20 april 2014: lees ook dit artikel over dabrafenib + trametinib welke dezelfde aanpak is als met vemurafenib: Dabrafenib is in principe hetzelfde medicijn met dezelfde werking als vemurafenib voor BRAFV600E and BRAFV600K positieve melanomen.

10 februari 2014: onderaan heb ik het abstract van een tussenevaluatie van de fase III studie: Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study geplaatst. In deze studie verdubbelde de overall overleving en progressievrije tijd van melanoompatiënten tot op dit moment en dat kan alleen maar beter worden zo lang de studie loopt. In dit artikel hieronder kunt u lezen waar vemurafenib wordt gegeven in Nederland. Dit is overigens een vorm van een op receptoren en genmutaties (BRAFV600E en BRAFV600K) gericht medicijn dat inmiddels algemeen erkend is en ook wordt vergoed.

Zie helemaal onderaan dit artikel het abstract uit The Lancet van 7 februari 2014.

 18 oktober 2012:

Ipilimumab (Yervoy) en vemurafenib (Zelboraf) zijn nieuwe behandelingen - medicijnen tegen uitgezaaide melanoom. Zie hieronder informatie over vemurafenib (Zelboraf) 

Of vemurafenib werkzaam kan zijn is afhankelijk van bepaalde zogeheten gen mutaties. Afgelopen week werd een lijst bekend gemaakt van welke Nederlandse ziekenhuizen deze twee medicijnen mogen voorschrijven. De behandeld arts moet namelijk over voldoende kennis beschikken over de medicijnen en moet deelnemen aan de centrale registratie van patiënten die deze behandeling ontvangen.

In de volgende ziekenhuizen werken artsen die over voldoende kennis daarover beschikken en deze ziekenhuizen mogen dan ook Ipilimumab (Yervoy)  of vemurafenib (Zelboraf) voorschrijven:

Universitair Medisch Centrum Groningen
Universitair Medisch Centrum Nijmegen
Universitair Medisch Centrum Maastricht
Erasmus Medisch Centrum - Rotterdam
Universitair Medisch Centrum Utrecht
Leids Universitair Medisch Centrum
VU Medisch Centrum - Amsterdam
Nederlands Kanker Instituut /Antoni van Leeuwenhoek - Amsterdam
Medisch Centrum Leeuwarden
Medisch Spectrum Twente - Enschede
Isala Kliniek Zwolle
Amphia Ziekenhuis Breda
Maxima Medisch Centrum Veldhoven
Atrium Medisch Centrum Heerlen

19 augustus 2011: Bron: FDA - US Food and Drug Adminstration

De FDA heeft per direct vemurafenib - Zelboraf officieel als medicijn aangemerkt voor melanoompatienten in gevorderd stadium (stadium III / IV), met de juiste BRAF expressie. Klik hier voor toestemmingsrapport.  Lees ook onderstaand artikel met een link naar het volledige studierapport dat als basis diende voor de FDA toestemming.  

6 jun i 2011: Bron Medscape en Asco

Het middel vemurafenib , ook wel onder de codenaam PLX4032 bekend werd op ASCO 2011 gepresenteerd als een doorbraak in de behandeling van melanomen met een BRAF expressie. ca. 50% tot 60% van de mensen met een melanoom zouden deze BRAF expressie hebben, aldus de onderzoekers op ASCO 2011. Op ASCO werden de resultaten uit een fase III studie gepresenteerd. Overigens die studie is niet placebo gecontroleerd maar de controlegroep kreeg de gebruikelijke chemo dacarzabine. Alle patiënten in de studie hadden een inoperabele, niet eerder behandeld stadium IIIC of stadium IV melanoom en positief getest voor de BRAF V600E mutatie. Dat betekent dat patiënten werden voorgeselecteerd dus niet dubbelblind gerandomiseerd. Opmerkelijk is ook dat slechts 5% van de groep die alleen dacarzabine kreeg deze aansloeg. Deze studie zou dus ook zomaar aan kunnen tonen dat dacarzabine gewoon niet een goede chemo is voor melanoompatiënten met een BRAF expressie. Dat zou al veel verklaren over de studieresultaten.

Na 6 maanden bleek de overleving 84% (95% betrouwbaarheidsinterval [BI], 78 tot 89) in de groep die vemurafenib had toegevoegd gekregen en 64% (95% CI, 56 tot 73) in de dacarbazine groep. Er zijn nog geen mediane algehele overlevingcijfers van de studie, omdat de gegevens nog niet het eindpunt van de follow-up studie hebben bereikt, aldus de auteurs, De resultaten voor de progressie-vrije overleving zijn wel definitief; patiënten die vemurafenib hadden gekregen hadden 5,3 maanden ziektevrije tijd tot progressie optrad, vergeleken met 1,6 maanden in de dacarbazine groep, aldus dr. Chapman, onderzoeksleider op ASCO 2011. Al met al een resultaat wat niet slecht is, maar nu ook weer niet als doorbraak kan worden betiteld wat de onderzoekers graag hun toehoorders wilden doen geloven.

Hier het abstract van de studie en als u het hele studieverslag wilt lezen klik dan hier, het is gratis in te zien.

Bron: NEJM

Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

Paul B. Chapman, M.D., Axel Hauschild, M.D., Caroline Robert, M.D., Ph.D., John B. Haanen, M.D., Paolo Ascierto, M.D., James Larkin, M.D., Reinhard Dummer, M.D., Claus Garbe, M.D., Alessandro Testori, M.D., Michele Maio, M.D., David Hogg, M.D., Paul Lorigan, M.D., Celeste Lebbe, M.D., Thomas Jouary, M.D., Dirk Schadendorf, M.D., Antoni Ribas, M.D., Steven J. O'Day, M.D., Jeffrey A. Sosman, M.D., John M. Kirkwood, M.D., Alexander M.M. Eggermont, M.D., Ph.D., Brigitte Dreno, M.D., Ph.D., Keith Nolop, M.D., Jiang Li, Ph.D., Betty Nelson, M.A., Jeannie Hou, M.D., Richard J. Lee, M.D., Keith T. Flaherty, M.D., and Grant A. McArthur, M.B., B.S., Ph.D. for the BRIM-3 Study Group

June 5, 2011 (10.1056/NEJMoa1103782)

Abstract

Article

References

Background

Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation.

Methods

We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths.

Results

At 6 months, overall survival was 84% (95% confidence interval , 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects.

Conclusions

Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann–La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.

23 januari 2011: Medscape

Nieuwe resultaten zouden aantonen dat het nieuwe experimentele middel, codenaam RG7204 of  PLX4032, voor een langere ziektevrije tijd kan zorgen bij patiënten met melanomen met een BRAF expressie. Dit meldt Medscape maar producent Roche/Genentech kunnen en willen nog geen studieresultaten publiceren. Beetje vreemd maar wellicht ook wel begrijpelijk als je de andere studieresultaten bekijkt en artsen constateren dat het middel wel bij veel patiënten aanslaat maar slechts korte tijd werkzaam is. Toch zijn andere oncologen wel optimistisch en positief over nieuwste studieresultaten. Lees hieronder achter elkaar een aantal publicaties over dit nieuwe middel. Te beginnen met citaat uit artikel van Medscape d.d. 19 januari 2011.

"A Major Breakthrough"

The results of a phase 1 trial presented last year drew praise and enthusiasm from the oncology community. In a phase 1 dose-escalation study, 81% of patients whose melanomas had an activating mutation in BRAF responded to the treatment (N Engl J Med. 2010;363:809-819). This represents "a major breakthrough," according to the authors of an editorial that accompanied the published study (N Engl J Med. 2010;363:876-879).

The results of an open-label phase 2 trial seemingly confirmed these early data. As reported by Medscape Medical News, of the 132 patients with advanced melanoma positive for the BRAF mutation, 82% experienced a response (52%) or stable disease (30%), and 52% experienced a decrease in their tumor size of 30% or more.

In the phase 2 trial, median progression-free survival was 6.2 months, which was much higher than the 2 months historically seen in this patient population. Overall survival is usually in the range of 6 to 9 months, but median overall survival had not yet been reached when the results were presented at the 7th International Melanoma Research Congress of the Society for Melanoma Research in Sydney, Australia in November 2010.

At that time, Antoni Ribas, MD, from the Jonsson Comprehensive Cancer Center at the University of California in Los Angeles, who was involved in both the phase 1 and phase 2 clinical trials, told Medscape Medical News that the responses were not durable. However, he speculated that response to RG7204 might lead to an improvement in survival by shifting the first part of the survival curve over by a few months.

26 november 2010: Bron Medscape

Een nieuwe fase II studie heeft bevestigd dat de response, het aanslaan van het nieuwe medicijn PLX4032 (RG7204), tegen melanomen, hoog blijft (zie hieronder abstract van veelbelovende studie). Echter er blijkt nu ook dat deze response niet zo erg lang aanhoudt. Al na 2 tot 7 maanden blijkt het uitgewerkt te zijn. Dit blijkt uit een fase II studie met 132 patienten met melanomen die de goede BRAF mutatie hadden. Een citaat uit artikel van medscape over deze nieuwe studie, waarvan u het volledige artikel kunt lezen als u hier klikt.

Early results in melanoma — from a phase 1 study of 32 melanoma patients with a BRAF mutation — showed responses in a "remarkable 81% of patients," which "represent a major breakthrough," enthused the authors of an editorial that accompanied the publication of the study in the New England Journal of Medicine (2010;363;809-819, 876-879).

The latest clinical results, presented recently at the International Melanoma Research Congress of the Society for Melanoma Research in Sydney, Australia, confirm the high response rates.

They come from an open-label phase 2 trial of 132 patients with previously treated advanced melanoma positive for the BRAF mutation. Researchers report that 82% of patients had a response (52%) or stable disease (30%), and 52% had a decrease in their tumor size of 30% or more.

The median progression-free survival was 6.2 months in these patients; typically progression-free survival for such patients is only about 2 months, according to the researchers. Overall survival is typically around 6 to 9 months, they add, but the median overall survival has not yet been reached in the trial.

The safety profile is similar to that already reported for the experimental agent, and includes the development again of the grade 3 cutaneous squamous cell carcinoma, this time in 26% (34 of 132) patients. In these cases, the cutaneous squamous cell carcinoma lesions were excised and the patients continued with the experimental therapy. In addition, abnormal liver function was reported in 14% of patients, joint pain/arthritis in 11%, and gastrointestinal symptoms (including gastritis and pancreatitis) in 10%. Rash, photosensitivity, and hair loss were also reported.

......

The responses are not durable; they last for an average of about 7 months before the disease progresses, Dr. Ribas noted. Even so, he speculates that the response to the drug might lead to an improvement in survival by shifting the first part of the survival curve over by a few months.

24 februari 2010: Bron: Pubmed en Plexxikon Inc.

PLX4032 lijkt een medicijn te zijn dat een deel van de ongeneeslijke melanoompatienten weer hoop kan geven op een herstel. Afgelopen jaren hebben al verschillende studies bewezen dat PLX4032 (RG7204), een heel gericht medicijn op tumoren met een BRAF mutatie, bij met name melanoompatienten met die BRAF mutatie (ca. 50% van alle melanoomtumorn hebben deze BRAS mutatie, aldus de onderzoekers) goede resultaten bewerkstelligd. Afgelopen week kwam de producent van PLX4032 naar buiten ett de eerste resultaten van een gerandomiseerde fase III studie die de eerdere resultaten uit fase II studies bevestigden.  

Hier achtereenvolgens een persbericht van Plexxikon Inc. en een paar citaten uit artikel uit Elsevier Global Medical News. Hier kunt u een uitgebreid artikel over gerichte aanpak met moleculen lezen.

Plexxikon Announces First Patient Dosed In Phase 3 Trial Of PLX4032 (RG7204) For Metastatic Melanoma

Berkeley, CA—January 8, 2010

Plexxikon Inc. announces that enrollment has been initiated and the first patient has been dosed in a pivotal Phase 3 trial of PLX4032 (RG7204) in patients with metastatic melanoma. PLX4032 is a novel, oral and highly targeted drug that is designed to inhibit the BRAF cancer-causingmutation that occurs in about 50 percent of melanomas and about eight percent of all solid tumors. The randomized, controlled, Phase 3 “BRAFInhibitor in Melanoma” (BRIM3) trial in previously untreated patients is part of the planned registration program for PLX4032. The initiation of the Phase 3 trial has triggered a significant milestone payment to Plexxikon from Roche, its co-development partner, under their 2006 collaboration agreement. Plexxikon also is entitled to receive additional payments for further milestone achievements as well as royalties on sales of PLX4032. A Phase 2 trial (BRIM2) in previously treated melanoma patients was initiated in September 2009, with enrollment ongoing.

“With some tumor shrinkage in nearly all mutation-positive melanoma patients, and 70 percent of patients achieving at least 30 percent tumor shrinkage in our most recent clinical study, PLX4032 has shown meaningful anti-tumor activity. The Phase 3 trial, with a primary endpoint of overall survival, will provide an assessment of clinical benefit of PLX4032 in a randomized, controlled study design, which should further build our registration program for this drug,” stated K. Peter Hirth, Ph.D., chief executive officer of Plexxikon.

BRIM3 is a Phase 3 trial expected to enroll approximately 700 previously untreated melanoma patients who will be randomized one-to-one with PLX4032 at a dose of 960 mg BID or dacarbazine (DTIC), a comparator drug approved for the treatment of metastatic melanoma. Patients will be monitored throughout the study for safety and efficacy endpoints. The primary endpoint of this trial is overall survival. Secondary endpoints include duration of response, progression-free survival and best overall response rate (BORR). The BRIM3 trial is a multicenter study being conducted at approximately 100 sites, including sites in the United States, Australia, Europe and Canada, with sites continuing to open through Q2 2010.

BRIM2 is a Phase 2 trial expected to enroll approximately 100 patients and is a single-arm study in previously treated melanoma patients. This trial is enrolling patients at 13 sites in the U.S. and Australia.

Patients enrolling in both BRIM3 and BRIM2 are being selected using an investigational companion diagnostic test that detects the BRAF mutation. This diagnostic is being co-developed in parallel with PLX4032 by Roche Molecular Systems, Inc. and Plexxikon. Patients interested in enrolling in the BRIM2 or BRIM3 trials may find additional information at the Roche Clinical Trials Registry (http://www.roche-trials.com/), at genentechclinicaltrials@druginfo.com, by visiting www.clinicaltrials.gov, or by contacting the Roche/Genentech Call Center at 888-662-6728. 

Phase 1 Data Support Advanced Clinical Development Program for PLX4032

Promising data from the Phase 1 extension cohort in mutation-positive melanoma patients were recently presented at the September 2009 ECCO/ESMO conference, and provided support for the initiation of the pivotal Phase 2 and Phase 3 trials in melanoma. These data showed some tumor shrinkage in nearly all patients treated with PLX4032, and 70 percent of patients achieving at least 30% tumor shrinkage by RECIST criteria. Patients in the Phase 1 melanoma extension cohort were treated with PLX4032 at a dose of 960 mg twice daily (BID), which was well tolerated. Drug-related adverse events were predominantly mild in severity, including rash, joint pain, photosensitivity and fatigue. Skin squamous cell carcinoma (keratoacanthoma subtype) was observed in 20 percent of patients and removed by excision while treatment with PLX4032 was continued.

Plexxikon conducted the Phase 1 dose escalation cohort and an extension cohort in mutation-positive melanoma patients. The company has also completed enrollment in a second extension cohort of mutation-positive colorectal cancer patients. Roche, and its wholly-owned subsidiary, Genentech, are conducting all future clinical trials of PLX4032, including BRIM2 and BRIM3.

BRAF Mutation in Melanoma and Other Cancers

The BRAF mutation has been shown, both in preclinical studies and PLX4032 clinical studies, to be a key driver of cancer, particularly in melanoma. This mutation is present in approximately 50 percent of melanoma skin cancers. Overall, about eight percent of all solid tumors carry this mutation, including melanoma, colorectal, thyroid, biliary tract, prostate, ovarian, lung and glioma cancers. The BRAF mutation represents a unique target for cancer therapy since the mutation occurs only in tumor cells and not in normal cells. The high degree of selectivity of PLX4032 for this target has enabled sufficient dose levels to achieve over 90 percent inhibition required for tumor shrinkage.  

Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAFV600E mutation and in patients with the less common BRAFV600K mutation

doi:10.1016/S1470-2045(14)70012-9
This article can be found in the following collections: Oncology (Skin cancer)

Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study

Original Text

Prof Grant A McArthur MB BS a , Prof Paul B Chapman MD b, Caroline Robert MD c, James Larkin MD d, John B Haanen MD e, Prof Reinhard Dummer MD f, Prof Antoni Ribas MD g, Prof David Hogg MD h, Omid Hamid MD i, Paolo A Ascierto MD j, Prof Claus Garbe MD k, Alessandro Testori MD l, Michele Maio MD m, Paul Lorigan MD n, Prof Celeste Lebbé MD o, Thomas Jouary MD p, Prof Dirk Schadendorf MD q, Stephen J O'Day MD r, Prof John M. Kirkwood MD s, Prof Alexander M Eggermont MD t, Prof Brigitte Dréno MD u, Prof Jeffrey A Sosman MD v, Keith T Flaherty MD w, Ming Yin PhD x, Ivor Caro MD x, Suzanne Cheng PhD y, Kerstin Trunzer PhD z, Prof Axel Hauschild MD aa

Summary

Background

In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAFV600 mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAFV600E and BRAFV600K mutation subgroups.

Methods

Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAFV600 mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m2 of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980.

Findings

675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7—16·0) on vemurafenib and 9·5 months (3·1—14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0—15·2] vs 9·7 months [7·9—12·8]; hazard ratio 0·70 [95% CI 0·57—0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1—7·0] vs 1·6 months [1·6—2·1]; HR 0·38 [95% CI 0·32—0·46]; p<0·0001). For the 598 (91%) patients with BRAFV600E disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9—14·9) compared with 10·0 months (8·0—14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60—0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2—7·0) and 1·6 months (1·6—2·1), respectively (HR 0·39 [95% CI 0·33—0·47]; p<0·0001). For the 57 (9%) patients with BRAFV600K disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2—not estimable) compared with 7·6 months (6·1—16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21—0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4—9·0) and 1·7 months (1·4—2·9), respectively (HR 0·30 [95% CI 0·16—0·56]; p<0·0001). The most frequent grade 3—4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events.

Interpretation

Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAFV600E mutation and in patients with the less common BRAFV600K mutation.

Funding

F Hoffmann-La Roche-Genentech.

Yervoy, vemurafenib, Zelboraf, BRAF mutatie, PLX4032 (RG7204), melanomen, ipilimumab

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• Vemurafenib is een heel gericht medicijn en blijkt ook in fase III studie voor goede resultaten te zorgen bij vergevorderde melanoompatienten met BRAF mutatie. FDA geeft per direct vemurafenib - zelboraf goedkeuring als officieel medicijn

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• vemurafenib plus cobimetinib, een MEK en BRAf remmer, geeft samen 49 procent langere progressievrije tijd en 35 procent minder kans op overlijden bij melanomen.