11 augustus 2018: Zie ook dit artikel:

https://kanker-actueel.nl/plaats-van-de-primaire-tumor-bij-uitgezaaide-darmkanker-geeft-grote-verschillen-in-overall-overleving-bij-patienten-met-ras-wild-type-die-eerstelijns-behandeling-met-panitumumab-krijgen.html

En in gerelateerde artikelen.

13 juni 2011:

Op ASCO werden de resultaten uit een langjarige fase III studie met Erbitux - cetuximab gepresenteerd die bevestigt dat alleen mensen met een vorm van darmkanker met een KRAS wild mutatie daarvan ook profiteren. Onderaan artikel heb ik abstract van die studie toegevoegd.

7 oktober 2010: Bron o.a. Medscape en J. Clin. Oncology

Erbitux (Cetuximab) en Vectibix (Panitumumab) - beiden zijn zogenaamde EGRF - anti-epidermal growth factor receptor gevoelige antimonoklonaal middelen - bewijzen in twee grote fase III studies dat zij een positief effect hebben op de mediane ziektevrije tijd bij zowel gevorderde darmkanker als ook gegeven posttoperatief bij operabele darmkanker. Echter alleen bij patienten die het wild type KRAS gen hebben. Degenen die dat niet hebben bleef het effect min of meer gelijk. Dit toont zowel een studie gedaan waarbij deze middelen mono werden gegeven alswel naast chemo. Opvallend is, maar bljikt uit ook recente studies, dat erbij wordt opgemerkt in een artikel op Medscape dat Avastin - Bevacizumab niet past in de behandeling samen met EGRF middelen. Dan blijken de bijwerkingen dermate ernstig te worden dat dit ook de mediane overleving en kwaliteit van leven negatief beïnvloed. Hier de abstracten van de 2 fase III studies en als u hier klikt kunt u een artikel hierover lezen van Medscape.

J Clin Oncol. 2010 Oct 4. [Epub ahead of print]

Randomized, Phase III Trial of Panitumumab With Infusional Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX4) Versus FOLFOX4 Alone As First-Line Treatment in Patients With Previously Untreated Metastatic Colorectal Cancer: The PRIME Study.

Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J.

Centre René Gauducheau, Nantes, France; Ospedale Niguarda Ca' Granda, Milan, Italy; The Beatson West of Scotland Cancer Centre, Glasgow; The Royal Marsden National Health Service Foundation Trust, London, United Kingdom; Vall d'Hebron University Hospital, Barcelona; Hospital Universitario Marqués de Valdecilla, Santander, Spain; Mount Sinai Hospital, Toronto; The Credit Valley Hospital, Mississauga, Ontario, Canada; Hospital de Gastroenterología, Buenos Aires, Argentina; Université Catholique de Louvain, Brussels; Grand Hôpital de Charleroi, Charleroi, Belgium; Szent Laszlo Hospital, Budapest, Hungary; Medical University of Gdansk, Gdansk; Wojewodzki Szpital Specjalistyczny, im. M. Kopernika, Lodz, Poland; Masarykuv Onkologicky Ustav, Brno; Institut Onkologie a Rehabilitace na Plesi s.r.o., Nová Ves pod Pleší, Czech Republic; University of the Witwatersrand, Johannesburg, South Africa; and Amgen, Thousand Oaks, CA.

Abstract

PURPOSE Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC.

PATIENTS AND METHODS In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status.

Results: KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio , 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy.

CONCLUSION This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC.

PMID: 20921465 [PubMed - as supplied by publisher]

J Clin Oncol. 2010 Oct 4. [Epub ahead of print]

Randomized Phase III Study of Panitumumab With Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) Compared With FOLFIRI Alone As Second-Line Treatment in Patients With Metastatic Colorectal Cancer.

Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J.

University Hospital Ghent, Ghent; University Hospital Gasthuisberg, Leuven, Belgium; Queen Elizabeth Hospital, Woodville; Monash Medical Center, East Bentleigh, Australia; Hospital Clínico, University of Valencia, Valencia, Spain; Ospedale San Martino, Genova, Italy; Institut Gustave Roussy, Villejuif, France; Uzhgorod National University, Uzhgorod Regional Oncology Dispensary, Uzhgorod, Ukraine; Hôpital Pitié-Salpétrière, Paris, France; Vanderbilt University Medical Center, Nashville, TN; Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany; Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; Christie Hospital, Manchester; Amgen, Uxbridge, United Kingdom; Institutul Oncologic I. Chiricuta, Cluj Napoca, Romania; Leningrad Regional Oncology Dispensary, Saint Petersberg, Russia; University Multiprofile Hospital for Active Treatment, Tzaritza Ioanna, Sofia, Bulgaria; and Amgen, Thousand Oaks, CA.

Abstract

PURPOSE Panitumumab is a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS) in chemotherapy-refractory metastatic colorectal cancer (mCRC). This trial evaluated the efficacy and safety of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone after failure of initial treatment for mCRC by tumor KRAS status.

PATIENTS AND METHODS Patients with mCRC, one prior chemotherapy regimen for mCRC, Eastern Cooperative Oncology Group performance status 0 to 2, and available tumor tissue for biomarker testing were randomly assigned 1:1 to panitumumab 6.0 mg/kg plus FOLFIRI versus FOLFIRI every 2 weeks. The coprimary end points of PFS and overall survival (OS) were independently tested and prospectively analyzed by KRAS status.

Results From June 2006 to March 2008, 1,186 patients were randomly assigned 1:1 and received treatment. KRAS status was available for 91% of patients: 597 (55%) with wild-type (WT) KRAS tumors, and 486 (45%) with mutant (MT) KRAS tumors. In the WT KRAS subpopulation, when panitumumab was added to chemotherapy, a significant improvement in PFS was observed (hazard ratio = 0.73; 95% CI, 0.59 to 0.90; P = .004); median PFS was 5.9 months for panitumumab-FOLFIRI versus 3.9 months for FOLFIRI. A nonsignificant trend toward increased OS was observed; median OS was 14.5 months versus 12.5 months, respectively (HR = 0.85, 95% CI, 0.70 to 1.04; P = .12); response rate was improved to 35% versus 10% with the addition of panitumumab. In patients with MT KRAS, there was no difference in efficacy. Adverse event rates were generally comparable across arms with the exception of known toxicities associated with anti-EGFR therapy.

CONCLUSION Panitumumab plus FOLFIRI significantly improved PFS and is well-tolerated as second-line treatment in patients with WT KRAS mCRC.

PMID: 20921462 [PubMed - as supplied by publisher]

Cetuximab Plus Irinotecan, Fluorouracil, and Leucovorin As First-Line Treatment for Metastatic Colorectal Cancer: Updated Analysis of Overall Survival According to Tumor KRAS and BRAF Mutation Status

Bron: Journal of Clinical Oncology

+ Author Affiliations

From the University Hospital Gasthuisberg, Leuven, Belgium; Klinikum Oldenburg, Oldenburg; University Hospital Carl Gustav Carus, Dresden; Merck KGaA, Darmstadt, Germany; National Institute of Oncology, Budapest, Hungary; MSC Memorial Cancer Center, Warsaw, Poland; Università Politecnica delle Marche, Ancona; Second University of Naples, Naples, Italy; National Cancer Institute, Kiev, Ukraine; Hospital Clínic, Barcelona, Spain; The Royal Marsden National Health Services Foundation Trust, London, United Kingdom; and the University of Versailles St Quentin, Hôpital Européen Georges Pompidou, Paris, France.

Corresponding author: Eric Van Cutsem, MD, PhD, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium; e-mail: eric.vancutsem@uz.kuleuven.ac.be.

Presented in part at 45th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 29-June 2, 2009; the European Society for Medical Oncology's (ESMO's) 11th World Congress on Gastrointestinal Cancer, Barcelona, Spain, June 24-27, 2009; the joint European Cancer Organization's 15th and ESMO 34th Multidisciplinary World Congress, Berlin, Germany, September 20-24, 2009; the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Orlando, FL, January 22-24, 2010; the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010; and ESMO's 12th World Congress on Gastrointestinal Cancer, Barcelona, Spain, June 30-July 03, 2010.

Abstract

Purpose

Purpose The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken.

Patients and Methods

Patients and Methods Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series.

Results

Results The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio , 0.796; P = .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P = .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P < .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis.

Conclusion

Conclusion The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.

Vectibix, Erbitux, EGRF, darmkanker, Folfori, Folfox