Erbitux - Cetuximab of panitumumab geeft alleen bij darmkanker patienten met KRAS wild type tumoren een positief klinisch effect van 10 % tot 15%. In alle andere gevallen (40%) werkt Erbitux

4 april 2009: Bron Medscape.

Darmkanker patienten met het KRAS wild type kunnen 10% tot 15% profijt hebben van Erbitux naast chemo maar darmkankerpatienten die niet het goede KRAS type hebben ervaren absoluut geen baat bij Erbitux - Cetuximab. Nog erger de effecten zijn negatief op ziektevrije tijd, mediane overleving en overall overleving toonde een fase III studie aan uitgevoerd in o.a. Nederland en België. Als u bedenkt dat al in 2002 Erbitux als aanvullend middel werd goedgekeurd naast chemo bij darmkanker door de Europese Commissie dan is het wel uitermate vreemd dat dit nu pas naar buiten komt. Heel snel zijn in ieder geval in Amerika nu de richtlijnen aangepast en moeten darmkankerpatienten eerst getest worden op het KRAS type voor ze Erbitux - Cetuximab of panitumumab. krijgen naast chemo. Dit is wel rijkelijk laat lijkt ons.

Hier een stukje vertaald uit een artikel uit Medscape van vandaag en het abstract van de studie daaronder en de studie karakteristieken waaronder de resultaten enz. :

Testen voor KRAS mutaties wrodt nu aanbevolen in dee National Cancer Comprehensive Network richtlijnen voor darmkan en was belangrijk onderwerp in een Provisional Clinical Opinion van ASCO, gepubliceerd online February 2 in the Journal of Clinical Oncology.

Dit is een razendsnelle verandering — van een onderzoeksresultaat naar de klinische richtlijnen binnen een jaar. Maar daarom, in de behandeling van darmkanker verandert de KRAS mutatie alles," becommentarieert John Marshall, MD, van de Lombardi Comprehensive Cancer Center, Georgetown University, in Washington, DC, in zijn Medscape Oncology expert blog.

De KRAS ontdekking heeft in principe darmkanker verdeeld in twee aparte ziektes, zegt Dr. Marshall. Ongeveer 40% van de kankerpatienten met uitgezaaide darmkanker hebben tumoren met een gemuteerde vorm van het KRAS gen, en deze patienten zullen niet reageren op behandelingen met Erbitux - cetuximab of panitumumab.

De andere patienten met het normale, of wild-type, KRAS gen zullen waarschijnlijk wel reageren op de behandelingen met Erbitux - cetuximab of panitumumab, zegt hij. Aanvullend Erbitux - cetuximab of panitumumab. op chemotherapie kan ca. 10% tot 15% verbetering geven in effectiviteit en resultaat, merkt hij op, hoewel zeker niet alle patienten positief zullen reageren "Maar nu kunnen we patienten vooraf uitselecteren die zeker niet positief zullen reageren", verduidelijkt hij.

Cetuximab in Colorectal Cancer Works Only in Wild-Type KRAS Tumors; CRYSTAL Trial Published

1: N Engl J Med. 2009 Apr 2;360(14):1408-17. Links

Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.

Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P.

University Hospital Gasthuisberg, Digestive Oncology Unit, Herestraat 49, 3000 Leuven, Belgium. eric.vancutsem@uz.kuleuven.ac.be

BACKGROUND: We investigated the efficacy of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer and sought associations between the mutation status of the KRAS gene in tumors and clinical response to cetuximab. METHODS: We randomly assigned patients with epidermal growth factor receptor-positive colorectal cancer with unresectable metastases to receive FOLFIRI either alone or in combination with cetuximab. The primary end point was progression-free survival.

RESULTS: A total of 599 patients received cetuximab plus FOLFIRI, and 599 received FOLFIRI alone. The hazard ratio for progression-free survival in the cetuximab-FOLFIRI group as compared with the FOLFIRI group was 0.85 (95% confidence interval , 0.72 to 0.99; P=0.048). There was no significant difference in the overall survival between the two treatment groups (hazard ratio, 0.93; 95% CI, 0.81 to 1.07; P=0.31). There was a significant interaction between treatment group and KRAS mutation status for tumor response (P=0.03) but not for progression-free survival (P=0.07) or overall survival (P=0.44). The hazard ratio for progression-free survival among patients with wild-type-KRAS tumors was 0.68 (95% CI, 0.50 to 0.94), in favor of the cetuximab-FOLFIRI group. The following grade 3 or 4 adverse events were more frequent with cetuximab plus FOLFIRI than with FOLFIRI alone: skin reactions (which were grade 3 only) (in 19.7% vs. 0.2% of patients, P<0.001), infusion-related reactions (in 2.5% vs. 0%, P<0.001), and diarrhea (in 15.7% vs. 10.5%, P=0.008).

CONCLUSIONS: First-line treatment with cetuximab plus FOLFIRI, as compared with FOLFIRI alone, reduced the risk of progression of metastatic colorectal cancer. The benefit of cetuximab was limited to patients with KRAS wild-type tumors. (ClinicalTrials.gov number, NCT00154102.) 2009 Massachusetts Medical Society

PMID: 19339720 [PubMed - indexed for MEDLINE]

The aim of this study is to evaluate the efficacy of cetuximab plus FOLFIRI as firstline treatment for metastatic colorectal cancer and to examine the associations between the mutation status of KRAS gene in tumors and clinical response to cetuximab.

Study Highlights

In this multicenter, open-label, phase 3 trial, patients were randomly assigned with epidermal growth factor–receptor-positive colorectal cancer with unresectable metastases to receive 14-day cycles of FOLFIRI either alone or in combination with cetuximab.
FOLFIRI consisted of irinotecan in combination with a simplified regimen of fluorouracil and leucovorin.
A total of 599 patients received cetuximab plus FOLFIRI, and 599 received FOLFIRI alone.
The primary end point was progression-free survival, defined as the time from randomization to disease progression or death from any cause within 60 days after the last tumor assessment or after randomization.
Secondary end points included overall survival time, the rate of best overall response, and safety end points.
Treatment was continued until disease progression, unacceptable toxic effects, or withdrawal consent occurred.
Computed tomography or magnetic resonance imaging was performed every 9 weeks until disease progression was observed to occur.
Results demonstrated that the hazard ratio for progression-free survival in the cetuximab-FOLFIRI group vs the FOLFIRI group was 0.85 (95% confidence-interval , 0.72 - 0.99; P = .048).
The adjusted hazard ratio for death with cetuximab plus FOLFIRI was 0.93 (95%CI, 0.81 - 1.07; P = .31).
There was no significant difference in the overall survival between the 2 treatment groups.
The adjusted odds ratio for a tumor response with cetuximab-FOLFIRI treatment vs FOLFIRI alone was 1.40 (95% CI, 1.12 - 1.77; P = .004).
Additionally, the rate of surgery for metastases was higher in the cetuximab-FOLFIRI group than in the FOLFIRI group, as was the rate of R0 resection with curative intent before disease progression (P = .002).
There was a significant interaction between the treatment group and KRAS mutation status for tumor response (P = .03) but not for progression-free survival (P = .07) or overall survival (P = .44).
The hazard ratio for progression-free survival among patients with wild-type KRAS tumors was 0.68 (95% CI, 0.50 - 0.94), in favor of the cetuximab-FOLFIRI group.
The following grade 3 or 4 adverse events were more frequent with cetuximab plus FOLFIRI than with FOLFIRI alone (P < .001); skin reactions (19.7% vs 0.2% of patients, P < .001), infusion-related reactions (2.5% vs 0%; P < .001), and diarrhea (15.7% vs 10.5%; P = .008). There were no cetuximab-related deaths.

Zosia Chustecka

April 1, 2009 —Results from a large phase 3 trial of cetuximab (Erbitux, Bristol-Myers Squibb) added to chemotherapy in colorectal cancer, which showed that only patients with KRAS wild-type tumors benefited from the targeted therapy, have now been published.

The trial, known as CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer), is reported in the April 2 issue of the New England Journal of Medicine.

The trial, involving 1198 patients, was headed by Eric Van Cutsem, MD, PhD, from University Hospital Gasthuisberg, in Leuven, Belgium. The results show that adding cetuximab to a chemotherapy regimen of irinotecan, fluorouracil, plus leucovorin (FOLFIRI) reduced the risk for progression of metastatic colorectal cancer, compared with FOLFIRI alone.

However, the benefit from cetuximab was limited to patients with KRAS wild-type tumors. Patients who had tumors with KRAS mutations did not benefit, the researchers noted.

The KRAS mutation results from this trial were presented last year at the annual meeting of American Society for Clinical Oncology (ASCO), and were highlighted by ASCO as a "major advance" in its year-end report, as previously reported by Medscape Oncology.

Already Incorporated Into Clinical Practice

The finding that cetuximab is effective in only colorectal cancer patients with tumors that express the wild-type KRAS, and not KRAS mutations, has already been incorporated in clinical practice. This finding was duplicated in several other trials, and extends to a similar targeted agent, panitumumab (Vectibix, Amgen), which also acts an inhibitor of epidermal growth-factor receptor.

Testing for KRAS mutations is now recommended in the National Cancer Comprehensive Network guidelines for colorectal cancer, and was featured in a Provisional Clinical Opinion from ASCO, published online February 2 in the Journal of Clinical Oncology.

This has been a very rapid uptake — from a research finding into clinical guidelines in little more than a year. But then, in the treatment of colon cancer, "KRAS changes everything," John Marshall, MD, from the Lombardi Comprehensive Cancer Center, Georgetown University, in Washington, DC, commented in his Medscape Oncology expert blog.

The KRAS discovery has effectively split colon cancer into 2 separate diseases, Dr. Marshall said. About 40% of patients with metastatic colon cancer have tumors with a mutated form of the KRAS gene, and these patients are unlikely to respond to treatment with cetuximab or panitumumab.

The other patients with the normal, or wild-type, KRAS genes are likely to respond to these drugs, he said. In some patients, the addition of cetuximab or panitumumab to chemotherapy can produce a 10% to 15% improvement in benefit, he noted, although not all patients respond. "But we have weeded out the patients who are not going to respond," he pointed out.

Dr. Marshall likened the situation to that in breast cancer, where the discovery of the human epidermal growth-factor receptor-2 divided patients into those who would and those who would not benefit from the monoclonal antibody trastuzumab (Herceptin, Genetech/Roche).

The study was supported by Merck (Darmstadt). Dr. Van Cutsem reports receiving consulting or advisory fees from Amgen, Merck (Darmstadt), Pfizer, Roche, and Sanofi-Aventis; lecture fees from Amgen, Merck (Darmstadt), Roche, and Sanofi-Aventis; and grant support from Merck (Darmstadt) and Roche. Several other coauthors report relevant financial relationships, and 2 coauthors are employees of Merck (Darmstadt), as detailed in the paper.

N Engl J Med. 2009;360:1408-1417.

cetuximab, panitumumab