FDA approves first treatment for certain patients with Erdheim-Chester Disease, a rare blood cancer
The U.S. Food and Drug Administration today expanded the approval of Zelboraf (vemurafenib) to include the treatment of certain adult patients with Erdheim-Chester Disease (ECD), a rare cancer of the blood. Zelboraf is indicated to treat patients whose cancer cells have a specific genetic mutation known as BRAF V600. This is the first FDA-approved treatment for ECD. Continue reading.
//////Zelboraf, vemurafenib, fda 2017, Erdheim-Chester Disease,
|Synonyms||PLX4032, RG7204, RO5185426|
|By mouth (tablets)|
|Chemical and physical data|
|Molar mass||489.92 g/mol|
|3D model (JSmol)|
Vemurafenib (INN, marketed as Zelboraf) is a B-Raf enzyme inhibitor developed by Plexxikon (now part of Daiichi-Sankyo) and Genentech for the treatment of late-stage melanoma. The name “vemurafenib” comes from V600E mutated BRAF inhibition.
Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011, making it the first drug designed using fragment-based lead discovery to gain regulatory approval.
Vemurafenib later received Health Canada approval on February 15, 2012.
On February 20, 2012, the European Commission approved vemurafenib as a monotherapy for the treatment of adult patients with BRAF V600E mutation positive unresectable or metastatic melanoma, the most aggressive form of skin cancer.
Mechanism of action
Vemurafenib causes programmed cell death in melanoma cell lines. Vemurafenib interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway − if the B-Raf has the common V600E mutation.
Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). About 60% of melanomas have this mutation. It also has efficacy against the rarer BRAF V600K mutation. Melanoma cells without these mutations are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases.
Three mechanisms of resistance to vemurafenib (covering 40% of cases) have been discovered:
- Cancer cells begin to overexpress cell surface protein PDGFRB, creating an alternative survival pathway.
- A second oncogene called NRAS mutates, reactivating the normal BRAF survival pathway.
- Stromal cell secretion of hepatocyte growth factor (HGF).
In a phase I clinical study, vemurafenib (then known as PLX4032) was able to reduce numbers of cancer cells in over half of a group of 16 patients with advanced melanoma. The treated group had a median increased survival time of 6 months over the control group.
A second phase I study, in patients with a V600E mutation in B-Raf, ~80% showed partial to complete regression. The regression lasted from 2 to 18 months.
In early 2010 a Phase I trial for solid tumors (including colorectal cancer), and a phase II study (for metastatic melanoma) were ongoing.
A phase III trial (vs dacarbazine) in patients with previously untreated metastatic melanoma showed an improved rates of overall and progression-free survival.
In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study. The BRIM3 trial reported good updated results in 2012.
Further trials are planned including a trial of vemurafenib co-administered with GDC-0973 (cobimetinib), a MEK-inhibitor. After good results in 2014 the combination was submitted to the EC and FDA for marketing approval.
In January 2015 trial results compared vemurafenib with the combination of dabrafenib and trametinib for metastatic melanoma.
At the maximum tolerated dose (MTD) of 960 mg twice a day 31% of patients get skin lesions that may need surgical removal. The BRIM-2 trial investigated 132 patients; the most common adverse events were arthralgia in 58% of patients, skin rash in 52%, and photosensitivity in 52%. In order to better manage side effects some form of dose modification was necessary in 45% of patients. The median daily dose was 1750 mg, 91% of the MTD.
A trial combining vemurafenib and ipilimumab was stopped in April 2013 because of signs of liver toxicity.
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