Incorporation of bevacizumab (B) and erlotinib (Er) with induction (Ind) and concurrent (Conc) carboplatin (Cb)/paclitaxel (P) and 74 Gy of thoracic radiotherapy in stage III non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7528-7528
Author(s):  
M. A. Socinski ◽  
T. E. Stinchcombe ◽  
J. S. Halle ◽  
D. T. Moore ◽  
W. J. Petty ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase Ii ◽  
Growth Factor Receptor ◽  
Conformal Radiotherapy ◽  
Vascular Endothelial ◽  
Treatment Paradigm ◽  
Epidermal Growth ◽  
Grade 3 ◽  
Endothelial Growth Factor ◽  
Pet Scans

7528 Background: Therapies directed at both the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathways have been shown to improve survival in NSCLC and also have radiosensitizing properties. Methods: Pts receive Ind Cb (AUC 6), P (225 mg/m2) and B (15 mg/kg) on d1 and 22. PET scans are done pre- and post-I. On day 43, pts receive weekly Cb (AUC 2 x 7) and P (45 mg/m2 x 7) with 74 Gy (2 Gy/d) of thoracic conformal radiotherapy (TCRT). Cohort I (n=5) received B at 10 mg/kg q2wks during C therapy. Cohorts II and III (both n=5) received the same dose of B as in cohort I but also received Er at 100 mg and 150 mg po Tuesday - Friday of each week of C therapy, respectively. The primary endpoint is PFS at 1 year. All histologies are allowed including squamous (SQ) (an early stopping rule is in place for pulmonary hemorrhagic (PH) complications in SQ pts). Results: Thus far, 31 eligible PS 0–1 pts have been accrued (med age 62 yrs, range 41–74, 19 non- squamous, 12 SQ, 63% IIIA, 37% IIIB). Ind CbP + B has been well tolerated (1 gr 3 hypertension). No PH during Ind has been seen (including the 12 SQ cell pts). Response after Ind, 37% PR, 59% SD, 4% PD. Tumor volumes and PET SUVs have significantly decreased comparing pre- and post-Ind studies (p=0.0001 and p=0.0002, respectively). Cohort II has been expanded as the phase II regimen. To date, 25 of 26 (96%) pts have achieved the dose of 74 Gy (1 pt stopped at 60 Gy due to ILD). During Conc therapy, the principal toxicity has been esophagitis (53.8% gr 2, 19.2% gr 3). One grade 3 PH occurred in 1 SQ pt. One gr 5 late (> 2 mos after treatment) PH occurred in a SQ pt. Overall response rate following treatment - 68.2% (95% CI, 45–86%). The PFS at 1 year is 58% (95% CI, 34–76%) with an estmated 1-year overall survival rate of 79% (95% CI, 53–92%) which compares favorably to our historical experience. Conclusions: Preliminarily, we conclude that 1) Incorporation of B and E into this treatment paradigm appears feasible, 2) Esophagitis remains the primary toxicity, 3) Phase II accrual continues but early analysis of survival appears promising. Further details regarding the TCRT parameters and toxicity will be presented. [Table: see text]

Cetuximab plus bevacizumab in patients (pts) with metastatic colorectal cancer (mCRC) who have failed on irinotecan, oxaliplatin and fluoropyrimidines-based chemotherapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14576-14576 ◽  
Author(s):  
J. Souglakos ◽  
K. Kalbakis ◽  
N. Vamvakas ◽  
A. Kalykaki ◽  
A. Kotsakis ◽  
...  
Keyword(s):  
Growth Factor ◽  
Growth Control ◽  
Growth Factor Receptor ◽  
Hematological Toxicity ◽  
Vascular Endothelial ◽  
Chemotherapeutic Drugs ◽  
Epidermal Growth ◽  
Grade 3 ◽  
Ecog Ps ◽  
Endothelial Growth Factor

14576 Background: Bevacizumab (AVASTIN®) and Cetuximab (ERBITUX®) are IgG1 monoclonal antibodies targeting the Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR), respectively. Both are active in mCRC pts as first and/or second line treatment. Preclinical data suggest potentially synergistic effect for the combination of the two antibodies. This phase II trial evaluates the safety and efficacy of cetuximab combined with Bevacizumab in the treatment of mCRC pts who have failed on Irinotecan, Oxaliplatin and Fluoropyrimidines-based chemotherapy. Methods: mCRC pts with ECOG PS = 2 who had refractory disease to all three active chemotherapeutic drugs were enrolled. Determination of EGFR status was not mandatory. Cetuximab was given at an initial dose of 400mg/m2, then 250mg/m2 iv weekly; Bevacizumab was administered at a dose of 10 mg/kg on d1 every 2 weeks. Results: From June 2005 to November 2006, 14 pts were enrolled. Median age was 65 years, and median PS was 1. Treatment was 3rd-line in 5 pts, and = 4th-line for 7 patients. 12 pts had received prior treatment with Cetuximab and 6 were Bevacizumab. Thirty-nine cycles were administered with a median of 3 cycles/patient. All pts were evaluable for toxicity and response. No grade 3–4 hematological toxicity was observed. Non-hematological toxicities included grade 3 fatigue (7.1%), grade 2 diarrhea (7.1%), grade 2 allergic reactions (14.1%). Amongst the 14 patients evaluable for response, there was 1 objective PR (7.1%; 95% CI: 6- 24%), and 2 (14.2%) SD (tumor growth control rate, TGCR: 21.3%). The median time to progression was 2.4 months and the median survival has not yet been reached. The estimated probability for 1-year survival was 65.7%. Conclusions: The combination of Cetuximab plus Bevacizumab in patients with mCRC refractory or resistant all active chemotherapeutic drugs is safe and has promising activity. No significant financial relationships to disclose.

Phase I/II Trial Evaluating the Anti-Vascular Endothelial Growth Factor Monoclonal Antibody Bevacizumab in Combination With the HER-1/Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib for Patients With Recurrent Non–Small-Cell Lung Cancer

2005 ◽  
Vol 23 (11) ◽  
pp. 2544-2555 ◽  
Author(s):  
Roy S. Herbst ◽  
David H. Johnson ◽  
Eric Mininberg ◽  
David P. Carbone ◽  
Ted Henderson ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase I ◽  
Phase Ii ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
Endothelial Growth Factor

Purpose Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody. Erlotinib HCl (Tarceva, OSI-774; OSI Pharmaceuticals, New York, NY) is a potent, reversible, highly selective and orally available HER-1/epidermal growth factor receptor tyrosine kinase inhibitor. Preclinical data in various xenograft models produced greater growth inhibition than with either agent alone. Additionally, both agents have demonstrated benefit in patients with previously treated non–small-cell lung cancer (NSCLC). Patients and Methods A phase I/II study in two centers examined erlotinib and bevacizumab (A+T) in patients with nonsquamous stage IIIB/IV NSCLC with ≥ one prior chemotherapy. In phase I, erlotinib 150 mg/day orally plus bevacizumab 15 mg/kg intravenously every 21 days was established as the phase II dose, although no dose-limiting toxicities were observed. Phase II assessed the efficacy and tolerability of A+T at this dose. Pharmacokinetic parameters were evaluated. Results Forty patients were enrolled and treated in this study (34 patients at phase II dose); the median age was 59 years (range, 36 to 72 years), 21 were female, 30 had adenocarcinoma histology, nine were never-smokers, and 22 had ≥ two prior regimens (three patients had ≥ four prior regimens). The most common adverse events were mild to moderate rash, diarrhea, and proteinuria. Preliminary data showed no pharmacokinetic interaction between A+T. Eight patients (20.0%; 95% CI, 7.6% to 32.4%) had partial responses and 26 (65.0%; 95% CI, 50.2% to 79.8%) had stable disease as their best response. The median overall survival for the 34 patients treated at the phase II dose was 12.6 months, with progression-free survival of 6.2 months. Conclusion Encouraging antitumor activity and safety of A+T support further development of this combination for patients with advanced NSCLC and other solid tumors.

Fortgeschrittenes medulläres Schilddrüsenkarzinom: Vandetanib verbessert das progressionsfreie Überleben

2012 ◽  
Vol 03 (02) ◽  
pp. 93-92
Author(s):  
Alexander Kretzschmar
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Phase Iii ◽  
Vascular Endothelial ◽  
Medulläres Schilddrüsenkarzinom ◽  
Epidermal Growth ◽  
Endothelial Growth Factor

Vandetanib ist ein oraler Hemmer des RET-Kinase-, VEGF (Vascular Endothelial Growth Factor Receptor)- und EGFR (Epidermal Growth Factor Receptor)-Signalwegs. In einer zulassungsrelevanten, randomisierten, doppelblinden, placebokontrollierten Phase- III-Studie verlängerte der Tyrosinkinasehemmer das progressionsfreie Überleben (PFS) signifikant länger als Placebo.

scholarly journals Vascular Endothelial Growth Factor Plus Epidermal Growth Factor Receptor Dual Targeted Therapy in Metastatic Colorectal Cancer: Synergy or Antagonism?

2009 ◽  
Vol 2009 ◽  
pp. 1-9 ◽  
Author(s):  
John L. Marshall
Keyword(s):  
Colorectal Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Efficacy And Safety ◽  
First Line ◽  
Epidermal Growth ◽  
Endothelial Growth Factor

There has been an intensive effort to develop novel therapies for the treatment of metastatic colorectal cancer (mCRC). The anti-epidermal growth factor receptor (EGFR) antibodies panitumumab and cetuximab and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab have demonstrated clinical efficacy and acceptable toxicity in the treatment of mCRC as single agents or in combination with chemotherapy. Recent clinical trials have explored the efficacy and safety of treatment regimens incorporating chemotherapy in combination with bevacizumab and either panitumumab or cetuximab in patients with mCRC. Results from the BOND-2 trial, which investigated cetuximab, bevacizumab, and chemotherapy in mCRC, provided support for this therapeutic approach. Two large randomized phase 3 trials were initiated to evaluate firstline treatment of mCRC. The Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study investigated the efficacy and safety of oxaliplatin- or irinotecan-based chemotherapy and bevacizumab with or without panitumumab; CAIRO2 assessed the efficacy and safety of capecitabine/oxaliplatin and bevacizumab with or without cetuximab. In both trials, the combination of bevacizumab, an EGFR-specific antibody, and chemotherapy in first-line treatment of mCRC was associated with increased toxicity and no improvement in patient outcome. These results suggest that these specific combinations should not be used in first-line mCRC outside investigational studies.

scholarly journals Quantifying the strength of heterointeractions among receptor tyrosine kinases from different subfamilies: Implications for cell signaling

2020 ◽  
Vol 295 (29) ◽  
pp. 9917-9933 ◽  
Author(s):  
Michael D. Paul ◽  
Hana N. Grubb ◽  
Kalina Hristova
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Eph Receptor ◽  
Vital Cell ◽  
Cell Processes ◽  
Epidermal Growth ◽  
Endothelial Growth Factor

Receptor tyrosine kinases (RTKs) are single-pass membrane proteins that control vital cell processes such as cell growth, survival, and differentiation. There is a growing body of evidence that RTKs from different subfamilies can interact and that these diverse interactions can have important biological consequences. However, these heterointeractions are often ignored, and their strengths are unknown. In this work, we studied the heterointeractions of nine RTK pairs, epidermal growth factor receptor (EGFR)–EPH receptor A2 (EPHA2), EGFR–vascular endothelial growth factor receptor 2 (VEGFR2), EPHA2–VEGFR2, EPHA2–fibroblast growth factor receptor 1 (FGFR1), EPHA2–FGFR2, EPHA2–FGFR3, VEGFR2–FGFR1, VEGFR2–FGFR2, and VEGFR2–FGFR3, using a FRET-based method. Surprisingly, we found that RTK heterodimerization and homodimerization strengths can be similar, underscoring the significance of RTK heterointeractions in signaling. We discuss how these heterointeractions can contribute to the complexity of RTK signal transduction, and we highlight the utility of quantitative FRET for probing multiple interactions in the plasma membrane.

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