2–5.6) for cixutumumab and 6.7 months (95% CI, 4.5–8.3) for ramucirumab. Median time to radiographic progression was 7.5 months for cixutumumab and 10.2 months for ramucirumab, with a median OS of 10.8 and 13.0 months, respectively. Fatigue was the most frequent adverse event (AE). Incidence of most non-haematologic grade 3–4 AEs was <10% on both arms. Grade 3 cardiac dysfunction occurred in 7.6% of patients on ramucirumab.ConclusionCombinations of cixutumumab or ramucirumab plus MP were feasible and associated with moderate toxicities in docetaxel-pretreated men with mCRPC. Of the two regimens, the ramucirumab regimen is worthy of further testing based on the observed cPFS relative to the historical control.     

Role of Antiangiogenic Agents Combined With EGFR Tyrosine Kinase Inhibitors in Treatment-naive Lung Cancer: A Meta-Analysis

BackgroundAntiangiogenic agents combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered potentially effective biologically synergistic drug combinations for EGFR-mutant advanced non–small-cell lung cancer (NSCLC), although some controversy remains. The European Commission has approved the use of bevacizumab plus erlotinib as first-line treatment of EGFR-mutated NSCLC; however, it has not yet been approved by the U.S. Food and Drug Administration. Recently, several phase III, randomized controlled trials of combinations of antiangiogenic agents and EGFR-TKIs have been reported. These studies have not yet been included in any previous meta-analysis.Materials and MethodsWe performed a meta-analysis to compare antiangiogenic agents plus EGFR-TKIs versus EGFR-TKIs alone for treatment of EGFR-mutant NSCLC. The main outcomes were progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), and adverse events (AEs).ResultsWe identified 9 previous reports of 6 randomized controlled trials and 1 prospective cohort study, involving 1295 patients. Compared with EGFR-TKIs alone, antiangiogenic agents plus EGFR-TKIs resulted in a higher PFS (hazard ratio, 0.58; 95% confidence interval [CI], 0.50-0.67; P < .001). However, no significant differences in OS (hazard ratio, 0.79; 95% CI, 0.53-1.18; P = .26) and ORR (risk ratio, 1.03; 95% CI, 0.97-1.10; P = .30) were found between the 2 groups. An increased risk of serious AEs (risk ratio, 1.41; 95% CI, 1.11-1.79; P = .005) was found in the combination drug therapy group.ConclusionsAntiangiogenic agents plus EGFR-TKIs enhanced PFS for patients with EGFR-mutant NSCLC but with a greater risk of serious AEs. No significant benefits for OS and ORR were found between the 2 groups.     

Phase 1 Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naive NSCLC

IntroductionData of first-line ramucirumab plus pembrolizumab treatment of programmed death-ligand 1 (PD-L1)–positive NSCLC (cohort E) are reported (NCT02443324).MethodsIn this multicenter, open-label phase 1a/b trial, patients received ramucirumab 10 mg/kg and pembrolizumab 200 mg every 21 days for up to 35 cycles. PD-L1 positivity was defined as tumor proportion score (TPS) greater than or equal to 1%. Exploratory NanoString biomarker analyses included three T-cell signatures (T-cell–inflamed, Gajewski, and effector T cells) and CD274 gene expression.ResultsCohort E included 26 patients. Treatment-related adverse events of any grade occurred in 22 patients (84.6%). Treatment-related adverse events of grade greater than or equal to 3 were reported in 11 patients (42.3%); the most frequent was hypertension (n = 4, 15.4%). Objective response rate was 42.3% in the treated population and 56.3% and 22.2% for patients with high (TPS ≥ 50%) and lower levels (TPS 1%–49%) of PD-L1 expression, respectively. Median progression-free survival (PFS) in the treated population was 9.3 months, and 12-month and 18-month PFS rates were 45% each. Median PFS was not reached in patients with PD-L1 TPS greater than or equal to 50% and was 4.2 months in patients with PD-L1 TPS 1% to 49%. Median overall survival was not reached in the treated population, and 12-month and 18-month overall survival rates were 73% and 64%, respectively. Biomarker data suggested a positive association among clinical response, three T-cell signatures, CD274 gene expression, and PD-L1 immunohistochemistry.ConclusionsFirst-line therapy with ramucirumab plus pembrolizumab has a manageable safety profile in patients with NSCLC, and the efficacy signal seems to be strongest in tumors with high PD-L1 expression.     

The safety and efficacy of ramucirumab in combination with docetaxel in the treatment of lung cancer

Introduction: Angiogenesis is critical for tumor growth, proliferation and metastasis with the crucial role of Vascular Endothelial Growth factor (VEGF) pathway. Ramucirumab is a monoclonal antibody that specifically targets the extracellular domain of Vascular Endothelial Growth Factor Receptor 2.

Areas covered: We performed a search on Medline to browse the current literature on Ramucirumab and anti-angiogenic agents, for the treatment of NSCLC. The REVEL study demonstrated a significant improvement of response rate, progression-free survival and overall survival by adding ramucirumab to docetaxel compared to docetaxel plus a placebo in second-line treatment of advanced non-small cell lung cancer, irrespective of histology, with an acceptable safety profile. This article has for objective to summarize efficacy and safety data of the use of ramucirumab in combination with docetaxel in second line in NSCLC.

Expert commentary: REVEL constitutes the first significant advance in second-line setting for patients eligible to anti-angiogenic therapy. The landscape of post-platinum therapy in NSCLC is considerably evolving and the role of ramucirumab or other anti-angiogenic agents as nintedanib in this setting has to be discussed for each patient with other available treatment options, among which immune checkpoints inhibitors, as well as the best treatment sequence.     

Understanding the mechanisms of action of antiangiogenic agents in metastatic colorectal cancer: A clinician’s perspective

Multiple clinical trials using bevacizumab, ziv-aflibercept, and regorafenib have recently demonstrated efficacy for patients with metastatic colorectal cancer. While the net clinical benefit of each of these therapies in the second-line and refractory disease setting appears to be similar, important distinctions exist between the agents at the pharmacodynamic, tumor microenvironment, and clinical levels. The purpose of this review is to survey the preclinical evidence regarding the mechanisms of action of these novel antiangiogenic agents and provide an overview of their respective clinical activity, while highlighting distinctions between therapies. Fundamental understanding of these distinctions may aid in clinical decisions and choice of antiangiogenic therapies.     

Selection of Second-line Anti-angiogenic Agents After Failure of Bevacizumab-containing First-line Chemotherapy in Metastatic Colorectal Cancer

Continuation of anti-angiogenic agents beyond progression in second-line therapy is recognized as a standard of care for patients with metastatic colorectal cancer, and there are 3 options based on the results of the phase III trials: bevacizumab (ML18147 trial), ramucirumab (RAISE trial), and aflibercept (VELOUR trial). However, the eligibility criteria of these three trials differed, and there are no established biomarkers for selecting the optimal agent. In a collaborative study of the RAISE trial, it was reported that vascular endothelial growth factor (VEGF)-D may be a predictive marker for remucirumab, which can prevent binding of VEGF-D to VEGF receptor, and establishment of the standard method for assessing VEGF-D is eagerly awaited. Although subset analysis in the ML18147 and VELOUR trials suggested that short progression-free survival (PFS) in first-line therapy with bevacizumab might have some adverse impacts on the efficacy of anti-angiogenic agent targeting VEGF ligands in second-line therapy, consistent hazard ratios in the subgroups divided by first-line PFS < and ≥ 9 months (0.84 [95% confidence interval, 0.69-1.02] and 0.89 [95% confidence interval, 0.72-1.09]) were observed in the RAISE trial. It is suggested that anti-angiogenic agents beyond progression can be selected by considering first-line PFS.     

Docetaxel Plus RAmucirumab With Primary Prophylactic Pegylated Granulocyte-ColONy Stimulating Factor Support for Elderly Patients With Advanced Non–small-cell Lung Cancer: A Multicenter Prospective Single Arm Phase II Trial: DRAGON Study (WJOG9416L)

We exhibit our ongoing multicenter, prospective, single-arm, phase II trial of docetaxel plus ramucirumab with primary prophylactic pegylated-granulocyte-colony stimulating factor (PEG-G-CSF) support for chemotherapy-naive elderly patients with advanced non–small-cell lung cancer (NSCLC) (University Hospital Medical Information Network database: UMIN000030598). Docetaxel monotherapy is the Japanese standard of care for chemotherapy-naive elderly patients with advanced NSCLC. Docetaxel plus ramucirumab showed superior survival benefit over docetaxel monotherapy in the second-line setting for NSCLC. A Japanese phase II study comparing docetaxel plus ramucirumab and docetaxel monotherapy in the second-line setting showed febrile neutropenia (FN) incidence of approximately one-third in the docetaxel plus ramucirumab arm. Docetaxel plus ramucirumab could be a promising candidate for elderly patients with NSCLC, but such high FN incidence is a clinically critical concern. To overcome this problem, we adopt a routine primary prophylactic PEG-G-CSF with docetaxel plus ramucirumab therapy. We hypothesize that primary prophylactic PEG-G-CSF reduces FN and maximizes the efficacy of docetaxel plus ramucirumab in Japanese elderly patients with NSCLC. Intravenous docetaxel (60 mg/m², day 1) plus ramucirumab (10 mg/kg, day 1) with subcutaneous PEG-G-CSF (3.6 mg, day 2) every 3 weeks is administered until progression. The primary endpoint is overall response rate (ORR). We decided the threshold ORR to be 20%, and the expected ORR 35%. Taking statistical points (α/β errors: 0.05/0.80) and ineligible patients into account, the sample size was set at 65. When the study results are promising, we will conduct a phase III trial to compare docetaxel plus ramucirumab with PEG-G-CSF support versus docetaxel monotherapy for chemotherapy-naive elderly patients with NSCLC.     

Osimertinib With Ramucirumab in EGFR-mutated,T790M-positive Patients With Progression During EGFR-TKI Therapy: Phase Ib Study

Background

Epidermal growth factor receptor (EGFR) T790M mutation is the most frequent mechanism of resistance among patients with progression during EGFR-tyrosine kinase inhibitor (TKI) therapy. A third-generation EGFR-TKI, osimertinib, demonstrated durable efficacy with mild adverse events in a phase III trial and is considered a novel standard regimen. The tolerability of osimertinib monotherapy has allowed for the development of a more efficacious combination regimen. Preclinical and clinical study data have suggested that vascular endothelial growth factor inhibition can enhance EGFR-TKI activity with tolerable toxicity.