Seanty's experiences with Metastatic Malignant Melanoma.
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There's a new melanoma story in the In Memoriam section: Ben's story
I'm told that the hottest new prospects for MM treatment at last week's ASCO conference were thought to be:
1. Combination therapy of BRAF and MEK inhibitors from GSK (Tafinlar/dabrafenib plus Mekinist /trametinib) - headline: resistance only develops after 9 instead of 6 months
Labels: Dabrafenib, ipilimumab, Lambrolizumab, MDX-1106, Mekinist, New melanoma drugs, Tafinlar, Trametinib, yervoy
There are so many new drugs coming through that it's hard to keep up. Here's a summary of drugs and their targets (mostly simplified from Wikipedia entries). Let me know if I've missed any, I know there are lots more under these target headings which just have codes for names at present.
BRAF is a human gene that makes a protein called B-Raf. The
B-Raf protein is involved in sending signals inside cells, which are involved
in directing cell growth. In 2002, it was shown to be faulty (mutated) in human
cancers. Drugs that treat cancers driven by BRAF have been developed. Two of
these drugs, vemurafenib and dabrafenib are approved by the US FDA for treatment of
Dabrafenib acts as an inhibitor of B-Raf. Dabrafenib has
clinical activity with a manageable safety profile in clinical trials of phase
1 and 2 in patients with BRAF(V600)-mutated metastatic melanoma. It was
approved for use against melanoma by the FDA in May
is a B-Raf enzyme inhibitor developed for the treatment of
late-stage melanoma. Vemurafenib received FDA approval for the treatment of
late-stage melanoma on August 17, 2011, Health Canada approval on February 15,
2012 and on February 20, 2012, the European Commission approved vemurafenib as
a monotherapy for the treatment of adult patients with BRAF V600 mutation
positive unresectable or metastatic melanoma, the most aggressive form of skin
A drug by Novartis disclosed at the
spring 2013 American Chemical Society meeting in New Orleans to treat melanoma
with a V600E mutation in the B-RAF kinase which it inhibits. The drug is
currently undergoing Phase II trials.
A MEK inhibitor is a chemical or drug that inhibits a biochemical
switch upstream of the gene which produces B-Raf, which is often overactive in BRAF-mutated
melanoma. Hence MEK inhibitors can both work as standalone drugs, and increase the effectiveness of BRAF drugs.
is a MEK inhibitor drug with anti-cancer activity. It
inhibits MEK1 and MEK2. In May 2013, trametinib was
approved by the FDA for the treatment of melanoma.
Cytotoxic T lymphocytes (CTLs) can recognize and destroy
cancer cells. However, there is also an inhibitory mechanism via a gene called
CTLA-4 that interrupts this destruction. CTLA-4 inhibitors turn off this mechanism and allows CTLs to continue to destroy cancer cells.
Ipilimumab was approved by the FDA in March 2011 to treat
patients with late-stage melanoma that has spread or cannot be removed by surgery.
On February 1, 2012, Health Canada approved ipilimumab for "treatment of
unresectable or metastatic melanoma in patients who have failed or do not
tolerate other systemic therapy for advanced disease." Additionally
Ipilimumab was approved in both the UK and European Union (EU), for second line
treatment of metastatic melanoma, November 2012.
Action as ipilimumab. The drug is currently undergoing Phase
Researchers have shown that several tumour types are able to
hide in plain sight by establishing a "molecular camouflage" that
deceives the body's immune system into thinking they are normal and therefore
allow them to grow unchecked. By utilizing the PD-1 pathway, a tumour cell can
prevent the activation of T-cells and therefore may block a key step that
triggers the immune system. Drugs targeting this pathway can remove the cells "camouflage", allowing the body to destroy them.
Lambrolizumab / MK-3475
is an antibody drug in development by Merck that targets the PD-1
receptor. The drug is intended for use in treating metastatic melanoma. Lambrolizumab
is being studied in multiple cancer types including melanoma.
Nivolumab is an antibody drug which acts on the PD1 receptor. A Phase 1 clinical trial tested nivolumab at
doses ranging from 0.1 to 10.0 mg per kilogram of body weight, every 2 weeks.
Response was assessed after each 8-week treatment cycle, and were evaluable for
236 of 296 patients. Study authors concluded that:"Anti-PD-1 antibody
produced objective responses in approximately one in four to one in five
patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the
adverse-event profile does not appear to preclude its use." Phase III
clinical trials of nivolumab are recruiting in the US and EU.
is an immune booster. In 1999, FDA granted Allovectin-7 orphan drug designation for the treatment of invasive and metastatic melanoma.
Talimogene laherparepvec/ T-VEC
Talimogene laherparepvec, often simply called "T-VEC" is a cancer-killing (oncolytic) virus currently being studied for the treatment of melanoma and other advanced cancers. The drug was initially developed by BioVex, Inc. under the name OncoVEX GM-CSF until it was acquired by Amgen in 2011. With the announcement of positive results in March 2013, T-VEC is the first oncolytic virus to be proven effective in a Phase III clinical trial
I have updated my pages on experimental
drugs to reflect the new possibilities. It hasn't been necessary to update my alternative medicine
page - it still doesn't work.
Labels: BRAF, CTLA-4, Dabrafenib, ipilimumab, Lambrolizumab, LGX818, MEK, Mekinist, MK-3475, Nivolumab, PD1, Tafinlar, Trametinib, vemurafenib, yervoy, Zanolimumab, zelboraf
I'm told that UK trials of the new and highly promising PD1 antibodies
for treatment-naive patients with advanced melanoma start in the next few weeks at Royal Marsden, Manchester and Southampton.
Labels: clinical trail, Lambrolizumab, Melanoma, Nivolumab, PD-1
Saw in the New Scientist today that there are a number of really promising new drugs for MM coming through: Lambrolizumab
, which both work on the PD-1 receptor, and a so far unnamed drug which works on another receptor.
All give great reductions in tumour volume, and there all in all cases apparent complete cures. They all work by rebooting the immune system, in just the same way as quack diets claim to do, but actually don't.
In other news, it seems that mucosal melanoma is really a different disease
from cutaneous melanoma.
Labels: boosting, immune system, Lambrolizumab, Malignant, Nivolumab. melanoma