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A Phase 1b/2 Study of Ramucirumab in Combination with Emibetuzumab in Patients with Advanced Cancer
James J. Harding1,2, Andrew X. Zhu3, Todd M. Bauer4, Toni K. Choueiri5, Alexander Drilon1,2, Martin H. Voss1,2, Charles Fuchs5, Ghassan K. Abou-Alfa1,2, Sameera Wijayawardana6, Xuejing A Wang6, Brian Moser6 Arantxa Uruñuela6, Volker Wacheck6, Johanna Bendell4 1 Memorial Sloan Kettering Cancer Center New York, New York 2 Weill Cornell Medical College, New York, New York 3Massachusetts General Hospital/ Harvard Medical School, Boston, Massachusetts4 4Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee 5Yale Cancer Center, Smilow Cancer Hospital, New Haven, Connecticut 6Eli Lilly and Company, Indianapolis, Indiana
Running Title: Phase 1b/2 of ramucirumab plus emibetuzumab
Keywords: Antibodies, phase Ib/2, emibetuzumab plus ramucirumab, MET protein, advanced or metastatic cancers.
Conflicts of Interest: J.J.H was in part supported through the NIH/NCI Cancer Center Support Grant P30 CA008748. J.J.H has received consulting fees from Bristol Myers Squibb, Eli Lilly, CytomX, and Eisai, and research funds from Bristol Myers Squibb. C.S.F. reports consulting role for Agios, Bain Capital, Bayer, Celgene, Dicerna, Five Prime Therapeutics, Gilead Sciences, Eli Lilly, Entrinsic Health, Genentech, KEW, Merck, Merrimack Pharmaceuticals, Pfizer, Sanofi, Taiho, and Unum Therapeutics. He also serves as a Director for CytomX Therapeutics and owns unexercised stock options for CytomX and Entrinsic Health. A.E.D. received honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Tyra Biosciences, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, Peerview, AstraZeneca, Genentech/Roche, Bayer; Consulting and Advisory role in Ignyta, Loxo, TP Therapeutics, AstarZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Takeda, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis and Bayer. SW, XAW, BM, AU and VW are employees and shareholders of Eli Lilly and Company. This study was funded by Eli Lilly and Company.
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Corresponding author James J. Harding Address: 300 East 66th Street Memorial Sloan Kettering Cancer Center, New York, Untied States of America. Phone: 646-888-4314 Fax: 646-888-4255
E-mail: [email protected]
Target journal: Clinical Cancer Research
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Statement of Translational Relevance:
Mesenchymal epithelial transition factor proto-oncogene receptor tyrosine kinase (MET)
signaling supports oncogenic processes including cell proliferation, invasion, and metastasis. MET activation also contributes to resistance to VEGF/VEGFR targeting agents. This phase 1b/2 study demonstrates a favorable safety profile for emibetuzumab, a humanized, bivalent monoclonal antibody targeting MET, when administered with the
VEGFR2 antibody ramucirumab. Exploratory data suggest that baseline tumoral MET expression is associated with clinical anti-tumor activity for this combination in HCC.
Patients with high MET expression exhibited an approximate 3-fold longer PFS relative to HCC patients with low MET expression. Given the negative prognosis associated with
MET-high HCCs (1), the median PFS of 8.1 months observed herein is of interest as it exceeds previously reported median PFS of 2.0 months for MET high HCC patients treated with MET targeted therapy (2). These translational data warrant additional studies to investigate MET inhibition as an antiangiogenic treatment in HCC.
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Abstract: Purpose: Inhibition of the vascular endothelial growth factor receptor-2 (VEGFR-2)
blocks angiogenesis and attenuates tumor growth, but cancers may evade this effect
through activation of the hepatocyte growth factor (HGF) receptor MET. Here we report
results of the phase 1b/2 study of ramucirumab, a monoclonal anti-VEGFR-2 antibody, plus the anti-MET monoclonal antibody emibetuzumab.
Patients and Methods: A 3+3 dose escalation of emibetuzumab plus ramucirumab
(Phase 1b) was followed by tumor-specific expansion cohorts. Primary objectives were to determine the recommended phase 2 dose (RP2D) and to evaluate antitumor activity.
Secondary objectives included safety, pharmacokinetics, and immunogenicity. Tumoral
MET expression was explored by immunohistochemistry.
Results: 97 solid tumor patients (6 phase 1b, 16 GEJ, 45 HCC, 15 RCC, and 15 NSCLC)
received emibetuzumab at 750 or 2000 mg flat dosing plus ramucirumab at 8mg/kg Q2W.
No DLTs were observed. Common AEs were primarily mild or moderate and included
fatigue (36.1%), peripheral edema (28.9%), and nausea (14.4%). Emibetuzumab
exposures were similar as in previous studies with no apparent drug-drug interactions.
Five partial responses (5.2%) were observed across all tumor types. The greatest anti- tumor activity was noted in HCC with a 6.7% ORR, 60% DCR, and 5.42 months (95% CI:
1.64-8.12) PFS. HCC with high MET expression showed improved PFS with approximately threefold increase in PFS (8.1 vs. 2.8 months) relative to low MET expression.
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Conclusions: Ramucirumab plus emibetuzumab was safe and exhibited cytostatic antitumor activity. MET expression may help to select patients benefitting most from this combination treatment in select tumor types.
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INTRODUCTION
Vascular endothelial growth factor (VEGF) and its receptor, vascular endothelial growth factor receptor-2 (VEGFR-2) have critical roles in the physiologic growth and maintenance of blood vessels. High levels of VEGF and other angiogenic factors are often associated with an increased level of tumor microvessel density, aggressive pathologic features, and poor clinical outcomes in a variety of cancer histology. In preclinical models, blockade of the VEGF/VEGFR-2 axis leads to tumor vascular remodeling and cancer cell death. Pathological dysregulation of angiogenesis is an established hallmark of malignancy, and both VEGFR-2 and its ligand are bona fide therapeutic targets either with selective monoclonal antibodies or via multi-targeted tyrosine kinase inhibitors, in a variety of tumor types, including non-small lung cancer (NSCLC), ovarian cancer, renal cell carcinoma (RCC), and several gastrointestinal malignancies such as colorectal cancer (CRC), gastric or gastroesophageal junction adenocarcinoma (GEJ), and hepatocellular carcinoma (HCC) (3-6).
Innate and acquired resistance to anti-angiogenic therapy is frequent and multi- factorial, but is in part mediated by the hepatocyte growth factor (HGF) receptor MET (7-
9). Both ligand-dependent and -independent MET activation is implicated in tumor cell motility, proliferation, survival, invasion, metastasis, and angiogenesis. Indeed, the MET receptor is overexpressed, activated, amplified, or mutated in a wide variety of solid tumors (9-11), and contributes to an aggressive tumor biology (12,13). Importantly, VEGF blockade leads to a reciprocal increase in MET concentration and activation (8), which in turn leads to MET-mediated anti-angiogenic escape (14). Simultaneous pharmacological inhibition of MET and VEGF signaling mitigates MET-mediated escape, thereby slowing
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tumor growth and reducing invasion and metastasis (14). Thus, there is compelling preclinical evidence to support co-targeting VEGF and MET pathways in malignances to enhance the activity of VEGF/VEGFR-2 monotherapy. Clinically the concept MET as a mechanism of anti-angiogenic resistance is also suggested in several correlative programs across multiple tumor types indicating that unopposed VEGF inhibition, either with monoclonal antibodies or TKIs, results in HGF/MET over expression on post- progression biopsies (2,14,15).
Ramucirumab, a human IgG1 VEGFR-2 targeting antibody, exhibits antitumor activity and when administered as monotherapy, or in combination, improves both progression-free and overall survival over placebo in patients with advanced gastric/GEJ cancers, alpha-fetoprotein (AFP)-high HCC, and NSCLC (16-19). Given the above data on the importance of MET as a bypass pathway circumventing VEGF/VEGFR-2 inhibition, it is reasonable to test ramucirumab in combination with MET targeting agents in solid tumors.
Emibetuzumab (LY2875358) is a humanized IgG4 bivalent monoclonal antibody that prevents HGF from binding to the extracellular domain of MET, thereby inhibiting ligand-dependent MET signaling. Emibetuzumab triggers MET receptor internalization and the degradation of total membrane MET expression, leading to inhibition of ligand- independent activation of MET signaling (20). The agent does not elicit antibody dependent cellular cytotoxicity (ADCC). In preclinical models, emibetuzumab inhibits growth of MET-dependent tumors and when combined with a murine surrogate antibody of ramucirumab in a xenograft model leads to additive antitumor activity (Supplemental
Figure 1). Clinically, emibetuzumab has shown to be safe and tolerable in cancer patients
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with limited anti-tumor activity as monotherapy in clinical studies for unselected cancer
patients (21,22). In prior studies, a maximum tolerated dose was not established due to
a favorable safety profile and the recommended phase 2 dose range of emibetuzumab
was established at 700mg to 2000mg every 2 weeks (21).
Herein we report results from a phase 1b/2 dose-escalation trial of ramucirumab
in combination with emibetuzumab in patients with advanced or metastatic cancers,
followed by tumor-specific expansion cohorts in patients with gastric or GEJ adenocarcinoma, RCC, HCC, or NSCLC. The primary objectives of this study were to identify a recommended phase 2 dose (RP2D) range for emibetuzumab when given in combination with ramucirumab, and to explore the anti-tumor activity of this combination
treatment in tumor types with established dependence on VEGF/VEGFR signaling.
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METHODS
Study design
This was a multicenter, nonrandomized, open-label Phase 1b/2 study of ramucirumab in combination with emibetuzumab in two parts (clinicaltrials.gov
NCT02082210, Figure 1). In Part A, a standard 3+3 dose escalation design was employed with an increasing dose of emibetuzumab in combination with a fixed FDA- approved dose of ramucirumab in patients with advanced and/or metastatic cancer. After
completion of dose escalation, additional patients were enrolled in Part B in tumor-specific
expansion cohorts for gastric or GEJ adenocarcinoma, HCC, RCC, or NSCLC for dose
confirmation and exploration of clinical activity.
The primary objectives of the study were to determine the recommended phase 2 dose (RP2D) range for emibetuzumab that can be safely administered in combination with ramucirumab and to evaluate the preliminary antitumor activity of the combination in tumor-specific expansion cohorts. Secondary objectives included safety, tolerability, pharmacokinetics (PK), and immunogenicity. Exploratory objectives included evaluation of tumoral MET expression and exploration of potential associations with observed antitumor activity.
The protocol was approved by Institutional Review Boards before patient recruitment, and each patient provided written informed consent before enrollment. The study was conducted in accordance with the International Conference on Harmonization
E6 Guidelines for Good Clinical Practice.
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Patient population
Eligible patients were ≥18 years of age with a confirmed diagnosis of advanced
and/or metastatic cancer after failure of standard-of-care therapy(s), or for whom there was no standard therapy, or for whom standard therapy would not be appropriate (i.e. in the event of patient refusal). Additional key eligibility criteria included adequate hematologic, renal and hepatic function (Child Pugh A), as well as an Eastern
Cooperative Oncology Group (ECOG) performance status of ≤ 2 in Part A and ≤ 1 in Part
B. Patients had measurable disease as defined by Response Evaluation Criteria in Solid
Tumors version 1.1 (RECIST1.1) (23). All patients were required to have a pre-treatment tumoral sample from the primary tumor or a metastasis obtained prior to study treatment and after progression on (or discontinuation from) the most recent line of systemic tumor therapy and within at least 6 months prior to initiation of study treatment.
Patients were excluded if they had received any previous cancer therapy within 21 days or 5 half-lives prior to study enrollment (whichever was shorter) and had not recovered from the acute effects of prior treatment-related toxicities. Additional exclusion criteria included history of hypertensive crisis, poorly controlled hypertension (i.e. A history of hypertensive crisis or hypertensive encephalopathy or blood pressure systolic
≥150 and/or diastolic ≥95 despite medical management), significant venous or arterial
thromboembolic events (i.e. any arterial thromboembolic event, including myocardial
infarction, unstable angina pectoris, cerebrovascular accident, or transient ischemic
attack within 6 months of study drug; patients with a history of deep venous thrombosis,
pulmonary embolism, or any other significant venous thromboembolic event during a 3- month period prior to enrollment. Chronic tumor portal venous thrombosis associated with
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HCC was not an exclusion criterion), and uncontrolled central nervous system metastasis.
Major blood vessel invasion and evidence of intratumoral cavitation were exclusionary for patients with NSCLC.
Study treatment
Patients participating in Part A (dose escalation) received emibetuzumab at doses of 750 mg (dose level 1) and 2000 mg (dose level 2) as an intravenous infusion, in
combination with an 8 mg/kg intravenous dose of ramucirumab, every 2 weeks (Q2W)
over a 28-day cycle. The starting dose and the dose range of emibetuzumab were selected based on clinical data and PK analyses from the phase 1 study, which indicated saturation of receptor-mediated clearance at dose levels at and above 700 mg Q2W (21).
No intrapatient dose escalations were allowed. In Part B, all eligible patients received emibetuzumab 750mg and ramucirumab 8 mg/kg IV every two weeks.
Safety
Safety and tolerability were assessed through clinical and laboratory evaluations at weekly intervals for the first two cycles and every 2 weeks thereafter. Adverse events
(AE) were graded according to the Common Terminology Criteria for Adverse Events
(CTCAE v.4.0) and were recorded for all patients who received at least one dose of study treatment. Dose-limiting toxicities (DLT) were defined as possibly drug-related AEs during cycle 1 if they met one of the following criteria: ≥ Grade 3 nonhematologic toxicity (except for Grade 3 nausea, vomiting, diarrhea, constipation, fatigue, or anorexia for ≤3 days or
Grade 3 hypertension which is controlled within ≤7 days), Grade 4 hematologic toxicity of
≥7 days duration, febrile neutropenia, or any other significant toxicity.
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Antitumor activity
Tumor response was assessed by CT scans or magnetic resonance imaging
according to RECIST1.1 (23) at baseline and thereafter every 6 weeks until radiographic
documentation of progressive disease for the first 9 cycles. Thereafter, patients had tumor
assessment every 8-12 weeks as clinically indicated. All patients receiving at least one
dose of study drugs were included in the evaluation of anti-tumor activity.
Pharmacokinetics
Serial serum samples for bioanalysis of ramucirumab and emibetuzumab were obtained at scheduled times around their sequential infusions: prior to infusion, at the end
of infusion, and at 3, 5, 8, 21, and 168 hours post-emibetuzumab (latter) infusion.
Additional samples were collected on Day 15, pre- and post-ramucirumab infusion and
pre-emibetuzumab infusion (nominally 334, 335, and 336 hours after the first
emibetuzumab dose on Day 1). Serum concentrations of both ramucirumab and
emibetuzumab were measured using validated enzyme-linked immunosorbent assays
(ELISAs) as previously described (21,24). In patients with complete PK sampling after the
first infusion, pharmacokinetic parameters for emibetuzumab were calculated by standard
noncompartmental methods using Phoenix WinNonlin Version 6.4 (Certara L.P).
Ramucirumab concentrations were descriptively overlaid with simulations from a
previously established ramucirumab population PK model using the nonlinear mixed-
effects program NONMEM Version 7.4.2 (ICON Development Solutions, Hanover, MD)
to determine the potential effect of emibetuzumab co-administration on ramucirumab
pharmacokinetics.
Immunogenicity
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Patient samples for immunogenicity assessment drawn during this study were
analyzed for the presence of antidrug antibodies (ADA). The formation of ADA was
assessed using a validated ELISA, following a 4-tier approach (25). The ADA screening assay was validated in accordance with the Food and Drug Administration (FDA)
Guidance for Industry: Assay Development for Immunogenicity Testing of Therapeutic
Proteins (FDA 2016) (26).
Biomarker assessments
Tumor biopsies were tested for MET expression by immunohistochemistry (IHC) using the Dako MET 2 pharmDxTM kit, an exploratory kit employing the A2H2-3 MET antibody clone. (27) A composite scoring system was devised to determine the status of
MET by IHC, enumerating the percentage of tumor cells with immunoreactivity of 0, 1+,
2+, or 3+ staining intensity in the cell membrane as described previously (27). The analysis was performed by a trained pathologist in a blinded fashion.
Locally generated next-generation sequencing (NGS) data of tumor samples from patients with RECIST responses using platforms compliant with Clinical Laboratory
Improvement Amendments (CLIA) regulations were provided as available(28).
Statistical Analysis
The co-primary objective antitumor activity was measured by the overall response rate (ORR), which was defined as the proportion of patients with confirmed CR and PR.
The disease control rate (DCR) was calculated as the proportion of patients with confirmed CR, PR, and stable disease. Progression-free survival (PFS) is defined as the time from the date of first dose to the date of objective disease progression or death,
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whichever was earlier. Median PFS was estimated using the Kaplan-Meier method.
Efficacy and safety analyses were performed on patients who had received at least 1
dose of study treatment.
The sample size of approximately 15 patients per expansion cohort was selected to allow adequate confirmation of safety and tolerability of emibetuzumab in combination
with ramucirumab, and to identify evidence of preliminary clinical activity worthy of further
investigation in Phase 2, analogous to the first stage of a Simon`s two-stage design. In
case of significant clinical activity in any of the tumor-specific expansion cohorts based
on response rate (i.e. at least 1 responder was observed from the initial 15 patients in
gastric and RCC cohorts, and at least 2 responders were observed in HCC and NSCLC
cohorts) or disease control rate relative to previously reported landmark studies, the
protocol allowed for enrollment of an additional 30 patients, for a total of approximately
45 patients per cohort to further characterize clinical activity of the combination treatment.
A sample size of 45 provided a weighted average power of 83% based on a 2-sided type
1 error rate of 5% to detect a significant dependence between biomarker status and
clinical activity. To better understand the relevance of MET expression as a potential
biomarker for emibetuzumab in combination with ramucirumab, the anti-tumor activity
endpoints were retrospectively assessed with respect to different MET expression cut-
points as a planned exploratory analysis.
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RESULTS
Patient Disposition and Characteristics
A total of 97 patients were enrolled and received at least 1 dose of study drugs.
This comprised 6 patients in the dose-escalation part (3 at each of the 2 dose levels) and
91 patients in the 4 tumor-specific expansion cohorts including 16 GEJ, 45 HCC, 15 RCC, and 15 NSCLC patients. The median number of cycles of emibetuzumab and ramucirumab completed was 3 (range 1-14 cycles) with relative median dose intensity of
100% and 98%, respectively. As of the data cut-off, all patients had discontinued from study treatment. The most common reason for study treatment discontinuation was progressive disease (85%), followed by withdrawal by subject (4%; Supplemental Table
1).
Patient baseline characteristics are summarized in Table 1. The majority of patients were Caucasian (83%), male (72%), and had a baseline ECOG performance status of 1 (61%). The median number of prior systemic therapies was 2, and ranged from 0 to 7. For the HCC cohort, all patients had a Child Pugh A score with non-virally mediated HCC pre-dominating (60%), and 18 patients (40%) had AFP > 400ng/ml. In total, 37 (82%) of 45 HCC patients failed prior sorafenib treatment, while 5 (11%) were treatment naïve and 3 (4%) received prior therapies other than sorafenib (Supplemental
Table 2).
Safety and Tolerability
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Combination treatment with ramucirumab and emibetuzumab was well tolerated.
No DLTs or DLT-equivalent toxicities were reported up to the maximum studied dose level of 2000 mg emibetuzumab in combination with ramucirumab. In total, 82 of the 97 (85%)
patients experienced at least 1 AE possibly related to study drugs. Most of these AEs
were of mild or moderate intensity with no observed dose relationship to emibetuzumab
at the doses administered. Among AEs possibly related to treatment, the most frequently
reported (≥10% of patients) included fatigue (36%), peripheral edema (29%), and nausea
(14%, Table 2). Twenty patients (21%) were reported to have possibly treatment-related
Grade ≥3 AEs. Grade ≥3 events reported for more than 2 patients were pulmonary
embolism [4 patients (4%)] and fatigue [3 patients (3%)]. Mild or moderate infusion-related
reactions (IRRs) were reported for 6 patients (6%), with symptoms manageable by
standard of care treatment or spontaneous resolution. Except for one patient who had an
IRR following the ramucirumab infusion but prior to emibetuzumab dosing, all IRRs
occurred after the administration of both ramucirumab and emibetuzumab. This precluded
causality assessment for either study treatment.
There were 9 deaths reported while patients were on study treatment or within 30 days after discontinuing study treatment. These deaths were either due to disease (n=7) or adverse events (2 cases of pneumonia). None of the deaths were related to study
treatment.
Pharmacokinetics and Immunogenicity
Supplemental Table 3 summarizes emibetuzumab noncompartmental PK parameters after the first dose, calculated from patients with complete sampling after the
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first infusions. While no formal dose proportionality assessments were performed in this study, emibetuzumab clearance is known to be linear in the dose range investigated, and was approximately dose-proportional between the 750-mg and 2000-mg dose levels.
Estimated half-life (t1/2) was approximately 7 days in both treatment groups. These results were also comparable to those from previous studies in which patients were treated with emibetuzumab alone (21,22), suggesting that co-administration of ramucirumab does not appreciably impact the PK of emibetuzumab. Likewise, an overlay plot comparing observed ramucirumab concentrations in this study with simulated values obtained from a ramucirumab population PK model fit to patients treated with ramucirumab alone (not shown) suggests that co-administration of emibetuzumab has no appreciable effect on the concentration–time profile of ramucirumab.
Immunogenicity samples available for evaluation of ADA were analyzed for the presence of anti-emibetuzumab antibodies from 93 patients and anti-ramucirumab antibodies from 96 patients. None of these patients developed treatment-emergent ADA against ramucirumab or emibetuzumab. Ten (11%) and 12 (13%) patients had detectable
ADA against emibetuzumab or ramucirumab, respectively, detected prior to dosing or at any time on treatment. For those detected while on treatment, titers did not reach the pre- specified criteria for treatment-emergent ADA.
Antitumor Activity
Across all cohorts, 87 of 97 patients (90%) receiving ≥1 dose of study drugs were evaluable for tumor response assessment by RECIST1.1. Overall, there were 5 confirmed
PRs (1 gastric/GEJ, 1 NSCLC, 3 HCC), and no CR observed, for an ORR of 5.2% (95%
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CI: 0-10) across the entire population (Table 3). Four of the 5 responders were previously
exposed to anti-VEGF treatment (3 HCC: sorafenib; gastric: ramucirumab). An additional
55 patients (57%) exhibited SD as best response to therapy for a disease control rate
(DCR) of 62% (95% CI: 50-70). Overall, a decrease in sum of target lesions relative to
baseline was observed in a total of 31 patients (32%, Figure 2A). The median PFS for
patients enrolled in the tumor-specific expansion cohorts ranged between 1.64 months
for gastric cancer (95% CI: 1.4-4.6) and 6.6 months for patients with NSCLC (95% CI:
2.9-9.7). Tumor response and PFS for each of the tumor-specific expansion cohorts are presented in Table 3.
Neither the RCC cohort nor the NSCLC cohorts met criteria to expand based on a prior assumption of anti-tumor activity. Although 1 PR was observed in the gastric/GEJ cohort, and therefore met the pre-determined boundary to expand, the principal investigators and the sponsor chose not to explore this given the short lived nature of this
PR (PFS of 1.6 months) and emerging contemporary clinical data indicating that MET inhibition might not be effective in this disease type(29). Among the initial 15 patients in the HCC expansion cohort, 2 of 16 patients (13%) had a confirmed PR and 9 of 11 evaluable patients showed a reduction in AFP. The HCC cohort was therefore expanded to enroll an additional 30 patients to further characterize the anti-tumor activity of emibetuzumab and ramucirumab. The ORR across the 45 total HCC patients finally enrolled was 6.7%, with a DCR of 60% (95% CI: 0.4-0.7). The median PFS in these patients was 5.4 months (95% CI: 1.6-8.1, Figure 2B).
Exploratory Biomarker Analysis of tumoral MET expression
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Of the 97 patients enrolled, 73 had sufficient tumor material for MET expression analysis. In the overall patient population, patient with MET expression of ≥2+ staining intensity in ≥50% of their tumor cells had a PFS of 7.4 months (N=41) versus a PFS of
2.8 months in patients with MET expression below this cut-off (N=32; HR: 0.48 [90% CI:
0.29−0.81]; Figure 3).
When assessing this biomarker separately by treatment effect for each of the
tumor-specific expansion cohorts, no obvious trend toward longer PFS was observed in
gastric cancer, RCC, or NSCLC patients with MET expression of ≥2+ in ≥50% of tumor
cells receiving emibetuzumab in combination with ramucirumab (Supplemental Figure
2). However, HCC patients with MET expression of ≥2+ in ≥50% of tumor cells had a
median PFS of 8.1 months (N=19) relative to patients below this MET expression cut-off,
who had a median PFS of 2.8 months (N=14; HR: 0.22, 90% CI: 0.08-0.59;
Supplemental Figure 2b). Further exploratory analysis of different MET expression cut-
offs (e.g. MET ≥2+ in ≥80% or ≥30%) did not provide any stronger association of MET
status and PFS for the treatment effect of emibetuzumab and ramucirumab
(Supplemental Figures 3a and 3b). This trend for a MET biomarker by treatment effect
in HCC patients was also observed for ORR, with 2 PRs observed out of 16 evaluable
patients for tumor response with MET ≥2+ in ≥50% of tumor cells, and no PRs noted in 9
patients with MET status below this cut-off (Supplemental Figures 3c and 3d). None of
the patients with a PR and next-generation sequencing data available had a MET
genomic amplification or alterations associated with MET sensitivity (Supplemental
Table 4).
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Discussion
This phase 1b/2 study determined the RP2D range of emibetuzumab when given
in combination with ramucirumab and explored anti-tumor activity across select solid
tumors. In the dose escalation phase, the safety profile of emibetuzumab in patients with
different solid tumors was consistent across both dose levels with no new safety signals
observed for the combination treatment. The combination was tolerable with no dose-
limiting toxicities or DLT-equivalent toxicities outside the DLT assessment period during treatment. A maximum tolerated dose for the combination was not established, and there
was no apparent emibetuzumab dose-dependent effect on anti-tumor activity.
Furthermore, PK assessments (noncompartmental/descriptive analyses and population modeling) indicated that saturation of target-receptor occupancy occurs at emibetuzumab exposures associated with dose levels >210 mg Q2W. Furthermore, population PK model simulations demonstrated that at doses of ≥700 mg emibetuzumab Q2W, 100% of the
population was predicted to have a minimum plasma concentration at steady state
(Cmin,ss) of ≥50 mg/mL, which is the emibetuzumab Cmin,ss associated with ≥90% tumor
growth inhibition in xenograft models (21). Consistent with monotherapy, no remarkable
differences in emibetuzumab PK profiles were observed among the patients with different
tumor types when emibetuzumab was co-administered with ramucirumab, nor were there
any signs of drug-drug interactions between the two antibodies when administered in
combination. Thus, given the totality of safety, PK, and preliminary efficacy data the
decision was made to select emibetuzumab at 750mg Q2W as the RP2D for solid tumor
cohort expansions.
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The most common adverse events included fatigue, peripheral edema, and
nausea, and the majority of events were of mild to moderate intensity (Grade 1 or 2). Not surprisingly, the overall safety profile of emibetuzumab and ramucirumab differed slightly based on tumor type. For example, edema, hypoalbuminemia, and thrombocytopenia predominated in the HCC cohort, while nausea and vomiting were more common in the
GEJ cohort. Nevertheless, the rates of Grade ≥3 adverse events were comparable in patients with different types of cancers.
Ramucirumab combined with emibetuzumab exhibited variable antitumor activity across a spectrum of solid tumors. Five confirmed partial responses according to
RECIST1.1 were reported and the disease control rate of 62% reflects the cytostatic mechanism of action expected for this combination. The clinical trial design allowed to explore activity of this combination in several tumor types that are known to be dependent on angiogenic pathways. No compelling antitumor activity was observed in NSCLC, gastric/GEJ or RCC in the initial expansion cohorts. Regarding RCC, this was somewhat surprising, especially given the favorable data observed in advanced RCC patients who were treated with cabozantinib, a multitargeted TKI that blocks both VEGFR2 and MET
(30) as well as several other key signaling proteins. Our novel approach of selectively inhibiting only MET and VEGFR2 by monoclonal antibodies suggests that perhaps other cabozantinib targets, such as AXL, or the relatively non-selective mechanism of action of the agent may be required for clinical benefit in RCC. Furthermore, the METEOR study indicates that tumoral MET expression is not predictive or prognostic in cabozantinib treated RCC patients, suggesting that the summation of multiple inhibitor signals might be required for antitumor activity (31).
21
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Indeed, only the HCC expansion cohort demonstrated meaningful antitumor
activity. Acknowledging the hazards of cross-trial comparison and the observation that
11% of the HCC cohort was sorafenib naïve, the objective response rate as well as PFS
observed in unselected HCC patients herein is comparable to that seen with multitargeted
tyrosine kinase anti-angiogenesis inhibitors in the second-line HCC setting (32-34). Our
preliminary clinical data is also in line with preclinical and emerging clinical data, supporting the notion that concurrent MET inhibition may delay anti-angiogenic resistance
(8,14). Single-agent ramucirumab led to a PFS of 2.8 months in two recent Phase 3 studies (19,35), while the addition of MET blockade in our study yielded a favorable PFS of 5.4 months in a similar advanced HCC patient population. Furthermore, MET expression has been shown to increase in HCC patients following treatment with anti- angiogenic agents (2), and recent positive phase III data of cabozantinib further bolster the biological rationale in this study of co-targeting MET signaling and the VEGF/VEGFR-
2 axis by emibetuzumab and ramucirumab, respectively (32). Our data underscore the importance of MET and VEGFR in HCC biology and highlight these two pathways as critical targets in HCC. Although further exploration of the combination of ramucirumab and emibetuzumab in HCC appears warranted based on efficacy and a favorable safety profile, the potential financial cost associated with such a regimen, the logistical concerns associated with biweekly intravenous administrations, and the emerging landscape of oral
TKIs (36) and immunotherapy for patients with HCC, limit the future potential of a ramucirumab plus emibetuzumab combination for HCC(37).
A critical question for the field is whether selecting for MET-high tumors will help select patients who will benefit from VEGFR-MET-targeted treatments. Acknowledging
22
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the small sample size of the study, our exploratory data indicate that determination of
MET status by IHC might not enrich for clinical activity of emibetuzumab in combination
with ramucirumab for tumor types such as gastric/GEJ, RCC, and NSCLC. In accordance
with the available literature (22,29,38,39), it may be that genomic MET alterations (e.g.
MET amplification, MET exon 14 variants in NSCLC, or MET kinase domain mutations)
are requisite for response to MET-targeted therapeutics in these cancer types. The observation that 4 out of the 5 patients with a PR in this study had no such genomic alterations suggests that functional methods such as RNA sequencing or improved methods of quantifying active MET may be required to help select patients with such tumor types who are apt to respond. In HCC, a randomized, prospective Phase III study restricting enrollment to high MET expression (IHC >2+, 50% cells) did not show efficacy with the low-potency, non-selective MET inhibitor tivantinib (2). Our data are informative,
suggesting that MET expression by IHC may have a predictive role for certain
combination strategies, such as selective inhibitors of MET and VEGFR2. Indeed, our
exploratory data indicate that HCC patients with higher tumoral MET expression at
baseline had an ~3-fold longer PFS than patients with lower MET expression when treated with ramucirumab and emibetuzumab (8.1 vs. 2.8 months; HR: 0.22).
A limitation of the current study is that the single-arm design clearly restricts the ability to evaluate the impact of prognostic patient baseline characteristics contributing to the treatment effects observed for the combination treatment. We are also unable to differentiate between the prognostic and the predictive effect of MET expression within this single-arm study. While in hepatocellular carcinoma MET expression by IHC has been shown to be a negative prognostic biomarker in Phase III with a median PFS of 2.0
23
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months using the same cut-off as that in our study (1), a randomized, controlled study stratifying for MET expression would be required to adequately differentiate between prognostic and predictive effects. Despite these shortcomings, we show that the combination of emibetuzumab and ramucirumab is safe and tolerable with favorable antitumor efficacy, particularly in patients with advanced HCC. Further evaluation of biomarkers to identify patients who may benefit from treatment with emibetuzumab in combination with ramucirumab is warranted.
Acknowledgements: We thank the study investigators and their support staff, as well as the patients and their caregivers for participating in the JTBF clinical trial. Sambasiva Kolati and Aditya
Pramod of Eli Lilly and Company provided medical Writing support.
24
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Tables:
Table 1: Summary of Baseline Patient and Disease Characteristics
Part A Part B Total Characteristics 750 mg 2000 mg Total Gastric HCC RCC NSCLC (N = 97) (N = 3) (N = 3) (N = 6) (N = 16)a (N = 45) (N = 15) (N = 15)
Gender, n (%)
Male 0 3 (100) 3 (50) 12 (75) 34 (76) 12 (80) 9 (60) 70 (72)
Race, n (%) 3 (100) 2 (67) 3 (83) 14 (93) 32 (74) 14 (100) 11 (79) 76 (83) Caucasian 49 61 53 62 62 64 56 61 Age, years, (18-57) (49-76) (18-76) (44-82) (43-81) (35-77) (44-76) (18-82) median (range) 3 (100) 3 (100) 6 (100) 15 (94) 45 (100) 14 (93) 15 (100) 95 (98) ECOG, n (%) 3 (100) 2 (67) 5 (83) 6 (38) 14 (31) 5 (33) 5 (33) 35 (36) 0
1 0 1 (33) 1 (17) 8 (50) 31 (69) 9 (60) 10 (67) 59 (61)
Prior Treatments 3 (100) 2 (67) 5 (83) 10 (63) 32 (71) 15 (100) 13 (87) 75 (77) ≥ 1 Prior Surgery 1 (33) 3 (100) 4 (67) 9 (56) 17 (38) 6 (40) 7 (47) 43 (44) ≥ 1 Prior Radiotherapy
≥ 1 Prior Systemic therapy 3 (100) 3 (100) 6 (100) 16 (100) 40 (89) 15 (100) 15 (100) 92 (95) Number of lines of prior systemic 2 (1-2) 3 (2-7) 2 (1-7) 2 (1-5) 1 (1-6) 3 (1-7) 2 (1-4) 2 (1-7) therapy, Median (Range) aIn the GEJ cohort, two patients consented at two separate institutions at the same time for the final spot on the cohort. In order to be patient-centered and for ethical purposes, both patients were allowed to enroll.
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Table 2: Treatment Related Adverse Events Occurring in ≥5% of Patients
Part A Part B Total 750 mg 2000 mg G/GEJ HCC RCC NSCLC Total (N=6) Total (N=91) (N=97) (N=3) (N=3) (N=16) (N=45) (N=15) (N=15) Any Any Any Any Any Any Any Any Any CTCAE terms, n (%) Grade ≥3 Grade ≥3 Grade Grade Grade Grade Grade Grade Grade Grade Grade Patients with any AE 2 (67) 1 (33) 3 (50) 2 (33) 14 (88) 38 (84) 13 (87) 14 (93) 79 (87) 18 (20) 82 (85) Fatigue 1 (33) 0 1 (17) 0 7 (44) 17 (38) 5 (33) 5 (33) 34 (37) 3 (3) 35 (36) Edema peripheral 1 (33) 0 1 (17) 0 1 (6) 20 (44) 3 (20) 3 (20) 27 (30) 1 (1) 28 (29) Nausea 1 (33) 0 1 (17) 0 5 (31) 4 (9) 2 (13) 2 (13) 13 (14) 0 14 (14) Hypoalbuminemia 0 0 0 0 1 (6) 10 (22) 0 0 11 (12) 0 11 (11) Hypertension 0 0 0 0 1 (6) 8 (18) 1 (7) 1 (7) 11 (12) 2 (2) 11 (11) Dyspnea 0 0 0 0 2 (13) 2 (4) 3 (20) 0 7 (8) 0 11 (11) Decreased Appetite 2 (67) 0 2 (33) 0 2 (13) 4 (9) 1 (7) 2 (13) 9 (10) 0 11 (11) Headache 0 0 0 0 2 (13) 2 (4) 2 (13) 3 (20) 9 (10) 0 9 (9) Thrombocytopenia 1 (33) 0 1 (17) 1 (17) 0 7 (16) 1 (7) 0 8 (9) 0 9 (9) Diarrhea 0 0 0 0 1 (6) 4 (9) 1 (7) 1 (7) 7 (8) 0 7 (7) Pyrexia 0 0 0 0 1 (6) 3 (7) 2 (13) 1 (7) 7 (8) 1 (1) 7 (7) Vomiting 0 0 0 0 4 (25) 1 (2) 0 2 (13) 7 (8) 0 7 (7) Constipation 0 0 0 0 1 (6) 3 (7) 1 (7) 1 (7) 6 (7) 0 6 (6) Anemia 0 0 0 0 4 (25) 2 (4) 0 0 6 (7) 1 (1) 6 (6) Stomatitis 0 0 0 0 0 2 (4) 1 (7) 3 (20) 6 (7) 0 6 (6) Infusion Related Reactions 0 0 0 0 0 2 (4) 2 (13) 2 (13)a 6 (7) 0 6 (6) Muscular Weakness 1 (33) 0 1 (17) 0 3 (19) 0 1 (7) 1 (7) 5 (6) 0 6 (6) Leukopenia 0 0 0 0 1 (6) 3 (7) 1 (7) 0 5 (6) 1 (1) 5 (5) Hyperbilirubinaemia 0 0 0 0 0 4 (9) 1 (7) 0 5 (6) 1 (1) 5 (5) a One patient had an IRR after the infusion of ramucirumab and prior to emibetuzumab dosing
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Table 3: Overall Response Rate and PFS
Part A Part B Total Response, n (%) 750 mg 2000 mg G/GEJ HCC RCC NSCLC (N=97) (N=3) (N=3) (N=16) (N=45) (N=15) (N=15) Partial Response (PR) 0 0 1 (6) 3 (7) 0 1 (7) 5 (5)
Stable Disease (SD) 3 (100) 2 (67) 7 (44) 24 (53) 7 (47) 12 (80) 55 (53)
Progressive Disease (PD) 0 1 (33) 7 (44) 13 (29) 5 (33) 1 (7) 27 (26)
Not Evaluable, n (%) 0 0 1 (6) 5 (11) 3 (20) 1 (7) 10 (10)
Overall Response Rate 0 0 1 (6) 3 (7) 0 1 (7) 5 (5) Disease Control Rate 3 (100) 2 (67) 8 (50) 27 (60) 7 (47) 13 (87) 60 (58) (CR + PR + SD)
Progression Free Survival, months, 95% CI
1.6 5.4 2.9 6.6 Median PFS NA NA (1.4-4.6) (1.6-8.1) (1.2-7.4) (2.9-9.7) 38.6 58.8 46.0 76.9 3 months NA NA (14.1-62.9) (41.5-72.6) (14.1-73.5) (44.2-91.9) 9.6 44.4 30.6 53.8 6 months NA NA (0.6-34.3) (27.1-60.4) (5.3-62.1) (24.8-76.0) 32.6 9 months NA NA 0.0 0.0 35.9 ( 11.7-61.3) (16.7-49.5)
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Figures:
Figure 1: Study Design
HCC= hepatocellular carcinoma; IV=intravenous; NSCLC=non-small cell lung cancer; PD=pharmacodynamics; PK=pharmacokinetics; RCC=renal cell carcinoma; Q2W= every 2 weeks
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Figure 2A: Waterfall Plot for Best Response
Best change in target lesions relative to baseline for patients treated with emibetuzumab (750mg or 2000mg) plus ramucirumab (8mg/kg) IV Q2W.
HCC= hepatocellular carcinoma; IV=intravenous; NSCLC=non-small cell lung cancer; RCC=renal cell carcinoma; Q2W= every 2 weeks
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Figure 2B: Progression-Free Survival (HCC Cohort)
Kaplan-Meier curve for PFS for HCC patients with 750mg flat dose emibetuzumab plus 8mg/kg ramucirumab IV Q2W
HCC= hepatocellular carcinoma
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Figure 3: Progression-Free Survival by MET expression (all patients)
Kaplan-Meier curve for PFS for patients with MET expression of ≥2+ staining intensity in ≥50% of their tumor cells (red curve) and patients with MET expression below this cut- off (blue curve). All patients were treated with emibetuzumab (750mg or 2000mg) plus ramucirumab (8mg/kg) IV Q2W.
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A Phase 1b/2 Study of Ramucirumab in Combination with Emibetuzumab in Patients with Advanced Cancer
James J Harding, Andrew X. Zhu, Todd M. Bauer, et al.
Clin Cancer Res Published OnlineFirst May 29, 2019.
Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-18-4010
Supplementary Access the most recent supplemental material at: Material http://clincancerres.aacrjournals.org/content/suppl/2020/05/30/1078-0432.CCR-18-4010.DC1
Author Author manuscripts have been peer reviewed and accepted for publication but have not yet been Manuscript edited.
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