ImClone Systems Research Articles

Marc Labelle

Marc Labelle, 61, died on Jan. 1 in Bedford, New Hampshire. “Marc was a visionary, charismatic, and talented scientist. He was an inspiration, with his unique approach to chemistry, infectious laugh, and strong zest for life. It was Marc’s creative intuition that led to the discovery of the asthma drug Singulair. After leaving Merck & Co. in 2000, he worked at Amgen, ImClone Systems, and Lundbeck Research USA. In 2011, while running a highly successful consulting business, he became an associate professor at the Université de Sherbrooke. Marc received numerous awards, including the American Chemical Society Heroes of Chemistry Award in 2003. Marc was a coauthor of nearly 100 patents and research articles.”—Tim Cushing, friend and colleague Most recent title: Owner, ML Pharma Consulting, and associate professor of chemistry, Université de Sherbrooke Education: BS, chemistry, 1978, and PhD, organic chemistry, 1983, University of Montreal Survivors: Wife, Helene Perrier; daughter, Evelyne

Olaratumab: First Global Approval.

Olaratumab (Lartruvo™) is a fully human IgG1 monoclonal antibody targeted against the human platelet-derived growth factor (PDGF) receptor α (PDGFRα). It was developed by Eli Lilly and Co. (previously ImClone Systems) after PDGFRα was identified as a potential therapeutic target in a variety of cancers. Olaratumab acts by selectively binding PDGFRα, thereby blocking PDGF ligand binding and inhibiting PDGFRα activation and downstream signalling. In October 2016, olaratumab received its first global approval, in the USA, for use in combination with doxorubicin for the treatment of adult patients with soft tissue sarcoma. The approval was granted by the US FDA under its Accelerated Approval Program based on the results of the JGDG phase II trial (NCT01185964). In addition, the EMA granted conditional approval for olaratumab in this indication in November 2016 following a review under the EMA's Accelerated Assessment Program. An international, confirmatory phase III trial in patients with soft tissue sarcoma is ongoing (ANNOUNCE; NCT02451943). Olaratumab has also been investigated in phase II trials in several other cancers. This article summarizes the milestones in the development of olaratumab leading to this first approval, for use in combination with doxorubicin for the treatment of soft tissue sarcoma in adults.

Necitumumab: First Global Approval.

Eli Lilly is developing necitumumab (Portrazza™), an intravenously administered fully human IgG monoclonal antibody directed against the epidermal growth factor receptor (EGFR), which is expressed in a variety of solid tumours and has been implicated in promoting oncogenesis and tumour progression. Necitumumab is approved as a part of combination therapy (with gemcitabine and cisplatin) in the USA for the first-line treatment of metastatic squamous non-small cell lung cancer (NSCLC), and regulatory submissions have been made in the EU for this same indication. Necitumumab was derived from the proprietary phage display library of Dyax Corp, and originated with ImClone Systems, which was acquired by Eli Lilly in November 2008. Necitumumab was also under phase II development for colorectal cancer in Belgium and Spain; however, no recent development has been reported for this indication. This article summarizes the milestones in the development of necitumumab leading to this first approval for the first-line treatment of metastatic squamous NSCLC, in combination with gemcitabine and cisplatin.

Ramucirumab (Ram) As Second-Line Treatment in Patients (Pts) with Advanced Hepatocellular Carcinoma (Hcc) Following First-Line Therapy with Sorafenib: Results from the Randomized Phase III Reach Study

ABSTRACT Aim: Vascular endothelial growth factor (VEGF) and VEGF-receptor 2-mediated signaling and angiogenesis likely contribute to HCC pathogenesis. RAM is a fully human IgG1 monoclonal antibody and a VEGF-receptor 2 antagonist. Methods: Eligible pts had advanced HCC, stage BCLC C or B refractory or not amenable to locoregional therapy; Child-Pugh A; ECOG PS 0 or 1; intolerance to sorafenib despite dose reduction, or disease progression during or following sorafenib; and adequate hematologic and biochemical parameters. Pts were randomized 1:1 to receive RAM (8 mg/kg IV) plus best supportive care (BSC) or placebo (PBO) plus BSC every 2 weeks until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. The sample size of 544 pts was calculated to enable 85% power to demonstrate statistical significance at an overall two-sided alpha of 0.05, assuming a hazard ratio (HR) of 0.75. Results: Between Nov 2010 and April 2013, 565 eligible pts were randomized (RAM 283; PBO 282). Baseline pt characteristics were balanced between arms. The OS HR was 0.866 (95% CI 0.717, 1.046; p = 0.1391); median OS was 9.2m for RAM vs 7.6m for PBO. Median PFS with RAM and PBO was 2.8m and 2.1m, respectively (HR 0.63, 95% CI 0.52–0.75; p 5% of treated RAM pts included: hypertension (12.3% RAM arm vs 3.6% PBO arm), asthenia (5.1% vs 1.8%), aspartate aminotransferase increased (5.4% vs 8.3%), and malignant neoplasm progression (6.5% vs 4.0%). In 250 pts with baseline alpha-fetoprotein (AFP) ≥400 ng/mL (pre-specified), OS HR was 0.67 (95% CI 0.51–0.90; p=0.0059) median OS was 7.8m for RAM vs 4.2m for PBO. Conclusions: No new safety signals were observed. The primary end point was not met. In a selected pt population with an elevated baseline AFP, a meaningful OS improvement in the RAM arm was observed. The relationship between AFP and RAM benefit warrants further investigation. Disclosure: J.F. Blanc: reports personal fees from Imclone systems / Lilly, during the conduct of the study; T.E. Pfiffer: reports Lilly, the sponsor of REACH trial, gave financial support to Instituto do Cancer do Estado de Sao Paulo ICESP to run part of the trial, during the conduct of the study; personal fees from Lilly, outside the submitted work; T. Okusaka: received grant money and personal fees from Eli Lilly. Relevant financial activities outside the submitted work include grant money and personal fees from several companies; J. Trojan: reports participation as a speaker and on the advisory board for Eli Lilly; J. Sastre: reports receiving personal fees for lectures from Eli Lilly, Roche, Merck, Bayer, Sanofi, and MSD; I. Chau: received research support from Eli Lilly & Co, honorarium from ImClone LLC and Eli Lilly & Co., has also been a consultant, received payment for lectures, educational presentations, and travel and meeting expenses from several other companies; S. Chang and P.B. Abada: is an employee of and has stock ownership in Eli Lilly & Co.; L. Yang: is an employee of ImClone Systems, a wholly owned subsidiary of Eli Lilly and Co., and has stock ownership in Eli Lilly and Co.; J. Schwartz: was an employee of Imclone Systems and has stock ownership in Eli Lilly. All other authors have declared no conflicts of interest.

Ramucirumab: first global approval.

Ramucirumab (Cyramza™ [US]), a fully human immunoglobulin G1 (IgG1) monoclonal antibody that inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), has been developed by Eli Lilly (formerly ImClone Systems) for the treatment of cancer. Ramucirumab has received its first global approval in the US for use as monotherapy in the treatment of advanced or metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma in patients who experience disease progression on or after fluoropyrimidine- or platinum-containing chemotherapy. Ramucirumab is the first treatment to be approved by the US FDA for this setting. This article summarizes the milestones in the development of ramucirumab leading to this first approval for the treatment of gastric cancer and gastro-oesophageal junction adenocarcinoma.

Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial

No standard treatment exists for refractory or relapsed advanced thymic epithelial tumours. We investigated the efficacy of cixutumumab, a fully human IgG1 monoclonal antibody targeting the insulin-like growth factor 1 receptor in thymic epithelial tumours after failure of previous chemotherapy. Between Aug 25, 2009, and March 27, 2012, we did a multicentre, open-label, phase 2 trial in patients aged 18 years or older with histologically confirmed recurrent or refractory thymic epithelial tumours. We enrolled individuals who had progressed after at least one previous regimen of platinum-containing chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had measurable disease and adequate organ function. Eligible patients received intravenous cixutumumab (20 mg/kg) every 3 weeks until disease progression or development of intolerable toxic effects. The primary endpoint was the frequency of response, analysed on an intention-to-treat basis. We also did pharmacodynamic studies. This trial is registered with ClinicalTrials.gov, number NCT00965250. 49 patients were enrolled (37 with thymomas and 12 with thymic carcinomas) who received a median of eight cycles of cixutumumab (range 1-46). At the final actuarial analysis when follow-up data were updated (Nov 30, 2012), median potential follow-up (from on-study date to most current follow-up date) was 24·0 months (IQR 17·3-36·9). In the thymoma cohort, five (14%) of 37 patients (95% CI 5-29) achieved a partial response, 28 had stable disease, and four had progressive disease. In the thymic carcinoma cohort, none of 12 patients (95% CI 0-26) had a partial response, five had stable disease, and seven had progressive disease. The most common grade 3-4 adverse events in both cohorts combined were hyperglycaemia (five [10%]), lipase elevation (three [6%]), and weight loss, tumour pain, and hyperuricaemia (two each [4%]). Nine (24%) of 37 patients with thymoma developed autoimmune conditions during treatment (five were new-onset disorders), the most common of which was pure red-cell aplasia. Two (4%) patients died; one was attributed to disease progression and the other to disease-related complications (respiratory failure, myositis, and an acute coronary event), which could have been precipitated by treatment with cixutumumab. Cixutumumab monotherapy is well-tolerated and active in relapsed thymoma. Development of autoimmunity during treatment needs further investigation. Division of Cancer Treatment and Diagnosis at the National Cancer Institute (National Institutes of Health), ImClone Systems.

Docetaxel or pemetrexed with or without cetuximab in recurrent or progressive non-small-cell lung cancer after platinum-based therapy: a phase 3, open-label, randomised trial

Available preclinical and phase 2 clinical data suggest that the addition of cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (EGFR), to chemotherapy might improve outcome in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to assess whether the addition of cetuximab to chemotherapy improved progression-free survival in patients with recurrent or progressive NSCLC after platinum-based therapy. In this unmasked, open-label randomised phase 3 trial we enrolled patients with metastatic, unresectable, or locally advanced NSCLC from 121 sites in Canada and the USA. Eligible patients were those aged 18 years or older who had experienced progressive disease during or after one previous platinum-based regimen. Initially, patients were randomly assigned to receive either pemetrexed (500 mg/m(2)) or docetaxel (75 mg/m(2)) and then randomly assigned within each group to receive their chemotherapy with or without cetuximab (400 mg/m(2) at first dose and 250 mg/m(2) weekly thereafter) until disease progression or unacceptable toxicity. However, after a change in the standard of care, investigators chose whether to treat with pemetrexed or docetaxel on a patient-by-patient basis. The primary analysis was changed to compare progression-free survival with cetuximab plus pemetrexed versus pemetrexed, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00095199. Between Jan 10, 2005, and Feb 10, 2010, we enrolled 939 patients; data for one patient was accidentally discarded. Of the remaining 938 patients, 605 received pemetrexed (301 patients with cetuximab and 304 alone) and 333 received docetaxel (167 in combination with cetuximab and 166 alone). Median progression-free survival with cetuximab plus pemetrexed was 2·9 months (95% CI 2·7-3·2) versus 2·8 months (2·5-3·3) with pemetrexed (HR 1·03, 95% CI 0·87-1·21; p=0·76). The most common grade 3-4 adverse events with cetuximab plus pemetrexed were fatigue (33 [11%] of 292 patients), acneiform rash (31 [11%]), dyspnoea (29 [10%]), and decreased neutrophil count (28 [10%]), and with pemetrexed alone were dyspnoea (35 [12%] of 289 patients), decreased neutrophil count (26 [9%]), and fatigue (23 [8%]). A significantly higher proportion of patients in the cetuximab plus pemetrexed group (119 [41%] of 292 patients) experienced at least one serious adverse event than those patients in the pemetrexed group (85 [29%] of 289 patients; p=0·0054). Nine (3%) of 292 treated patients in the cetuximab and pemetrexed group died of adverse events compared with five (2%) of 289 treated patients in the pemetrexed alone group. The use of cetuximab is not recommended in combination with chemotherapy in patients previously treated with platinum-based therapy. Eli Lilly and Company and ImClone Systems LLC, a wholly owned subsidiary of Eli Lilly and Company.

Complexions of compliance

Division of Hematology Oncology Massachusetts General Hospital Boston, Massachusetts Financial disclosure/conflicts of interest: R.T.P. has served in the scientific advisory boards of Genentech Inc., AstraZeneca, Lifecore Biomedical, Biomarin Pharmaceuticals Inc., Clovis Oncology, and Seattle Genetics, and has received research funding from ImClone Systems Inc., Endocyte Inc., AstraZeneca, Eisai Inc., and Amgen Inc.

1287P - Final Results of a Phase 2, Open-Label Study of Ramucirumab (IMC-1121B; RAM), an IGG1 MAB Targeting Vegfr-2, with Paclitaxel and Carboplatin as First-Line Therapy in Patients (PTS) with Stage IIIB/IV Non-Small Cell Lung Cancer (NSCLC) (NCT00735696)

ABSTRACT Background VEGF-mediated angiogenesis contributes to NSCLC pathogenesis. RAM is a recombinant human mAb that binds the extracellular domain of the vascular endothelial growth factor receptor-2 (VEGFR-2) and inhibits cancer growth in diverse preclinical models. Methods Pts with advanced NSCLC (Stage IIIb not suitable for locoregional therapy or Stage IV) were eligible. Squamous histology and treated brain metastases were allowed. Exclusion criteria included prior bevacizumab, blood vessel invasion, intratumor cavitation, and recent gross hemoptysis. Pts received RAM 10 mg/kg, paclitaxel 200 mg/m2, and carboplatin AUC = 6 on Day 1 of a 3-week cycle for up to 6 cycles, followed by maintenance RAM. The primary endpoint was PFS at 6 months (m); secondary/exploratory endpoints were safety, ORR, OS rate at 1 year, PK/PD profiles, and immunogenicity. Results 40 pts were treated (15M:25F; median age 60; 39 nonsquamous / 1 squamous); all have discontinued. 39 pts were evaluable for response. 22 of 40 treated pts had an objective response (1 CR, 21 PR; ORR = 55%). 14 pts had a best response of SD. Median PFS was 7.85 m (95% CI: 5.49 m-9.86 m), and the PFS rate at 6 m was 62.5% (90% CI: 48.3%-75.3%); the 1-year survival rate was 74.6% (95% CI: 57.9%-85.4%). 34 of 40 pts (85%) reported an AE at least possibly related to RAM; the most common related AEs were fatigue (53%), peripheral neuropathy (33%), nausea (28%), myalgia (23%), and epistaxis (23%). Related AEs of Gr ≥ 3 were reported for 15 pts; the most common were neutropenia (5 pts), thrombocytopenia (4 pts), fatigue, febrile neutropenia (3 pts each), peripheral neuropathy and pulmonary embolism (2 pts each). There were 5 pts with a total of 6 Gr 4 related events: febrile neutropenia, pulmonary embolism (2 pts each), neutropenia and thrombocytopenia (1 pt each). Conclusions RAM in combination with paclitaxel and carboplatin shows promising efficacy based on the overall disease control rate (CR + PR + SD) reaching 90% and PFS rate at 6 m of 62.5%, and is well tolerated by patients with NSCLC. Disclosure D.R. Camidge: I have received research funding from Eli Lilly and Company and honoraria from ImClone Systems. R.C. Doebele: Research Funding: ImClone Systems, Eli Lilly & Co., Pfizer Inc. Honoraria: Boehringer Ingelheim, Abbott Laboratories, Pfizer Inc Stock: Ariad ( M. Ballas: I now have an employment position at Bristol Myers Squibb (BMS), own T. Jahan: I have received additional research funding from Eli Lilly & Co. for other trials, as well as research funding from Morphotek, Pfizer, and Genentech. I have no speaker or consultant income to disclose. S. Yurasov: Employed by ImClone/Eli Lilly; own Lilly stock. All other authors have declared no conflicts of interest.

1245P - A Phase 2 Randomized Open-Label Study of Ramucirumab (IMC 1121b; RAM) in Combination with Platinum-Based Chemotherapy in Patients (PTS) with Recurrent or Advanced Non-Small Cell Lung Cancer (NSCLC): Results From Non-Squamous (NSQ) PTS (NCT01160744)

ABSTRACT Background Vascular endothelial growth factor (VEGF)-mediated angiogenesis plays an important role in NSCLC pathogenesis. RAM is a fully human IgG1 monoclonal antibody that inhibits VEGF receptor-2 (VEGFR-2) binding and signaling. This study investigates RAM in combination with first-line platinum-based chemotherapy in advanced NSCLC. Methods NSQ pts with Stage IV NSCLC, ECOG PS ≤ 2, adequate hematologic, hepatic and renal function were randomized to either Arm A: pemetrexed + carboplatin/cisplatin or Arm B: RAM + pemetrexed + carboplatin/cisplatin, once every 3 weeks. The primary analysis will be when 103 progression-free survival (PFS) events are observed in NSQ pts. This pre-planned interim analysis was performed when 61 NSQ PFS events were observed. Other interim endpoints: objective response rate, disease control rate (DCR), and safety. Results Arm A (n = 71) median (medn) age 64, 63% male (M), 37% female (F), ECOG PS 0-1 / 2 (91.6% / 5.6%). Arm B (n = 69) medn age 64, 52% M, 48% F, ECOG PS 0-1 / 2 (89.9% / 7.2%). Interim efficacy analyses Arm A (N = 71) n (%) Arm B (N = 69) n (%) PFS Events Censored Median (months) 90% CI 37 (52) 34 (48) 4.3 (3.8, 5.7) 24 (35) 45 (65) 6.3 (5.7, -) Best Response PR SD DCR (SD + PR) 26 (37) 25 (35) 51 (72) 30 (44) 30 (44) 60 (88) Nonhematologic adverse events (AEs) were fatigue (61%; 17% Grade[G]3), nausea (55%; 7% G3), vomiting (36%; 4% G3), constipation (30%; 1% G3), hypertension (HTN) (6%; 1% G3), proteinuria (4%; 0 G3), on Arm A; fatigue (63%; 12% G3), nausea (51%; 10% G3), vomiting (33%; 8% G3), constipation (27%; 0 G3), HTN (19%; 10% G3), proteinuria (5%; 0 G3) on Arm B. Hematologic AEs were anemia (A) (55%; 16% G3), neutropenia (N) (23%; 16% G3), thrombocytopenia (T) (23%; 12% G3) on Arm A; A (39%; 8% G3), N (33%; 13% G3), T (31%; 15% G3) on Arm B. Conclusions Based on interim analyses of PFS and acceptable tolerability and safety, RAM may provide clinical benefit in combination with first-line platinum-based chemotherapy in NSQ NSCLC. Enrollment of pts in squamous Arms C and D is ongoing. Disclosure R. Doebele: Research funding: ImClone Systems, Eli Lilly & Co., Pfizer Inc. Honoraria: Boehringer Ingelheim, Abbott Laboratories, Pfizer Inc. Stock: Ariad ( M. Reck: Honoraria for Lectures: Lilly, Hoffmann-La Roche, AstraZeneca, Daiichi-Sankyo Advisory Board (compensated): Lilly, Hoffmann-La Roche, AstraZeneca, Daiichi-Sankyo, Pfizer, Merck, BMS. S. Verma: Advisory Board and honoraria from Eli Lilly. S. Yurasov: I am employed by Eli Lilly and own Lilly stock. D.R. Camidge: Advisory role and honoraria: ImClone Reserach Funding: Eli Lilly. All other authors have declared no conflicts of interest.

Preliminary Data from a Multicenter, Phase II, Randomized, Non-Comparative Clinical Trial of Radiation and Temozolomide with or without Vandetanib in Newly-Diagnosed Glioblastoma (GBM) (S45.006)

Objective: We conducted a randomized phase II study of vandetanib in patients with newly-diagnosed GBM in combination with radiation (RT) and temozolomide (TMZ). Background EGFR and VEGFR signaling have been implicated in the development and growth of GBM. In addition, angiogenesis inhibitors may enhance radiation sensitivity. Vandetanib is an inhibitor of VEGFR-2 and EGFR tyrosine kinase activities. Design/Methods: We planned to randomize a total of 114 newly-diagnosed GBM patients in a ratio of 1:2 to Arm A: RT/TMZ or Arm B: vandetanib 100 mg daily + RT/TMZ. All pts received RT (60 Gy) and concurrent TMZ 75 mg/m 2 daily, followed by adjuvant TMZ for up to 12 cycles (150-200 mg/m 2 on days 1-5 of each 28 day cycle). Pts with age ≥ 18, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary endpoint was overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS) and safety. Results: We enrolled 106 pts (36 in Arm A, 70 in Arm B) with median age 59 yrs (range: 23-83) and median KPS 90 (range: 60-100). Most frequent Gr ≥ 3 AEs in the vandetanib arm were lymphopenia (20%), thrombosis (12.5%), transaminitis (8%) and leukopenia (5%). Preliminary median OS is 487 days with 95% CI (350, NR) in Arm A and 503 days with 95% CI (451, 634) in Arm B. Median PFS is 141 days with 95% CI (104. 252) in Arm A and 127 days with 95% CI (93. 165) in Arm B. Due to an unplanned interim analysis demonstrating no survival difference, enrollment was terminated early and the study was closed. Conclusions: Although reasonably well-tolerated, the addition of vandetanib to standard chemoradiation in newly-diagnosed GBM may not significantly prolong OS compared to the parallel control arm. Updated efficacy and toxicity data will be presented. Supported by: AstraZeneca. Disclosure: Dr. Lee has received personal compensation for activities with Norvartis and Genentech as an advisory board member.Dr. Lee has received personal compensation in an editorial capacity for UpToDate, Inc. Dr. Batchelor has received personal compensation for activities with Roche Diagnostics Corporation, Genentech, Inc., Merck & Co. Inc., and Millennium. Dr. Batchelor has received personal compensation in an editorial capacity for UpToDate Inc. Dr. Batchelor has received research support from Pfizer Inc, AstraZeneca Pharmaceuticals and Millennium. Dr. Kaley has nothing to disclose. Dr. Schiff has received personal compensation for activities with Novocure and Genentech. Dr. Schiff has received research support from Exelixis. Dr. Lassman has received personal compensation for activities with Schering-Plough Corp., ImClone Systems, Genentech, Inc., Eisai Inc., Cephalon, Inc., Physicians Education Resource, The Robert Michael Educational Institute, and Medical Communications Media.Dr. Lassman has received research support from Keryx Biopharmaceuticals, Genentech, and Schering Plough Corp. Dr. Wong has received research support from AstraZeneca Pharmaceuticals, Exelixis, Novartis and NovoCure as a researcher. Dr. Mikkelsen has received personal compensation for activities with Merck and Roche. Dr. Purow has nothing to disclose. Dr. Drappatz has nothing to disclose. Dr. Norden has nothing to disclose. Dr. Beroukhim has received personal compensation for activities with Novartis as a consultant. Dr. Beroukhim holds stock and/or stock options in AstraZeneca, which sponsored research in which Dr. Beroukhim was involved as an investigator. Dr. Beroukhim holds stock and/or stock options in Baxter, CareFusion, Edwards Lifesciences, and Cardinal Health. Dr. Beroukhim has received research support from Novartis. Dr. Weiss has received personal compensation for activities with a consulting firm as RT expert. Dr. Weiss has received research support from Aposence. Dr. Alexander has nothing to disclose. Dr. McCluskey has nothing to disclose. Dr. Gerard has nothing to disclose. Dr. Teulings has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Muzikansky has nothing to disclose. Dr. Wen has received personal compensation for activities with Merck & Co., and Novartis as consutant and/or speaker. Dr. Wen has received personal compensation in an editorial capacity for UptoDate. Dr. Wen has received research support from Amgen Inc, AstraZeneca Pharmaceuticals, Eisai Inc, Exelixis, Genentech, Inc., Medimmune, Merck & Co., Novartis, Sanofi-Aventis Pharmaceuticals and Vascular Biogenics.

Abstract 5296: The role of VEGF receptors 1 and 2 on tumor vascularization and progression in single VEGF isoform expressing tumors

Abstract Background Murine fibrosarcoma cell lines that express single VEGF isoforms (VEGF120 VEGF165 and VEGF188) and a wild-type control (VEGFWT) have been developed. The most extreme differences in vascular properties are observed between VEGF120 and VEGF188 tumors, with VEGF120 tumors developing more immature vessels. These differences impact on therapeutic outcome. We hypothesised that differential signaling through VEGF receptors 1 and 2 underlie the isoform-specific differences. Methods VEGFWT, VEGF120 and VEGF164 tumors were implanted sub-cutaneously (s/c), and VEGF188 tumors s/c or in dorsal skin-flap window-chambers (WC) in SCID mice. Mice were treated with ImClone neutralizing antibodies against VEGFR-1 (MF-1) or VEGFR-2 (DC101). Excised s/c tumors were stained for blood vessels (CD31), pericytes (αSMA), necrosis (H&E) or apoptosis (Caspase III). Tumor vascular development in WCs was imaged using intra-vital microscopy. Results VEGFWT and VEGF188 tumors were most sensitive to growth inhibition following treatment with DC101, whereas MF-1 had no effect on growth of any tumor type. In vitro, DC101 had no effect on proliferation of any tumor cell types. Immunohistochemical studies showed no changes in necrosis or apoptosis in VEGF120 tumors, but a significant decrease in vascular area with DC101. VEGF188 tumors showed no change in apoptosis, but both treatments increased necrosis. Vascular area was significantly reduced post DC101 treatment but significantly increased post MF-1 treatment. Both antibodies significantly increased αSMA staining, primarily due to myofibroblast infiltration. WC studies using VEGF188 tumors supported the effects observed with DC101, showing a significantly reduced blood vessel number and length. Furthermore, MF-1 treatment (either immediately post tumor implantation or to established tumors) resulted in more hemorrhagic tumors with large peripheral feeder vessels. Early DC101 treatment impaired tumor development, and once tumors developed on cessation of treatment, the vessels were highly chaotic. Conclusions DC101-induced tumor growth retardation, and corresponding vascular effects in VEGF188 tumors, confirms a role for VEGFR2 signaling in tumor progression and vascular development. However, the lack of growth effect in VEGF120 and VEGF164 tumors following treatment with either antibody suggests a level of receptor redundancy. MF-1 increased angiogenesis in VEGF188 tumors, despite no change in growth rate, and these neo-vessels appeared hemorrhagic, implying increased permeability. These data suggest a role for VEGFR-1 in tumor angiogenesis, involving vascular maturation, at least where VEGF188 is highly expressed. This may occur via specific VEGFR-1 signaling and/or sequestration of VEGF to control signaling via VEGFR-2. Acknowledgements Supported by CR-UK We thank ImClone Systems for providing MF-1 and DC101. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5296. doi:1538-7445.AM2012-5296

Blockade of Insulin-Like Growth Factor Type-1 Receptor with Cixutumumab (IMC-A12): A Novel Approach to Treatment for Multiple Cancers

Insulin-like growth factor type-1 receptor (IGF-1R) plays a central role in cell proliferation and survival and is overexpressed in many tumor types. Notably, IGF-1R-mediated signaling confers resistance to diverse cytotoxic, hormonal, and biologic agents, suggesting that therapies targeting IGF-1R may be effective against a broad range of human malignancies. Cixutumumab (IMC-A12; ImClone Systems) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically inhibits IGF-1R signaling. Binding of cixutumumab to IGF-1R results in receptor internalization and degradation. Because cixutumumab is an IgG1 monoclonal antibody, it may induce additional cytotoxicity via immune effector mechanisms such as antibody-dependent cellular cytotoxicity. In preclinical studies, cixutumumab monotherapy resulted in growth inhibition of multiple experimental cancers. Moreover, cixutumumab safely enhanced the tumor growth inhibitory and cytotoxic effects of a broad range of chemotherapeutics, and modulated the action of agents that target hormone receptors and signal transduction, which may have implications for cancer therapy. Herein, we review published preclinical and clinical data for cixutumumab and provide a comprehensive overview of selected clinical studies.

Abstract A145: EGFR-targeting of carbon nanovectors loaded with paclitaxel improves their antitumor efficacy and radiosensitization of head and neck squamous cell carcinoma in vivo.

Abstract Nanoparticels have been researched broadly as new generation of diagnostics, imaging agents, and drugs for detecting and treating cancer. We previously developed PEGylated small hydrophilic carbon clusters (PEG-HCCs) and reported that PEG-HCCs conjugated with paclitaxel (PTX/PEG-HCCs) is a stable effective drug delivery system with minimal toxicity. Here, we describe the establishment of targeted nanovectors by simply mixing PTX/PEG-HCCs with cetuximab (ImClone Systems), an anti-epidermal growth factor receptor (EGFR) monoclonal antibody. The specificity of this EGFR targeted method of delivery of PTX/PEG-HCCs was demonstrated in mice implanted subcutaneously on opposing flanks with EGFR expressing, OSC-19 (head and neck squamous cell carcinoma: HNSCC) cells and non-EGFR-expressing MCF-7 cells in a nude mouse. The targeted nanovector system, Cet/PTX/PEG-HCCs, showed greater efficacy superior than PTX/PEG-HCCs on OSC-19 tumor growth, but not on MCF-7 tumors. Cet/PTX/PEG-HCCs also showed greater growth inhibition prolonged survival compared to PTX or PTX/PEG-HCCs in an orthotopic nude mouse model of human HNSCC. These results suggested that Cet/PTX/PEG-HCCs can targeted to HNSCC overexpressing EGFR cells. In addition, Cet/PTX/PEG-HCCs were found to radiosensitize HNSCC cells both in vitro and in vivo. Cet/PTX/PEG-HCCs plus radiation inhibited tumor growth and prolonged survival in vivo. This work is highly significant as success would allow for targeted chemotherapy for HNSCC by simply mixing commercially available drugs and antibodies with a nanovector solution. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A145.

The Structural Basis for the Function of Two Anti-VEGF Receptor 2 Antibodies

The anti-VEGF receptor 2 antibody IMC-1121B is a promising antiangiogenic drug being tested for treatment of breast and gastric cancer. We have determined the structure of the 1121B Fab fragment in complex with domain 3 of VEGFR2, as well as the structure of a different neutralizing anti-VEGFR2 antibody, 6.64, also in complex with VEGFR2 domain 3. The two Fab fragments bind at opposite ends of VEGFR2 domain 3; 1121B directly blocks VEGF binding, whereas 6.64 may prevent receptor dimerization by perturbing the domain 3:domain 4 interface. Mutagenesis reveals that residues essential for VEGF, 1121B, and 6.64 binding are nonoverlapping among the three contact patches.

Association of rash with improved outcomes by the addition of cetuximab (C) to second-line mitoxantrone plus prednisone (MP) for progressive mCRPC after docetaxel-based chemotherapy.

e15040 Background: A previously reported phase II trial demonstrated that the addition of C, a chimeric monoclonal antibody that binds EGFR to MP for mCRPC following docetaxel did not extend overall time to progression (TTP) or overall survival (OS). In an unplanned analysis, we retrospectively analyzed the association of skin rash, a marker of biologic activity of C, with outcomes in CMP patients. Methods: The open-label phase II trial enrolled 115 patients with progressive mCRPC after docetaxel randomized 2:1 to CMP or MP. Therapy was M 12mg/m2 intravenously (IV) on Day 1, oral prednisone 10mg daily in both arms, and C 250mg/m2 IV (400mg/m2 Day 1, Cycle 1) on Days 1, 8, and 15 in the CMP arm. Cycles, a maximum of 10, were repeated every 21 days. Radiological assessments of disease and PSA occurred every 4 cycles. The primary endpoint was TTP defined as disease progression or death from any cause. 75 CMP patients were eligible for analyzing the association of rash with outcomes. Results: No MP arm patients developed rash. In the CMP arm, 51 patients (68%) had no rash, 24 (32%) had rash of any grade including 1 patient (1.3%) with grade 3 rash, and no grade 4 rash. Median TTP with and without rash was 10.3 months (95% CI: 5.4-11.8) vs 2.8 months (95% CI: 2.5-4.9), p(logrank)=0.004. Median survival with and without rash was 21.3 months (95% CI: 11.3-22.8) vs 9.3 months (95% CI: 5.3-12.3), p=0.01. On multivariable analysis including rash, baseline PSA (<median vs >/=median), performance status (0 vs 1-2) and visceral metastasis, rash was the only variable statistically significantly associated with TTP (HR=0.43, p=0.01), and demonstrating a trend for association with survival (HR=0.54, p=0.07). The overall CMP safety profile was consistent with profiles of components of study treatment. Conclusions: Patients with progressive mCRPC receiving CMP after docetaxel who developed rash demonstrated a significant extension of both TTP and OS. This finding is hypothesis-generating and may warrant the further study of higher doses of cetuximab coupled with pharmacodynamic and pharmacogenomic studies. Partially supported by ImClone Systems and Eli Lilly.

Insulin-like growth factor-I receptor (IGF-IR) targeting with monoclonal antibody cixutumumab (IMC-A12) inhibits IGF-I action in endometrial cancer cells

Specific insulin-like growth factor-I receptor (IGF-IR) targeting emerged in recent years as a promising therapeutic strategy in cancer. Endometrial cancer is the most common gynaecological cancer in the Western world. The aim of this study was to evaluate the potential of cixutumumab (IMC-A12, ImClone Systems), a fully human monoclonal antibody against the IGF-IR, to inhibit IGF-I-mediated biological actions and cell signalling events in four endometrial carcinoma-derived cell lines (ECC-1, Ishikawa, USPC-1 and USPC-2). Our results demonstrate that cixutumumab was able to block the IGF-I-induced autophosphorylation of the IGF-IR. In addition, the PI3K and MAPK downstream signalling pathways were also inactivated by cixutumumab in part of the cell lines. Prolonged (24 h and 48 h) exposures to cixutumumab reduced IGF-IR expression. Furthermore, confocal microscopy of GFP-tagged receptors shows that cixutumumab treatment led to IGF-IR redistribution from the cell membrane to the cytoplasm. Antiapoptotic effects were evaluated by cleavage of caspase 3 and PARP, and mitogenicity and transformation by proliferation and cell cycle assays. Results obtained showed that cixutumumab abrogated the IGF-I-stimulated increase in proliferation rate, and increased caspase-3 and PARP cleavage, two markers of apoptosis. Of importance, cixutumumab had no effect neither on insulin receptor (IR) expression nor on IGF-I activation of IR. In summary, in a cellular model of endometrial cancer cixutumumab was able to inhibit the IGF-I-induced activation of intracellular cascades, apoptosis and proliferation.

Ramucirumab (IMC-1121B): Monoclonal Antibody Inhibition of Vascular Endothelial Growth Factor Receptor-2

Angiogenesis, a well-recognized characteristic of malignancy, has been exploited more than any other pathway targeted by biologic anti-neoplastic therapies. Vascular endothelial growth factor receptor-2 (VEGFR-2) is the critical receptor involved in malignant angiogenesis with its activation inducing a number of other cellular modifications resulting in tumor growth and metastases. Ramucirumab (IMC-1121B; ImClone Systems Corporation, Branchburg, NJ) is a fully human monoclonal antibody developed to specifically inhibit VEGFR-2. Ramucirumab is currently being investigated in multiple clinical trials across a variety of tumor types. Herein, angiogenesis inhibition in cancer is reviewed and up-to-date information on the clinical development of ramucirumab is presented.

Butyrate-rich Colonic Microenvironment Is a Relevant Selection Factor for Metabolically Adapted Tumor Cells

The short chain fatty acid (SCFA) butyrate is a product of colonic fermentation of dietary fibers. It is the main source of energy for normal colonocytes, but cannot be metabolized by most tumor cells. Butyrate also functions as a histone deacetylase (HDAC) inhibitor to control cell proliferation and apoptosis. In consequence, butyrate and its derived drugs are used in cancer therapy. Here we show that aggressive tumor cells that retain the capacity of metabolizing butyrate are positively selected in their microenvironment. In the mouse xenograft model, butyrate-preselected human colon cancer cells gave rise to subcutaneous tumors that grew faster and were more angiogenic than those derived from untreated cells. Similarly, butyrate-preselected cells demonstrated a significant increase in rates of homing to the lung after intravenous injection. Our data showed that butyrate regulates the expression of VEGF and its receptor KDR at the transcriptional level potentially through FoxM1, resulting in the generation of a functional VEGF:KDR autocrine growth loop. Cells selected by chronic exposure to butyrate express higher levels of MMP2, MMP9, α2 and α3 integrins, and lower levels of E-cadherin, a marker for epithelial to mesenchymal transition. The orthotopic model of colon cancer showed that cells preselected by butyrate are able to colonize the animals locally and at distant organs, whereas control cells can only generate a local tumor in the cecum. Together our data shows that a butyrate-rich microenvironment may select for tumor cells that are able to metabolize butyrate, which are also phenotypically more aggressive.

Companion diagnostic development and commercialization: The good, the bad, and the ugly

Abstract QIAGEN (formerly DxS Ltd) has established itself as the market leader in the successful co-development of drug-diagnostic solutions with pharmaceutical partners. QIAGEN has a considerable portfolio of over 15 ongoing collaborations with drug giants such as Amgen, AstraZeneca, Bristol-Myers Squibb and ImClone Systems, Pfizer and Boehringer Ingelheim. This presentation will outline the current state of companion diagnostics as a driver of personalized healthcare; investigate the regulatory and commercial hurdles involved in bringing a companion diagnostic to market and the importance of pharma partnering during clinical development as a way to overcome these hurdles, as well as discuss some of the challenges inherent to companion diagnostic partnerships. Focusing on two of QIAGEN's key experiences with companion diagnostic development for cancer, the presentation will look first at the KRAS story and the challenge of producing the first companion diagnostic of its kind — the TheraScreen®: K-RAS Mutation Kit to predict patient response to metastatic colorectal cancer therapies Vectibix® (Amgen) and Erbitux® (BMS/Imclone Systems) based on the mutation status of the KRAS oncogene. Next, it will examine the importance of another companion diagnostic, the TheraScreen: EGFR29 Mutation Test Kit and its role in facilitating the marketing approval of AstraZeneca's non-small cell lung cancer drug IRESSA® in Europe for EGFR mutation positive patients. With the global perspective on personalized healthcare shifting and pharma recognizing the importance of independent partners for the co-development of drug and diagnostic, the obstacles to bringing companion diagnostic tests to market have shifted. While victories have been won winning the hearts and minds of drug companies, regulators and physicians in key markets like oncology, we are now fighting for value-based reimbursement so that predictive tests can be made available patients and expand the utility of companion diagnostics to new therapeutic areas. The personalized healthcare landscape is set to continue its rapid evolution to meet these new challenges.