Abstract LB-220: Translational research with RG7160 (GA201) leads to a phase II clinical study in combination with FOLFIRI in 2nd line metastatic colorectal cancer (mCRC)
| العنوان: | Abstract LB-220: Translational research with RG7160 (GA201) leads to a phase II clinical study in combination with FOLFIRI in 2nd line metastatic colorectal cancer (mCRC) |
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| المؤلفون: | Christoph Mancao, David Oppenheim, Ben Markman, David Carlile, Giuseppe Aprile, Antonio Cubillo, Salvatore Siena, Sophia Soehrman, John Bridgewater, Chrstian Gerdes, Jon Chick, Alexandre Passioukov, Josep Tabernero, Luigi Manenti, Carles Pericay, Jean-Charles Soria, Maria Longauer Banholzer, Andrés Cervantes, L. Arés, Stéphane Temam, Sophie Golding, Ashita Waterston |
| المصدر: | Cancer Research. 72:LB-220 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Oncology, Cancer Research, medicine.medical_specialty, Chemotherapy, Cetuximab, Colorectal cancer, business.industry, medicine.medical_treatment, medicine.disease, medicine.disease_cause, Irinotecan, Fluorouracil, Internal medicine, Immunology, medicine, FOLFIRI, Biomarker (medicine), KRAS, business, medicine.drug |
| الوصف: | GA201 is a novel dual-acting humanized, engineered IgG1 anti-EGFR mAb designed to enhance ADCC in combination with signaling inhibition. Superior efficacy was demonstrated versus cetuximab in orthotopic CRC xenograft models. Preclinical data indicated an increase in macrophages (4-5 fold) and NK cells (2-3 fold) infiltration in tumors treated with GA201 compared to cetuximab. In a phase I clinical study objective responses and long lasting disease stabilizations were observed. A marked reduction in circulating NK cells and an increased infiltration of immune cells into skin rash was seen. Preliminary evidence of the enhanced ADCC capacity of GA201 was investigated in 25 third line patients with KRAS-mutant mCRC. Best overall response was SD in 40% of patients and median OS was 9.4 months. Reduction in peripheral NK cells and regulatory T-cells was observed. Comparison of pre- and post-treatment tumour biopsies revealed that tumour-infiltrating immune cells, in particular CD68+ and CD3+ cells increased overall. EGFR-membrane staining in baseline tumour biopsies was markedly higher than in the corresponding archival tumour specimens (median H-score 52 vs 3, respectively), which might reflect technical, but most importantly, biological variability. Based on these results and the commitment to investigate the tumor immune infiltration profile as a potential predictive biomarker, a fresh tumor biopsy at baseline was mandated in the ongoing randomized phase II trial (GAIN-C). This compares GA201 plus irinotecan, infusional fluorouracil and leucovorin (FOLFIRI) with FOLFIRI alone in KRAS-mutant 2nd line mCRC patients and with cetuximab plus FOLFIRI in KRAS-wild type patients (n=160). Primary objective is PFS. The fresh tumor biopsy will be centrally analyzed for EGFR and KRAS. A comprehensive biomarker program was implemented to investigate potential predictive biomarkers, with an emphasis on the real time tumor immune-infiltration status. The safety run-in phase with 36 patients was completed. Most common treatment related AEs on GA201 arms vs cetuximab vs. chemotherapy included (≥ grade 3): rash (33 vs. 17 vs. 0%), IRR (10 vs. 0 vs. 0%), diarrhea (17 vs. 0 vs. 11%), fatigue/asthenia (0 vs. 17 vs. 0%), hypomagnesaemia (17 vs. 0 vs. 0%), stomatitis (17 vs. 0 vs. 0%) and vomiting/nausea (6 vs. 0 vs. 0%). So far, no patient discontinued due to EGFR-related skin toxicity. Immunological profiling is ongoing. Extensive research efforts, including a fresh tumor biopsy in second line mCRC patients, are taken to understand the immunological mechanism of action of GA201 and to select and test (ph. II) and validate (ph. III) potential predictive biomarkers. To guide personalized cancer immunotherapies there is a clear need for reliable biomarkers which would necessitate a tumor assessment directly prior to the therapy and immune monitoring throughout treatment. 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 LB-220. doi:1538-7445.AM2012-LB-220 |
| تدمد: | 1538-7445 0008-5472 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::9d1b9f3ff137f7949b412aed9ea88d78Test https://doi.org/10.1158/1538-7445.am2012-lb-220Test |
| رقم الانضمام: | edsair.doi...........9d1b9f3ff137f7949b412aed9ea88d78 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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