5 april 2017: lees ook dit artikel:

https://kanker-actueel.nl/NL/veel-farmaceutische-bedrijven-misbruiken-kankerpatienten-in-arme-landen-voor-hun-wetenschappelijk-onderzoek-aldus-kritisch-rapport-van-de-somo.html

Hier het officiele studieverslag gepubliceerd in The Lancet van de studie: Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial Het abstract staat onderaan artikel

Interpretation

Bevacizumab does not prolong disease-free survival when added to adjuvant chemotherapy in resected stage III colon cancer. Overall survival data suggest a potential detrimental effect with bevacizumab plus oxaliplatin-based adjuvant therapy in these patients. On the basis of these and other data, we do not recommend the use of bevacizumab in the adjuvant treatment of patients with curatively resected stage III colon cancer.

24 september 2010: Bron Reuters en Pharmatimes

Avastin - Bevacizumab faalt als postoperatieve behandeling bij operabele darmkanker naast chemo. Dit blijkt uit een gerandomiseerde fase III studie (AVANT studie). Dit meldt Reuters op hun website. Nergens kan ik het abstract of studieverslag vinden tot nu toe en ook Medscape is uiterst summier met informatie over deze studie. Zij vermelden slechts een gedeelte van Reuters persbericht. Maar dit bericht is natuurlijk wel belangrijk. Avastin - Bevacizumab is een zeer duur medicijn dat de afgelopen jaren enorm is gepromoot en Roche heeft daarmee miljarden verdiend. Na het bericht dat Avastin - Bevacicumab bij borstkanker geen effect op de mediane overleving heeft maar alleen extra bijwerkingen geeft en sterk verminderde kwaliteit van elven is dit nu al de tweede fase III studie die aantoont dat Avastin - Bevacicumab ook bij operabele darmkanker geen positief effect geeft. Lees berichtgeving hierover in linkerkolom en hieronder. Eerst het persbericht van Reuters:

* Study shows Avastin doesn't improve disease-free survival

ZURICH, Sept 20 (Reuters) - Roche Holding AG's (ROG.VX) cancer drug Avastin was dealt another blow when it again failed in a study to improve disease-free survival in early-stage colon cancer immediately after surgery.

..........

COLON SETBACK

The AVANT study in early-stage colon cancer had shown that standard chemotherapy plus one year of Avastin after surgery was not effective in reducing the risk of relapses, the world's largest maker of cancer drugs said.

The group is now evaluating the data from this study and another previous one, known as C-08, to help define the next steps for the ongoing post-surgery, or adjuvant, Avastin programme.

"Following the first failure in the adjuvant setting, analysts and investors have removed any financial expectations with regard to Avastin in the adjuvant setting," Vontobel analyst Andrew Weiss said.

"Hence, the failure of AVANT should not result in any adjustment of consensus expectations. We leave our revenue expectations for Avastin unchanged," Weiss said.

Roche's pipeline has been hit by a number of setbacks over recent months and the drugmaker, once seen as the favourite of the pharma sector, announced an efficiency drive earlier this month to offset development disappointments and rising pricing pressures. [ID:nLDE68203L] (Reporting by Katie Reid; Editing by Hans Peters and Ben Hirschler)

8 juni 2009: Lees aub andere meer recente berichtgeving over Avastin en monoklonale middelen bij darmkanker en met name over KRAS gen c.q. KRAS mutatiepatroon onder deze artikelenreeks. En risico op maag- en darmperforaties door gebruik van Avastin - Bevacizumab aangetoond in grote meta-abalyse van vele gerandomiseerde studies en gepubliceerd in The Lancet d.d. 1 juni 2009.

Verder werden op ASCO de resultaten van een grote gerandomiseerde fase III studie gepubliceerd die geen significant verschil laat zien in ziektevrije tijd en overall overlevingen bij darmkanker. Alleen het eerste half jaar tot een jaar is er enig verschil in effect, maar dit verdwijnt na het eerste jaar heel snel. Zie hier abstract zoals dat is gepubliceerd op ASCO 2009 Daaronder het bericht van september 2003 dat Avastin wel een significant verschil zou maken bj darmkanker. :

A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08.

Abstract:

Background: The primary aim of this two-arm randomized prospective study was to determine whether mFOLFOX6 plus bevacizumab (mFF6+B) would prolong disease-free survival (DFS) compared to mFOLFOX6 (mFF6) alone. Methods: Between September 2004 and October 2006, 2,672 patients with follow-up (1,338 and 1,334 in respective arms) with stage II (24.9%) or III carcinoma of the colon were randomized to receive either mFF6 (oxaliplatin 85 mg/m² IV d1, leucovorin 400 mg/m² IV d1, 5-FU 400 mg/m² IV bolus d1, and 5-FU 2400 mg/ m² CI over 46 hrs (d1+2) q14d x 12 cycles) or mFF6+B (same mFF6 regimen + bevacizumab 5 mg/kg IV q 2 wks x 1 yr). The primary end point was DFS. Events were defined as first recurrence, second primary cancer, or death.

Results: The median follow-up for patients still alive was 36 months. The hazard ratio (HR: FF6+B vs. mFF6) was 0.89; 95% CI (0.76-1.04); p=0.15. Data censored at intervals disclosed an initial benefit for bevacizumab that diminished over time: The smoothed estimate of the DFS HR over time indicated that bevacizumab significantly reduced the risk of a DFS event during the interval from 0.5 to 1.0 year. There was no evidence that patients receiving bevacizumab had a worse DFS compared to those receiving mFF6 alone following treatment.

Conclusions: The addition of bevacizumab to mFF6 did not result in an overall statistically significant prolongation in DFS. There was a transient benefit in DFS during the one-year interval that bevacizumab was utilized. Consideration may be given to clinical trials assessing longer duration of bevacizumab administration. Supported by PHS grants U10CA-12027, -69974, -37377, and -69651 from the NCI and a grant from Genentech, Inc.


	N	Ev	3yDFS	P		Yr	1	1.5	2	2.5	3

mFF6	1338	312	75.5	HR	0.60	0.74	0.81	0.85	0.87
mFF6+B	1334	291	77.4	0.15	P	0.0004	0.004	0.02	0.05	0.08

d.d. 22 september 2003: vervolginformatie over Avastin bij darmkanker.

Roche Holding meldt vandaag 22 september 2003 op de beurs (DOW) dat een Fase III studie bij 900 patiënten met uitgezaaide darmkanker een significant positief resultaat heeft gegeven voor het gebruik van Avastin in combinatie met de standaard chemokuren bij darmkanker. Al eerder hebben wij de studieresultaten van een fase II studie gemeld en al eerder ook kwamen de resultaten van deze fase III studie naar buiten, zoals u in het artikel hieronder kunt lezen. Avastin is een angiogeneseremmer, het blokkeert de bloedtoevoer naar de kankercellen zoals bv. ook methylglyoxal (zie ook verhaal van meneer B.) lijkt te doen. Als het waar is dat Avastin dit doet vragen we ons wel af waarom het verschil in gemiddelde overlevingstijd oplopend van 'slechts' 15.6 maanden naar 20.3 maanden niet veel langer is. Als het waar is dat Avastin de bloedtoevoer naar de kankercellen afsluit dan zou de logische gevolgtrekking o.i. moeten zijn dat ALLE kankercellen binnen een bepaald tijdsbestek gewoon afsterven. Maar blijkbaar groeien de kankercellen toch nog bij een aantal patiënten en worden patiënten toch weer resistent tegen ook Avastin?. Nu zijn wij geen arts of medisch deskundige dus is misschien onze overweging hier pure onzin. Maar we zouden graag eens van een oncoloog, liefst darmkankerspecialist horen hoe het dan werkelijk zit. We zullen ook een woordvoerder bij Roche hier eens naar vragen.
Overigens kregen we recent van twee bezoekers van de site het bericht dat zij hadden geprobeerd in Amerika informatie te krijgen over trials met Avastin bij longkanker, maar beide personen kregen te horen dat er geen trials met longkanker op dit moment lopen. Terwijl in dit bericht wel melding wordt gemaakt van lopende trials met Avastin bij alvleesklierkanker, longkanker en nierkanker. We vinden dit wel vreemd. Ook kennen we verschillende mensen met uitgezaaide darmkanker die met alleen dieet en extra suppletie, al of niet als aanvulling bij reguliere therapiën en bepaalde levensstijl hun overlevingstijd verdubbelen of zelfs nog meer tegenover de prognoses. Zie ook ervaringsverhalen van kankerpatiënten onder uw verhaal.

Of deze publicatie nu wel de weg vrijmaakt voor grootschalig gebruik van Avastin durven we dus niet te zeggen. Lees het persbericht van de DOW en daaronder het persbericht over de fase III trial van de website van Genentech, producent van Avastin.

-- Roche: Phase III Trials Show Avastin Improves Suvival --

Edited Press Release

LONDON -(Dow Jones)- Roche Holding said Monday that treatment with Avastin
(bevacizumab, rhuMAb-VEGF) - a new agent designed specifically to restrict the
blood supply to tumours - can significantly improve survival in advanced
colorectal cancer compared to established chemotherapy alone, according to data
presented at the European Cancer Conference (ECCO).
These results, from a 900-patient randomised Phase III study, showed that
Avastin increased survival duration by over 30% when combined with first-line
chemotherapy (IFL1) for advanced (metastatic) colorectal cancer.
In addition to the 30% survival rate, the study found that when Avastin was
added to IFL, patient survival time was extended from 15.6 months with
chemotherapy alone to 20.3 months. The time to disease progression, response
rate and duration of response were also all improved by Avastin, Roche said.
These clinical benefits were seen across all relevant patient subgroups in the
population, the data shows.
The combination of Avastin and chemotherapy was well tolerated, with only
grade 3 hypertension (> 180mmHg / > 110mmHg, which was manageable using standard
oral medication) clearly more frequent in the Avastin-containing arm of the
trial. Avastin is also under investigation in other forms of metastatic
cancer, including non-small cell lung cancer, pancreatic and renal cell
carcinoma.
An application for approval of Avastin in treating colorectal cancer will be
made to the European Union regulatory authorities in the coming months.

Phase III study of Avastin™ (bevacizumab, rhuMAb-VEGF) plus chemotherapy in previously untreated metastatic colorectal cancer patients met its primary endpoint. It improved overall survival. The magnitude of the benefit observed far exceeded what the study was designed to demonstrate. The trial also met the secondary endpoints of progressionfree survival, response rate, and duration of response. Genentech plans to submit data from this Phase III metastatic colorectal cancer trial to the annual meeting of the American Society of Clinical Oncology (ASCO), May 31 - June 3. This is good news, especially about a drug that analysts were skeptical about its promises and critics took advantage to underrate the stock because of it. Avastin is an antibody designed to inhibit Vascular Endothelial Growth Factor (VEGF), a protein that plays a critical role in tumor angiogenesis (the formation of new blood vessels to the tumor). By inhibiting VEGF, Avastin is designed to interfere with processes that are critical to tumor growth and metastasis. According to Susan D. Hellmann, M.D., M.P.H., Genentech's executive vice president Development and Product Operations, and chief medical officer, the data strongly suggest that inhibiting VEGF -- a growth factor first cloned by Genentech scientists -- results in clinical benefit for colorectal cancer patients and has the potential to change the practice of treating cancer. The study also provides the first Phase III clinical validation of the longpursued 'anti-angiogenic' hypothesis -- that by targeting a tumor's blood supply, you may impact its viability. Based on the strength of these data, Genentech plans to discuss the filing of a Biologics License Application with the U.S. Food and Drug Administration," continued Dr. Hellmann. * This multi-center study enrolled more than 900 patients, and randomized 800 patients to receive either Avastin plus the standard of care chemotherapy (5-FU/Leucovorin/CPT-11, called the Saltz regimen) or the Saltz regimen plus an Avastin placebo. A third arm of the study treated 100 patients with Avastin plus 5-FU/Leucovorin chemotherapy. This arm was dropped, as pre-specified, once safety with the Saltz regimen was established.

Adverse Events
The addition of Avastin to chemotherapy was well tolerated. While bleeding, thrombosis, asymptomatic proteinuria and hypertension were identified in Phase II studies as possible safety events, only Grade 3 hypertension, easily managed with oral medications, was clearly increased in this Phase III study. Gastrointestinal perforation, although uncommon, may be increased by the addition of Avastin to chemotherapy. Based on preclinical and clinical studies showing that VEGF may play a broad role in a range of cancers, Genentech is pursuing a late stage clinical development program with Avastin evaluating its potential use in metastatic colorectal, renal cell (kidney), breast and non-small cell lung cancers. To date, more than 2,000 patients have been treated with Avastin in clinical studies. Results from a second Genentech study in metastatic colorectal cancer are expected later this year. In October 2001, a Phase II study with Avastin in metastatic renal cell carcinoma conducted by the National Cancer Institute (NCI) was stopped early after reaching its pre-specified efficacy endpoint. Results from this study were presented at last year's ASCO meeting. Based on the positive data observed in this trial, two Phase III trials in metastatic kidney cancer are scheduled to begin enrollment this year. In addition, Phase III Eastern Cooperative Oncology Group (ECOG) studies continue to evaluate Avastin in second-line metastatic colorectal, first-line metastatic non-small cell lung, and first-line metastatic breast cancer. Additional studies are ongoing through the NCI in more than 20 different tumor types.

Comments:

Investors were led to believe that Avastin’s side effects would cause problem towards Avastin approval. The above-mentioned news might change this feeling, as the rewards seem to exceed, by far, the risk of side effects. This is definitely good news for Genentech, whose drug Xolar was recommended approval by the FDA advisory Committee.

Sub-category: Colorectal Cancer (including liver metastases)

Category: Gastrointestinal (Colorectal) Cancer

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4) Abstract No: LBA4

Author(s): N. Wolmark, G. Yothers, M. J. O'Connell, S. Sharif, J. N. Atkins, T. E. Seay, L. Feherenbacher, S. O'Reilly, C. J. Allegra; Allegheny General Hospital, Pittsburgh, PA; University of Pittsburgh; National Surgical Adjuvant Breast and Bowel Project; National Surgical Adjuvant Breast and Bowel Project, Allegheny General Hospital; Southeast Cancer Control Consortium; Atlanta Cancer Care; Kaiser Permanente, Northern California, Vallejo; All Ireland Clinical Oncology Research Group; University of Florida

Bevacizumab does not prolong disease-free survival when added to adjuvant chemotherapy in resected stage III colon cancer. Overall survival data suggest a potential detrimental effect with bevacizumab plus oxaliplatin-based adjuvant therapy in these patients. On the basis of these and other data, we do not recommend the use of bevacizumab in the adjuvant treatment of patients with curatively resected stage III colon cancer.

Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial

Prof Aimery de Gramont, MD

Correspondence information about the author Prof Aimery de Gramont

Email the author Prof Aimery de Gramont

Prof Eric Van Cutsem, MD

Prof Hans-Joachim Schmoll, MD

Josep Tabernero, MD

Prof Stephen Clarke, FRACP

Prof Malcolm J Moore, MD

Prof David Cunningham, MD

Thomas H Cartwright, MD

Prof J Randolph Hecht, MD

Fernando Rivera, MD

Prof Seock-Ah Im, MD

Prof György Bodoky, MD

Prof Ramon Salazar, MD

Frédérique Maindrault-Goebel, MD

Einat Shacham-Shmueli, MD

Prof Emilio Bajetta, MD

Martina Makrutzki, MD

Aijing Shang, MD

Thierry André, MD

Prof Paulo M Hoff, FACP

Published: 16 November 2012

DOI: http://dx.doi.org/10.1016/S1470-2045(12)70509-0

Article Info

Summary

Background

Bevacizumab improves the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer. Our aim was to assess the use of bevacizumab in combination with oxaliplatin-based chemotherapy in the adjuvant treatment of patients with resected stage III or high-risk stage II colon carcinoma.

Methods

Patients from 330 centres in 34 countries were enrolled into this phase 3, open-label randomised trial. Patients with curatively resected stage III or high-risk stage II colon carcinoma were randomly assigned (1:1:1) to receive FOLFOX4 (oxaliplatin 85 mg/m², leucovorin 200 mg/m², and fluorouracil 400 mg/m² bolus plus 600 mg/m² 22-h continuous infusion on day 1; leucovorin 200 mg/m² plus fluorouracil 400 mg/m² bolus plus 600 mg/m² 22-h continuous infusion on day 2) every 2 weeks for 12 cycles; bevacizumab 5 mg/kg plus FOLFOX4 (every 2 weeks for 12 cycles) followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks); or bevacizumab 7·5 mg/kg plus XELOX (oxaliplatin 130 mg/m² on day 1 every 2 weeks plus oral capecitabine 1000 mg/m² twice daily on days 1–15) every 3 weeks for eight cycles followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks). Block randomisation was done with a central interactive computerised system, stratified by geographic region and disease stage. Surgery with curative intent occurred 4–8 weeks before randomisation. The primary endpoint was disease-free survival, analysed for all randomised patients with stage III disease. This study is registered with ClinicalTrials.gov, number NCT00112918.

Findings

Of the total intention-to-treat population (n=3451), 2867 patients had stage III disease, of whom 955 were randomly assigned to receive FOLFOX4, 960 to receive bevacizumab–FOLFOX4, and 952 to receive bevacizumab–XELOX. After a median follow-up of 48 months (range 0–66 months), 237 patients (25%) in the FOLFOX4 group, 280 (29%) in the bevacizumab–FOLFOX4 group, and 253 (27%) in the bevacizumab–XELOX group had relapsed, developed a new colon cancer, or died. The disease-free survival hazard ratio for bevacizumab–FOLFOX4 versus FOLFOX4 was 1·17 (95% CI 0·98–1·39; p=0·07), and for bevacizumab–XELOX versus FOLFOX4 was 1·07 (0·90–1·28; p=0·44). After a minimum follow-up of 60 months, the overall survival hazard ratio for bevacizumab–FOLFOX4 versus FOLFOX4 was 1·27 (1·03–1·57; p=0·02), and for bevacizumab–XELOX versus FOLFOX4 was 1·15 (0·93–1·42; p=0·21). The 573 patients with high-risk stage II cancer were included in the safety analysis. The most common grade 3–5 adverse events were neutropenia (FOLFOX4: 477 [42%] of 1126 patients, bevacizumab-FOLFOX4: 416 [36%] of 1145 patients, and bevacizumab–XELOX: 74 [7%] of 1135 patients), diarrhoea (110 [10%], 135 [12%], and 181 [16%], respectively), and hypertension (12 [1%], 122 [11%], and 116 [10%], respectively). Serious adverse events were more common in the bevacizumab groups (bevacizumab–FOLFOX4: 297 [26%]; bevacizumab–XELOX: 284 [25%]) than in the FOLFOX4 group (226 [20%]). Treatment-related deaths were reported in one patient receiving FOLFOX4, two receiving bevacizumab–FOLFOX4, and five receiving bevacizumab–XELOX.