19 augustus 2014: Bron: ASCO 2014:

Voor wie geinteresseerd is in het verschil tussen Avastin - bevacizumab en Erbitux - Cetuximab zou het abstract van dit studierapport: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). tegen betaling is het volledige studierapport op te vragen, eens kunnen lezen. Uiteindelijk lijkt Cetuximab - Erbitux voor darmkankerpatiënten met KRAS wild type beter op 5 jaar. 1% van de patienten met Avastin naast Folofox of Folfiri bereikte een complete remissie tegenover 4% van de patienten voor Erbitux - Cetuximab.

Zie hier alle studieresultaten: 

In deze studie werden bevacizumab en cetuximab, in combinatie met FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin) of FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin), gebruikt als eerstelijns behandeling voor uitgezaaide darmkanker of rectumkanker. Hoewel nooit is aangetoond dat FOLFOX met Avastin - bevacizumab betere resutlaten zu geven dan alleen FOILFOX zeggen de odnerzoekers op ASCO 2014. (Red: dit is toch wel een heel opmerkelijke uitspraak als je bedenkt dat Avastin €5.000,-- per maand kost en dat zonder enig bewijs van effectiviteit)

De onderzoekers deelden gerandomiseerd 1137 patiënten met KRAS wild-type (codons 12 en 13) onbehandelde uitgezaaide darmkanker in naar chemotherpaie plus bevacizumab - Avastin (5 mg/kg bij aanvang en daarna iedere twee weken) of cetuximab (een startende dosis van 400 mg/m² gevolgd door  250 mg/m² een keer per week).

Welke chemokuur werd aan de behandelend arts overgelaten ; 26.6% kreeg FOLFIRI en 73.4% ontving FOLFOX. Mediane follow-up was 24 maanden.

Na 40 maanden waren nog 94 patienten ziketevrij na een operatie. Het bijwerkingeprofiel lag min of meer gelijk zoals verwacht. Hier het originele abstract met de resultaten:

Results: Between November 2005 and March 2012, 3,058 unselected pts enrolled, 2,334 KRAS wt pts randomized; final N =1137 (333 pre-amend eligible retrospective KRAS test, 804 post-amend), median f/u = 24 mos; Median age – 59 y; 61% male. Chemo/BV – 559; chemo/CET – 578. FOLFIRI = 26.6%, mFOLFOX6 = 73.4%. OS analysis planned at 849 events; efficacy futility boundary crossed at 10^th interim analysis on 1/29/14. OS - chemo/BV v. chemo/CET = 29.04 (25.66 - 31.21) v. 29.93 (27.56 - 31.21) mos; HR = 0.92 (0.78, 1.09) (p value = 0.34). PFS (by investigator): chemo/BV v. chemo/CET: 10.84 (9.86 - 11.4) v. 10.45 (9.66 - 11.33) mos.

There were 94 pts free of disease following surgery, median f/u 40 mos (range 8.0 - 86.0). Outcomes similar by gender. On-study toxicity and deaths as expected. Analyses underway: Expanded RAS, FOLFOX v. FOLFIRI, subsequent therapies, long-term survivors, correlates.

Conclusions: Chemo/CET and chemo/BV equivalent in OS in pts KRAS wt (codons 12 + 13) MCRC; either is appropriate in first line. Overall OS of 29 + mos and 8% long-term survivors confirms progress in MCRC. The preference for FOLFOX limits chemotherapy comparison. Expanded RAS and other molecular and clinical analyses may identify subsets of pts who get more or less benefit from specific regimens.

6 februari 2009: Bron: New England Journal of Medicine

Darmkankerpatienten die naast chemo ook Avastin en Erbitux krijgen hebben beduidend meer en ernstiger bijwerkingen en hun kanker wordt eerder progressief en er zijn minder overall overlevingen dan wanneer alleen chemo plus Avastin wordt gegeven. Dit blijkt uit een Nederlandse gerandomiseerde fase III studie bij 732 darmkankerpatienten. Zie hieronder respectievelijk een artikel gepubliceerd door Reuters en daaronder het studierapport zoals dat gisteren is gepubliceerd in New England Journal of Medicin. .

Mixing Erbitux, Avastin Bad for Advanced Colon Cancer (Correct)

In a trial of 732 participants, Dutch researchers found that adding Eli Lilly & Co.’s Erbitux to Genentech Inc.’s Avastin, along with a regimen of powerful chemotherapy drugs, worsened cancer and caused patients more severe discomfort than Avastin plus chemotherapy alone. The research appears in the Feb. 5 New England Journal of Medicine.

The combination studies tested a theory that pairing biological therapies -- medicines made from living organisms -- with a chemotherapy cocktail could boost benefits. They found that patients in the Erbitux group experienced faster tumor progression than those in the Avastin group. Those taking Erbitux also had more severe skin reactions and lower quality of life, plus a trend to lower overall survival that didn’t reach statistical significance, researchers said.

“More is not always better,” said Harvard Medical School professor Robert J. Mayer, vice chair of academic affairs at the Dana Farber Cancer Institute in Boston, in an editorial accompanying the journal report.

The study, called CAIRO2, is the second trial in two years to find that colorectal cancer patients fared worse when a second antibody-based drug was added to Avastin and chemotherapy. In March 2007, the PACCE study adding Amgen Inc.’s Vectibix to Avastin and chemotherapy was halted because of a higher death rate and toxicity.

The CAIRO2 study was first presented at the American Society for Clinical Oncology meeting in June 2008. This week’s journal article is its first publication in a peer-reviewed journal.

Targeted Therapies

Avastin, Erbitux and Vectibix are among a new generation of cancer medicines called targeted therapies, because they attack malignant cells by interfering with specific biological pathways involved in cancer. Erbitux and Vectibix are laboratory-designed antibodies that disable a protein known as epidermal growth factor receptor, or EGFR, involved in tumor cell division. Avastin, also an antibody, works by blocking vascular endothelial growth factor, or VEGF, a substance that stimulates growth of blood vessels that feed tumor growth.

“We think there may have been a negative interaction between the two antibodies,” said study author Cornelis J.A. Punt, chairman of the department of medical oncology at Radboud University Nijmegen Medical Center in Nijmegen, the Netherlands, in an e-mail.

Wrong Combination

The CAIRO2 study added Erbitux to a regimen of Avastin plus chemotherapy drugs capecitabine and oxaliplatin.

“Our results argue against the combined use of anti-VEGF and anti-EGFR monoclonal antibodies with chemotherapy in cases of metastatic colorectal cancer,” wrote lead authors Punt and Jolien Tol of Radboud University Nijmegen Medical Center.

Erbitux, which generated $182 million in North America in the fourth quarter of 2008, is marketed in the U.S. by Indianapolis-based Lilly and New York-based Bristol Myers-Squibb Co., and sold overseas by Germany’s Merck KGaA, who hasn’t reported its fourth-quarter sales yet. Genentech, of South San Franciso, California, sells Avastin, which had $2.69 billion in U.S. sales last year, with Swiss drugmaker Roche Holding AG. The Dutch Colorectal Cancer Group, which supported the study, received funds from Roche, Merck KGaA, Sanofi-Aventis AG and DxS Ltd.

The study, started in 2005, also confirms more recent findings that colorectal cancer patients with a mutated version of a gene called KRAS don’t benefit from Erbitux.

Patients with a mutated KRAS gene who got Erbitux “had significantly decreased progression-free survival” compared with patients with a normal KRAS gene who got Erbitux or patients with a mutated KRAS gene who got only Avastin and chemotherapy, the authors wrote.

Unexpected Interactions

While the outlook for patients with colorectal cancer “has brightened considerably” with new drug regimens, biological therapies may belie the more-is-better approach, Mayer wrote in the editorial. Biologic drugs may trigger unexpected interactions in cellular signaling that aren’t yet understood and could interfere with benefits of the treatment.

Cocktails of drugs with different mechanisms and side effects often provide synergistic benefits, Mayer said in an interview.

“There are intracellular interactions that may not be noticed until a double whammy is provided,” he added. “When you turn your key to start the car, it doesn’t start because of the key but because seven or eight things happened under the hood,” he said. “With Avastin and Erbitux, they act under the hood. This is a bit more complex than we have seen before.”

ABSTRACT

Background Fluoropyrimidine-based chemotherapy plus the anti–vascular endothelial growth factor (VEGF) antibody bevacizumab is standard first-line treatment for metastatic colorectal cancer. We studied the effect of adding the anti–epidermal growth factor receptor (EGFR) antibody cetuximab to a combination of capecitabine, oxaliplatin, and bevacizumab for metastatic colorectal cancer.
Source Information

Methods We randomly assigned 755 patients with previously untreated metastatic colorectal cancer to capecitabine, oxaliplatin, and bevacizumab (CB regimen, 378 patients) or the same regimen plus weekly cetuximab (CBC regimen, 377 patients). The primary end point was progression-free survival. The mutation status of the KRAS gene was evaluated as a predictor of outcome.

Results The median progression-free survival was 10.7 months in the CB group and 9.4 in the CBC group (P=0.01). Quality-of-life scores were lower in the CBC group. The overall survival and response rates did not differ significantly in the two groups. Treated patients in the CBC group had more grade 3 or 4 adverse events, which were attributed to cetuximab-related adverse cutaneous effects. Patients treated with cetuximab who had tumors bearing a mutated KRAS gene had significantly decreased progression-free survival as compared with cetuximab-treated patients with wild-type–KRAS tumors or patients with mutated-KRAS tumors in the CB group.

Conclusions The addition of cetuximab to capecitabine, oxaliplatin, and bevacizumab resulted in significantly shorter progression-free survival and inferior quality of life. Mutation status of the KRAS gene was a predictor of outcome in the cetuximab group. (ClinicalTrials.gov number, NCT00208546 [ClinicalTrials.gov] .)

From Radboud University Nijmegen Medical Center, Nijmegen (J.T., M.K., J.R.D., M.E.V.-B., J.H.J.M.K., C.J.A.P.); the Netherlands Cancer Institute, Amsterdam (A.C., N.F.A., O.D.); Meander Medical Center, Amersfoort (C.J.R.); Catharina Hospital, Eindhoven (G.J.M.C.); Spaarne Hospital, Hoofddorp (J.G.S.); Maasland Hospital, Sittard (F.L.G.E.); Bernhoven Hospital, Oss (A.H.V.); the Free University Medical Center, Amsterdam (C.J.G.); Jeroen Bosch Hospital, `s-Hertogenbosch (H.A.M.S.); the Amsterdam Medical Center, Amsterdam (D.J.R.); University Medical Center, Utrecht (E.E.V.); and the Comprehensive Cancer Center East, Nijmegen (L.M.) — all in the Netherlands.

Address reprint requests to Dr. Punt at the Department of Medical Oncology, Radboud University Nijmegen Medical Center, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands, or at c.punt@onco.umcn.nl .

Bevacizumab - Avastin and Cetuximab - Erbitux have similar survival benefits in Colorectal Cancer

darmkanker, erbitux, bevacizumab

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• Bevacizumab - Avastin en Erbitux naast chemo veroorzaakt ernstiger bijwerkingen en kortere tijd tot progressie en minder overall overlevingen bij uitgezaaide darmkanker, aldus Ned. fase III studie.

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• Erbitux - een monoklonaal middel geeft indien gegeven naast irinotecan een significant positief resultaat op overlevingstijd bij uitgezaaide darmkanker, maar alleen bij darmkankerpatienten met KRAS mutatie wild type

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• Erbitux - Cetuximab of panitumumab geeft alleen bij darmkankerpatienten met KRAS wild type tumoren een positief klinisch effect van 10 - 15 procent. In alle andere gevallen (40 procent) werkt Erbitux - Cetuximab of panitumumab.niet.

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• Erbitux - Cetuximab faalt als aanvulling bij chemo (FOLFOX) voor darmkankerpatienten. Fase III studie is daarom afgebroken. Bij KRAS wild type werkt Erbitux wel.