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Cancers Jan 2023Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for molecularly-targeted...
Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for molecularly-targeted therapeutics that otherwise have shown unprecedented successes in disease control. The hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and has been a subject of targeted drug development for nearly 30 years. To anticipate and study specific resistance mechanisms associated with targeting this pathway, we engineered resistance to the HGF-neutralizing antibody rilotumumab in glioblastoma cells harboring autocrine HGF/Met signaling, a frequent abnormality of this brain cancer in humans. We found that rilotumumab resistance was acquired through an unusual mechanism comprising dramatic HGF overproduction and misfolding, endoplasmic reticulum (ER) stress-response signaling and redirected vesicular trafficking that effectively sequestered rilotumumab and misfolded HGF from native HGF and activated Met. Amplification of and genes, with evidence of rapidly acquired intron-less, reverse-transcribed copies in DNA, was also observed. These changes enabled persistent Met pathway activation and improved cell survival under stress conditions. Point mutations in the HGF pathway or other complementary or downstream growth regulatory cascades that are frequently associated with targeted drug resistance in other prevalent cancer types were not observed. Although resistant cells were significantly more malignant, they retained sensitivity to Met kinase inhibition and acquired sensitivity to inhibition of ER stress signaling and cholesterol biosynthesis. Defining this mechanism reveals details of a rapidly acquired yet highly-orchestrated multisystem route of resistance to a selective molecularly-targeted agent and suggests strategies for early detection and effective intervention.
PubMed: 36672409
DOI: 10.3390/cancers15020460 -
British Journal of Clinical Pharmacology Nov 2015Rilotumumab is a fully human monoclonal antibody against hepatocyte growth factor, the only known ligand of the MET receptor. Over the last decade, rilotumumab has been... (Review)
Review
Rilotumumab is a fully human monoclonal antibody against hepatocyte growth factor, the only known ligand of the MET receptor. Over the last decade, rilotumumab has been extensively tested in preclinical studies and in clinical studies in a variety of cancer types. In this review, we examine the pharmacokinetic and pharmacodynamic data that have been collected in the rilotumumab programme to date, and discuss retrospectively how the knowledge acquired in this programme can be applied to a number of key issues in oncology drug development, including: (i) using preclinical data to inform first-in-human study design; (ii) the role of biomarkers in the identification of a target patient population; (iii) the potential for drug interactions between therapeutic proteins and other anticancer agents; and (iv) pharmacokinetic and pharmacodynamic considerations in phase 3 study design.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Biomarkers; Clinical Trials, Phase III as Topic; Drug Evaluation, Preclinical; Drug Interactions; Humans; Neoplasms; Research Design
PubMed: 25912961
DOI: 10.1111/bcp.12663 -
Clinical Cancer Research : An Official... Jun 2015Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor. In a randomized phase II study, trends toward improved survival were... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor. In a randomized phase II study, trends toward improved survival were observed with rilotumumab (7.5 or 15 mg/kg) plus epirubicin, cisplatin, and capecitabine (ECX) versus placebo plus ECX in gastric/gastroesophageal junction (GEJ) cancer patients, especially in MET-positive patients. Here, we quantitatively characterized the longitudinal exposure-response [tumor growth (TG) and overall survival (OS)] relationship for rilotumumab.
EXPERIMENTAL DESIGN
Rilotumumab concentrations, tumor sizes, and survival time from the phase II study were pooled to develop a longitudinal exposure versus TG model and parametric OS model that explored predictive/prognostic/treatment effects (MET expression, rilotumumab exposure, relative tumor size). Model evaluation included visual predictive checks, nonparametric bootstrap, and normalized prediction distribution errors. Simulations were undertaken to predict the relationship between rilotumumab dose and OS.
RESULTS
Rilotumumab exhibited linear time-independent pharmacokinetics not affected by MET expression. The TG model adequately described tumor size across arms. A Weibull distribution best described OS. Rilotumumab exposure and change in tumor size from baseline at week 24 were predictive of OS. MET-positive patients showed shorter survival and responded better to rilotumumab than MET-negative patients. Simulations predicted a median (95% confidence interval) HR of 0.38 (0.18-0.60) in MET-positive patients treated with 15 mg/kg rilotumumab Q3W.
CONCLUSIONS
Rilotumumab plus ECX demonstrated concentration-dependent effects on OS, influenced by MET expression, and tumor size in gastric/GEJ cancer patients. These findings support the phase II testing of rilotumumab 15 mg/kg every 3 weeks in MET-positive gastric/GEJ cancer (RILOMET-1; NCT01697072).
Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Cisplatin; Dose-Response Relationship, Drug; Epirubicin; Female; Hepatocyte Growth Factor; Humans; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Stomach Neoplasms
PubMed: 25712685
DOI: 10.1158/1078-0432.CCR-14-1661 -
Immunotherapy 2014In 2014, outcomes for patients with advanced gastric cancer remain extremely poor with a high level of unmet need regarding effective therapeutic options. However,... (Review)
Review
In 2014, outcomes for patients with advanced gastric cancer remain extremely poor with a high level of unmet need regarding effective therapeutic options. However, recent years have seen increasing interest in the role of the MET signaling pathway in this disease subtype, leading to the development and evaluation of MET-targeted therapeutics. Rilotumumab is a monoclonal antibody directed against hepatocyte growth factor, the only known ligand for the MET receptor. It is an unlicensed product which is currently undergoing evaluation in a randomized Phase III trial in 'MET-positive' gastric cancer. Here we discuss the background to the treatment of gastric cancer as well as the characteristics of rilotumumab and reported results with this agent in the trials performed to date.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Hepatocyte Growth Factor; Humans; Immunotherapy; Molecular Targeted Therapy; Proto-Oncogene Proteins c-met; Randomized Controlled Trials as Topic; Signal Transduction; Stomach Neoplasms
PubMed: 25524381
DOI: 10.2217/imt.14.91 -
The Lancet. Oncology Nov 2017Rilotumumab is a fully human monoclonal antibody that selectively targets the ligand of the MET receptor, hepatocyte growth factor (HGF). We aimed to assess the... (Randomized Controlled Trial)
Randomized Controlled Trial
Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial.
BACKGROUND
Rilotumumab is a fully human monoclonal antibody that selectively targets the ligand of the MET receptor, hepatocyte growth factor (HGF). We aimed to assess the efficacy, safety, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine, and to assess potential biomarkers, in patients with advanced MET-positive gastric or gastro-oesophageal junction adenocarcinoma.
METHODS
This multicentre, randomised, double-blind, placebo-controlled, phase 3 study was done at 152 centres in 27 countries. We recruited adults (aged ≥18 years) with unresectable locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, MET-positive tumours (≥25% of tumour cells with membrane staining of ≥1+ staining intensity), and evaluable disease, who had not received previous systemic therapy. Eligible patients were randomly assigned (1:1) via a computerised voice response system to receive rilotumumab 15 mg/kg intravenously or placebo in combination with open-label chemotherapy (epirubicin 50 mg/m intravenously; cisplatin 60 mg/m intravenously; capecitabine 625 mg/m orally twice daily) in 21-day cycles for up to ten cycles. After completion of chemotherapy, patients continued to receive rilotumumab or placebo monotherapy until disease progression, intolerability, withdrawal of consent, or study termination. Randomisation was stratified by disease extent and ECOG performance status. Both patients and physicians were masked to study treatment assignment. The primary endpoint was overall survival, analysed by intention to treat. We report the final analysis. This study is registered with ClinicalTrials.gov, number NCT01697072.
FINDINGS
Between Nov 7, 2012, and Nov 21, 2014, 609 patients were randomly assigned to rilotumumab plus epirubicin, cisplatin, and capecitabine (rilotumumab group; n=304) or placebo plus epirubicin, cisplatin, and capecitabine (placebo group; n=305). Study treatment was stopped early after an independent data monitoring committee found a higher number of deaths in the rilotumumab group than in the placebo group; all patients in the rilotumumab group subsequently discontinued all study treatment. Median follow-up was 7·7 months (IQR 3·6-12·0) for patients in the rilotumumab group and 9·4 months (5·3-13·1) for patients in the placebo group. Median overall survival was 8·8 months (95% CI 7·7-10·2) in the rilotumumab group compared with 10·7 months (9·6-12·4) in the placebo group (stratified hazard ratio 1·34, 95% CI 1·10-1·63; p=0·003). The most common grade 3 or worse adverse events in the rilotumumab and placebo groups were neutropenia (86 [29%] of 298 patients vs 97 [32%] of 299 patients), anaemia (37 [12%] vs 43 [14%]), and fatigue (30 [10%] vs 35 [12%]). The frequency of serious adverse events was similar in the rilotumumab and placebo groups (142 [48%] vs 149 [50%]). More deaths due to adverse events occurred in the rilotumumab group than the placebo group (42 [14%] vs 31 [10%]). In the rilotumumab group, 33 (11%) of 298 patients had fatal adverse events due to disease progression, and nine (3%) had fatal events not due to disease progression. In the placebo group, 23 (8%) of 299 patients had fatal adverse events due to disease progression, and eight (3%) had fatal events not due to disease progression.
INTERPRETATION
Ligand-blocking inhibition of the MET pathway with rilotumumab is not effective in improving clinical outcomes in patients with MET-positive gastric or gastro-oesophageal adenocarcinoma.
FUNDING
Amgen.
Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Cisplatin; Disease-Free Survival; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Epirubicin; Esophageal Neoplasms; Esophagogastric Junction; Humans; Internationality; Kaplan-Meier Estimate; Middle Aged; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins c-met; Stomach Neoplasms; Survival Analysis; Treatment Outcome
PubMed: 28958504
DOI: 10.1016/S1470-2045(17)30566-1 -
The Lancet. Oncology Aug 2014Dysregulation of the hepatocyte growth factor (HGF)/MET pathway promotes tumour growth and metastasis. Rilotumumab is a fully human, monoclonal antibody that neutralises... (Comparative Study)
Comparative Study Randomized Controlled Trial
Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study.
BACKGROUND
Dysregulation of the hepatocyte growth factor (HGF)/MET pathway promotes tumour growth and metastasis. Rilotumumab is a fully human, monoclonal antibody that neutralises HGF. We aimed to assess the safety, efficacy, biomarkers, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine (ECX) in patients with advanced gastric or oesophagogastric junction cancer.
METHODS
We recruited patients (≥18 years old) with unresectable locally advanced or metastatic gastric or oesophagogastric junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who had not received previous systemic therapy, from 43 sites worldwide. Phase 1b was an open-label, dose de-escalation study to identify a safe dose of rilotumumab (initial dose 15 mg/kg intravenously on day 1) plus ECX (epirubicin 50 mg/m(2) intravenously on day 1, cisplatin 60 mg/m(2) intravenously on day 1, capecitabine 625 mg/m(2) twice a day orally on days 1-21, respectively), administered every 3 weeks. The phase 1b primary endpoint was the incidence of dose-limiting toxicities in all phase 1b patients who received at least one dose of rilotumumab and completed the dose-limiting toxicity assessment window (first cycle of therapy). Phase 2 was a double-blind study that randomly assigned patients (1:1:1) using an interactive voice response system to receive rilotumumab 15 mg/kg, rilotumumab 7·5 mg/kg, or placebo, plus ECX (doses as above), stratified by ECOG performance status and disease extent. The phase 2 primary endpoint was progression-free survival (PFS), analysed by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00719550.
FINDINGS
Seven of the nine patients enrolled in the phase 1b study received at least one dose of rilotumumab 15 mg/kg, only two of whom had three dose-limiting toxicities: palmar-plantar erythrodysesthesia, cerebral ischaemia, and deep-vein thrombosis. In phase 2, 121 patients were randomly assigned (40 to rilotumumab 15 mg/kg; 42 to rilotumumab 7·5 mg/kg; 39 to placebo). Median PFS was 5·1 months (95% CI 2·9-7·0) in the rilotumumab 15 mg/kg group, 6·8 months (4·5-7·5) in the rilotumumab 7·5 mg/kg group, 5·7 months (4·5-7·0) in both rilotumumab groups combined, and 4·2 months (2·9-4·9) in the placebo group. The hazard ratio for PFS events compared with placebo was 0·69 (80% CI 0·49-0·97; p=0·164) for rilotumumab 15 mg/kg, 0·53 (80% CI 0·38-0·73; p=0·009) for rilotumumab 7·5 mg/kg, and 0·60 (80% CI 0·45-0·79; p=0·016) for combined rilotumumab. Any grade adverse events more common in the combined rilotumumab group than in the placebo group included haematological adverse events (neutropenia in 44 [54%] of 81 patients vs 13 [33%] of 39 patients; anaemia in 32 [40%] vs 11 [28%]; and thrombocytopenia in nine [11%] vs none), peripheral oedema (22 [27%] vs three [8%]), and venous thromboembolism (16 [20%] vs five [13%]). Grade 3-4 adverse events more common with rilotumumab included neutropenia (36 [44%] vs 11 [28%]) and venous thromboembolism (16 [20%] vs four [10%]). Serious adverse events were balanced between groups except for anaemia, which occurred more frequently in the combined rilotumumab group (ten [12%] vs none).
INTERPRETATION
Rilotumumab plus ECX had no unexpected safety signals and showed greater activity than placebo plus ECX. A phase 3 study of the combination in MET-positive gastric and oesophagogastric junction cancer is in progress.
FUNDING
Amgen Inc.
Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Cisplatin; Confidence Intervals; Deoxycytidine; Disease-Free Survival; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Epirubicin; Esophagogastric Junction; Female; Fluorouracil; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Proportional Hazards Models; Stomach Neoplasms; Survival Rate; Treatment Outcome
PubMed: 24965569
DOI: 10.1016/S1470-2045(14)70023-3 -
Cancer Discovery Sep 2014Patients with gastric or esophagogastric cancer treated with combination chemotherapy and rilotumumab, an anti-HGF monoclonal antibody, had longer progression-free...
Patients with gastric or esophagogastric cancer treated with combination chemotherapy and rilotumumab, an anti-HGF monoclonal antibody, had longer progression-free survival than patients treated with chemotherapy alone, according to results from a phase II clinical trial. The survival benefit was greatest in patients with MET-positive disease; a phase III trial testing the drug combination's effect on this patient population is now under way.
Topics: Adenocarcinoma; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Esophagogastric Junction; Female; Humans; Male; Stomach Neoplasms
PubMed: 25185191
DOI: 10.1158/2159-8290.CD-NB2014-113 -
European Journal of Cancer (Oxford,... Jul 2019Epidermal growth factor receptor (EGFR) and hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) pathways, which promote tumour growth and... (Comparative Study)
Comparative Study Randomized Controlled Trial
FOLFOX alone or combined with rilotumumab or panitumumab as first-line treatment for patients with advanced gastroesophageal adenocarcinoma (PRODIGE 17-ACCORD 20-MEGA): a randomised, open-label, three-arm phase II trial.
BACKGROUND
Epidermal growth factor receptor (EGFR) and hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) pathways, which promote tumour growth and proliferation, are often deregulated in advanced gastroesophageal adenocarcinomas. We assessed whether adding panitumumab (an EGFR inhibitor) or rilotumumab (a HGF inhibitor) to first-line fluoropyrimidine-based and platinum-based chemotherapy (modified oxaliplatin, leucovorin and fluorouracil [mFOLFOX6]) benefits to patients with advanced gastroesophageal adenocarcinoma.
PATIENTS AND METHODS
This phase II, open-label, randomised, three-arm study enrolled patients ≥18 years, with advanced gastroesophageal adenocarcinoma, Eastern Cooperative Oncology Group performance status 0-1 and no known HER2 overexpression. Patients were randomly assigned (1:1:1) mFOLFOX6 (oxaliplatin 85 mg/m, leucovorin 400 mg/m, 5-fluorouracil 400 mg/m bolus then 2400 mg/m over 46 h) alone or combined with panitumumab (6 mg/kg) or rilotumumab (10 mg/kg) every 2 weeks until limiting toxicity, patient's refusal or disease progression. The primary end-point was the 4-month progression-free survival (PFS) rate. Secondary end-points included overall survival (OS) and tolerance.
RESULTS
The study enrolled 162 patients in 29 French centres. The median follow-up was 23.6 months (interquartile range = 16.4-29.0). The 4-month PFS rate was 71% (95% confidence interval [CI] = 57-82) with chemotherapy alone, 57% (95% CI = 42-71) combined with panitumumab and 61% (95% CI = 47-74) combined with rilotumumab. Median OS was 13.1 months (95% CI = 8.7-16.9) with chemotherapy alone, 8.3 months (95% CI = 6.2-13.2) combined with panitumumab and 11.5 months (95% CI = 7.9-17.1) combined with rilotumumab. Adverse events grade ≥III occurred less frequently with chemotherapy alone (62%) than with panitumumab (83%) and rilotumumab (89%).
CONCLUSIONS
We found no benefit in adding panitumumab or rilotumumab to mFOLFOX6 first-line chemotherapy to treat advanced gastroesophageal adenocarcinoma patients.
TRIAL REGISTRATION
European Clinical Trials Database, number 2009-012797-12.
Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Esophageal Neoplasms; Female; Fluorouracil; France; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Panitumumab; Progression-Free Survival; Stomach Neoplasms; Time Factors
PubMed: 31129386
DOI: 10.1016/j.ejca.2019.04.020 -
MAbs 2016The antibody rilotumumab, which has been tested in multiple Phase 2 and Phase 3 trials, has been reported to neutralize hepatocyte growth factor (HGF), the ligand for...
The antibody rilotumumab, which has been tested in multiple Phase 2 and Phase 3 trials, has been reported to neutralize hepatocyte growth factor (HGF), the ligand for the oncogene MET. However, we report that rilotumumab does not prevent HGF from directly binding to MET on conventional and primary patient-derived human gliomasphere lines, a trait driven by the HGF α-chain, which remains free to engage cell-surface glycosaminoglycans and the receptor MET. This binding induces MET phosphorylation, initiates robust AKT and ERK signaling and potentiates biological effects such as cell scattering. This partial antagonism was highly exacerbated in the presence of activated epidermal growth factor receptor, which is common in several cancers. Hence, we confirm that rilotumumab is only a partial antagonist of HGF activity, a finding that has considerable implications for the therapeutic use of rilotumumab.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neutralizing; Cell Line, Tumor; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Glycosaminoglycans; Hepatocyte Growth Factor; Humans; MAP Kinase Signaling System; Phosphorylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met
PubMed: 26750997
DOI: 10.1080/19420862.2015.1122149 -
Journal of Pharmaceutical Sciences Jan 2014Rilotumumab is an investigational, fully human, monoclonal antibody immunoglobulin G2 against hepatocyte growth factor (HGF) that blocks the binding of HGF to its...
Rilotumumab is an investigational, fully human, monoclonal antibody immunoglobulin G2 against hepatocyte growth factor (HGF) that blocks the binding of HGF to its receptor MET and has shown trends toward improved survival in a phase 2 clinical trial in gastric cancer. To characterize rilotumumab pharmacokinetics in patients with cancer and to identify factors affecting the pharmacokinetics, rilotumumab concentration data from seven clinical trials were analyzed with a nonlinear mixed-effect model. We found that rilotumumab exhibited linear and time-invariant kinetics over a dose range of 0.5-20 mg/kg. Typical systemic clearance and central volume of distribution were 0.184 L/day and 3.56 L, respectively. Body weight is the most significant covariate, and sex, cancer type, coadministration of chemotherapeutics, baseline plasma HGF and tumor MET levels, and renal and hepatic functions did not have an effect on rilotumumab pharmacokinetics. The concentration-time profiles for the rilotumumab clinical regimens were projected well with the model.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Dose-Response Relationship, Drug; Female; Hepatocyte Growth Factor; Hepatocytes; Humans; Immunoglobulin G; Male; Middle Aged; Neoplasms; Young Adult
PubMed: 24186235
DOI: 10.1002/jps.23763