Success rate comparison of different medications for the cure of positive advanced melanomas resulting
from BRAF gene V600E mutation.
Paper by: Junwoo Jang
Abstract:
This paper will first investigate the role of the BRAF gene and the effect of the mutation and will compare
and analyze the efficacy of various treatments and treatments for BRAF mutant melanomas. Scientists now
attain the means to compare the efficacy of various medications available today for metastatic melanoma
and assess which drugs should be recommended for long or short term use. When previous medications
were compared with the current ones, the new treatments show greater regression in tumors which show
that future medicine that target the BRAF gene will be more effective in targeting melanomas. This research
paper primarily will gather data from journals, government agencies, and other research from private
institutions such as The Scott Hamilton CARES Initiative and Bristol-Myers Squibb that will provide more
information on the BRAF gene or the treatment to melanoma. There are plethora of different medications
utilized in the treatment of the BRAF gene, but the assessment and the comparison among these drugs are
not well established. This paper will determine the effectiveness of the drug by primarily noting down the
statistical measurement of common and uncommon side effect occurrences. This paper limits its research
by depending on the results of the actual experiments conducted by each health institution which implicates
that the standard of assessment may vary. To attain as much universal standard in the comparing the drugs,
this paper shall solely focus on covering the severity of the side effects that each drug produces.
Introduction:
The BRAF gene also known as the B-Raf proto-oncogene, serine/threonine kinase is responsible
for producing the B-Raf protein that controls the MAP kinase/ERKs signaling pathway which affects
proliferation, differentiation, migration and apoptosis (1). This gene is located on the q arm of chromosome
7 at position 24. To be more exact, it is located from base pair 140,719,333 to 140,294,763 (2).
The BRAF gene belongs to a class of oncogenes which contain the potential to convert normal cells
to cancerous ones when mutated. One of the most common mutations is the BRAF V600E mutation. This
mutation is caused when the thymine at nucleotide 1799 is substituted by adenine which changes the valine
in codon 600 to become glutamate. This mutation causes an increase in kinase activity which results to the
activation of the downstream activation pathway causing increased cell proliferation (3).
The increased cell proliferation due to the BRAF gene causes different types of cancers and our
knowledge of this has allowed pharmaceutical companies to discover treatments that inhibit the BRAF
protein. One of the cancers caused by this mutation is melanoma. Among the patients with melanoma, 66%
of them had BRAF mutations and among these patients, 92% of them had the BRAF V600E mutation.
Other cancers associated with this mutation is thyroid cancer and colorectal cancer in which 18-87% and
9-14% of those patients respectively had the BRAF V600E mutation. Since this mutation is present in many
of the cancers and could likely be the leading cause, more research on how this gene affects our bodies can
allow new medications to be more efficient in inhibiting the BRAF protein (3).
The most widely used test to detect BRAF V600 mutations in melanoma is the cobas 4800 test
which has been approved by the FDA on August 17, 2011. Doctors first extract a small tissue sample from
the melanoma and performs a biopsy. The tissue is then placed in a block of paraffin wax where it is divided
into thin slices for use in the test. The DNA is taken out from the tumor cells and is mixed with reagents
that bind, detect and replicate the BRAF gene. This reaction creates fluorescence which enables doctors to
determine whether a mutation is present in the gene. When the test indicates that a mutation is present, then
the doctors can prescribe treatments that will specifically target positive advanced melanomas resulting
from BRAF gene V600E mutation (4).
When this mutation is confirmed, patients will then have options to various treatments that will
combat the melanoma. The treatments compared in this paper are DTIC, vemurafenib, trametinib,
dabrafenib, trametinib taken with dabrafenib (represented as dabrafenib + trametinib in this paper) and
ipilimumab (5,6,7).
Results:
Dacarbazine (DTIC) is a chemotherapy drug, more specifically an alkylating agent that inhibits the
growth of cancer cells. It was the first treatment that targeted stage IV melanomas and most of the drugs
that came after it used DTIC as their control group. The DTIC response rates varied from 6% to 20% and
the response lasted from 6 to 8 months. However, this drug did not show an improvement in progression
free or overall survival. Also, this medication triggers various side effects that patients should be aware
about (8).
Among the various drug nomenclatures, the ones with -nib are mostly used to combat melanomas
caused by the BRAF V600E mutation. These drugs are targeted therapies which has been discovered with
100 years of research to find the difference between normal cells and cancer cells. Before this technology,
scientists have focused on the rate of cell proliferation and observed that cancer cells generally divide more
rapidly than normal cells. However, there are a few anomalies where normal cells divide as fast as cancer
cells and this generates multiple side effects. However the newly discovered targeted therapies enable
scientists to generate new differences between cancerous and normal cells (9).
There three main categories to targeted therapy. One category focuses on the internal characteristics
and role of the cancer cell. Then the therapy uses small molecules that enter in the cell that interrupts the
cell’s function, causing them to die. Other types of targeted therapy affects the inside components of the
cell and also the receptors that are located on the outside of the cell. These receptor targeting therapies are
known as monoclonal antibodies whose drugs end in a -mab. There are also antiangiogenesis inhibitors that
target blood vessels that supply oxygen to the cancerous cells, causing them to die (9).
Vermurafenib is a type of targeted therapy also known as a kinase inhibitor that is taken orally.
Since the kinase with a mutated BRAF gene instructs cells to grow and divide uncontrollably. However,
the vemurafenib is able to block the mutated form of kinase and other kinases as well (10). Compared with
dacarbazine, an antineoplastic chemotherapy drug to also cure advanced melanomas, vemurafenib showed
a 63% reduction of the risk of death and 74% reduction of the risk of tumor progression. The median overall
survival has also reached about 16 months while that of dacarbazine was less than 10 months (11). Hence
in phase III of the drug, it was discovered that the response rate from patients taking vemurafenib was nine
times higher than patients who those treated with chemotherapy. The hazard ratio (HR) for death was 0.37
and for tumor progression it was 0.37. Also the median progression-free-survival (PFS) 5.3 months for
vemurafenib compared to the 1.6 months with DTIC (12). An independent review committee has reported
a response rate of 52% with the duration being 6.5 months (13).
Trametinib is an oral tablet that also inhibits the mitogen activated protein kinase that has potential
antineoplastic activity. Trametinib binds to MEK 1 and MEK 2 which inhibits the rate of cell proliferation
by slowing down the RAS/RAF/MEK/ERK signaling pathway. To measure the efficacy of this drug, the
progression-free-survival (PFS), which is the length of time where the disease being treated does not get
worse, was measured. The PFS for trametinib was 4.8 months which proves its higher efficacy than the
PFS for dacarbazine which was 1.6 months (14). The higher efficacy is also suggested by the tumor
shrinkage that the patients experienced. When trametinib is compared with dacarbazine, 22% of the patients
on trametinib experienced shrinkage compared to the 8% of the patients that were on the regular
chemotherapy (15). The response rate of this drug was 22% which is higher than the DTIC chemotherapy
(16). The duration of this response rate was 5.7 months (17). The median overall survival rate for this drugs
was 6 months (18).
Dabrafenib is an orally administered drug that also is an inhibitor of mutated forms of BRAF
kinases. Approved on May 29, 2013, dabrafenib is the most recent drug to be approved by the Food and
Drug Administration that combats metastatic melanoma. Among 156 melanoma patients during phase I
trials of this drug, the median PFS was 5.5 months in both BRAF V600E and BRAF V600K patients,
meaning that now it can target both mutations. Among patients with BRAF V600 melanoma and previously
untreated brain metastases, 90% of them experienced a decrease in brain tumor size and 40% of them
achieved complete responses. During phase II of the drug trial, the FPS increased to 6.2 months for patients
with the BRAF V600E but decreased to 4.6 months for patients with the BRAF V600K mutation. The
response rate for this drug is 54% with a 5.6 month duration (12). However, the median overall survival
duration was 15 months (18).
When dabrafenib and trametinib is administered together, the efficacy of the medication increases.
The response rate was 76% with an average time of 10.5 months compared to the 54% and 5.6 months that
dabrafenib had (12). In the ASCO 2014 meeting, it had been announced that the median overall survival is
25 months (18). Its PFS was a very high 9.4 months as well (19).
Different from all the other previous drugs, ipilimumab is a treatment known as immunotherapy
that targets metastatic melanomas. In our bodies, there are cytotoxic T lymphocytes (CTLs) that detect and
destroy cancer. However, there is an inhibitor of this action known as the CTLA-4 inhibitory signal.
Ipilimumab serves to block this signal which allow the CTLs to continue to destroy the cancer cells (20).
According to Bristol-Myers Squibb, the company who produced this drug, patients who took ipilimumab
with an experimental drug shows a median overall survival of 10 months. The company defines an
experimental drug as “a substance or agent that, after laboratory testing has been approved by the FDA for
testing in humans”. They have not explicitly stated which drug they are using. However, they announced
that the median overall survival for patients taking this experimental drug is 6 months. The company also
showed that 46% of the patients taking only ipilimumab were alive at year 1, and 24% at year 2, compared
to the 25% and 14% of the experimental drug (21). The response rate for this drug is 12% but long term
stable disease was common with patients using this drug (22). However, an injection of this drug costs
$30,000 meaning that a course of therapy would cost $120,000 (23).
The next two graphs compare the response rate percentage and duration for all of the current
medication available for malignant melanoma with BRAF V600E mutation. A response rate refers to the
percentage of people of whose tumors responded (either shrunk or disappeared) to the drug that is prescribed.
The response rate duration refers to the length of time in which the drug affects the tumor.
Figure 1
Figure 2
In graph 1, vemurafenib, dabrafenib and dabrafenib + trametinib were over 50% in terms of the
response rate percentage, but DTIC, trametinib, and ipilimumab has a relatively low response rate
percentage meaning that only a few of the patients are able to benefit from the effects of this drug. However
in graph 2, it can be seen that DTIC, vemurafenib, trametinib, and dabrafenib all have similar response
durations. The dabrafenib with trametinib has the highest duration while dabrafenib has the lowest median
duration of 5.6 months. However, even though the response rate percentage was only 12% for ipilimumab,
the duration for some of the patients lasted more than a year. Just by looking at graph 1 and 2, the drug with
the highest efficacy is dabrafenib + trametinib, but it is hard to justify which drug is the least effective .
There are other factors that doctors consider in prescribing the required drug. One of it is the
progression free survival (PFS) duration which is the length of time where the patient, who still has the
disease, does not get worse from the disease during or after the treatment.
Figure 3
According to graph 3, DTIC has the lowest PFS duration with a time of 1.6 months, vemurafenib,
trametinib and dabrafenib all have similar PFS durations, and the dabrafenib with trametinib medication
has the highest PFS duration. Sorafenib was not included in this data, because this drug was mostly tested
for thyroid cancer and the PFS for that trial would be different if it were tested for metastatic melanoma
caused by BRAF V600E. The results pertaining to trials for combating metastatic melanoma did not
contain any data about the PFS of this drug. There is also no known information about the median
progression free survival duration, but it is known that 30% among patients has experienced a six-month
progression free survival (24).
Figure 4
It is evident from graph 4 that the dabrafenib and trametinib combination has the longest median
survival duration compared to all of the other drugs. The drug with the lowest median overall survival was
trametinib. An anomaly in this data set is ipilimumab because the median overall survival indicated is 10
months, but there are cases of patients who have survived metastatic melanoma for 2 years and above.
Side effects:
Doctors find it crucial to measure the efficacy of the drug by seeing how well the drug affects the
specific diseases. However, all drugs come with unwanted side effects and it is crucial to evaluate the
efficacy of a drug by considering its side effects.
Among patients taking DTIC, over 30% of them has experienced: local pain, burning sensation and
irritation at the site of infusion, low blood counts, vomiting, nausea, poor appetite, and elevation of blood
liver enzymes. Less common side effects that were present among 10-29% of patients include: flu-like
symptoms, sunlight sensitivity, and numbness or tingling in the feet or hands. One delayed effect of DTIC
is that there is a slight risk of having blood cancer (leukemia) after taking this drug (25).
Vemurafenib has the ability to interact with other drugs and the other drugs can either lower the
levels of vemurafenib to make the medication less effective, or cause vemurafenib to build up in the blood
stream which will worsen the side effects. Hence, patients consuming vemurafenib must be extra cautious
about their intake of other medication and be aware of the side effects. Some of the common side effects
include: joint pain, hair loss, rash, skin itching, sensitivity to sunlight, and squamous cell skin cancer. Some
rare side effects include: allergic reactions, changes in heart rhythms, weight loss, other skin cancers and
inflammations of veins (10).
Among the patients taking trametinib, these were the common side effects: increased aspartate
aminotransferase (60%), rash (57%), lymphedema (43%), diarrhea (43%), hypoalbuminemia (42%),
increased alanine aminotransferase (39%), and anemia (38%) (26). In rare cases, this drug can cause lung
damage, change in taste, eye problems (minor vision changes to blindness) and muscle breakdown.
The common side effects (greater than 30%) that patients experienced while taking dabrafenib are:
hyperglycemia, hyperkeratosis, hypophosphatemia, and headaches. The less common side effects (between
10%-29%) of patients include fever, joint pain, papilloma, squamous cell carcinoma, hair loss, hand-foot
syndrome, rash, back pains, constipation and coughs (27).
The most common side effects that were recorded for patients taking dabrafenib + trametinib were:
fever, chills, tiredness, rash, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, joint
pain, night sweats, decreased appetite, constipation and muscle pain. The side effects that were considered
serious includes: blood clot formation, bleeding, skin and eye problems, and heart failure. The existence of
squamous cell carcinoma for patients taking both dabrafenib and trametinib was 7% while the incidence of
squamous cell carcinoma for patients taking only dabrafenib was 19%. This shows that taking two different
drugs would not necessarily include both of their side effects, since the one drug could be combating the
side effect that the other drug is producing (28).
Figure 5
Even though the long term effect of ipilimumab looks promising, its side effects are deadly if not
managed. Some of the common, non-lethal side effects include rash, itching, diarrhea and fatigue. However
side effects that needs immediate attention are: holes or tears in the intestines caused by inflammation,
inflammation of the liver that leads to liver failure, inflammation of skin that leads to toxic epidermal
necrolysis, inflammation of nerves that leads to paralysis, inflammation of hormone glands and eyes (29).
Among all of the treatments, dabrafenib + trametinib have the most common side effects, but most
of them are manageable with the help of other medications. However, peripheral edema is one side effect
that may be hard to treat since the treatment involves treating the underlying cause of the edema which is
the medication itself. Although vemurafenib has a few common side effects, some of them are very lethal
to the patient. Sensitivity to sunlight is one of the side effects and this would require the patient to stay
indoors for the whole time which is not a lifestyle that patients would enjoy. Squamous cell carcinoma is
also a side effect and this is a big risk for patients because patients will then have two cancers that doctors
must treat which would increase the side effects due to the new medication.
When all the less common side effects are compared, dabrafenib has the most with some of them
being very lethal. Papilloma, hand-foot syndrome and squamous cell carcinoma are all side effects that
either needs surgery to be treated or does not have medication to be completely cured; they can only be
managed. However the less common side effects to ipilimumab are the most severe since the inflammation
caused by the drug leads to conditions that are hard to cure such as paralysis, holes or tears in the liver, or
liver failure.
Discussion:
To define a drug that has the highest efficiency, scientist must consider many aspects. If only the ability to
target the cancer cell is observed, then dabrafenib + trametinib is the most effective drug to take. If the
length of survival is the main objective of the doctors, then ipilimumab is the most effective drug. If the
common side effects are observed, dabrafenib has the least and most of them are treatable and manageable.
If the less common side effects are compared, DTIC has the most manageable and treatable symptoms.
However the drug that is considered the most efficient is the one that is able to target the disease well with
the least possible side effects, so the patient would not experience more pain that is accentuated by the side
effects. All drugs have their strengths and weaknesses, but the drug that has the best overall effect in treating
metastatic melanoma is dabrafenib + trametinib. This treatment had the highest response rate percentage,
response rate duration, median progression free survival duration and median overall survival duration
which shows that the drug potency is greatest. Compared to the other treatments, dabrafenib + trametinib
does have the most common side effects, but all of them but one can be managed by other medications.
When the less common side effects are compared, the ones caused by dabrafenib + trametinib are less
severe than ones caused by ipilimumab, sorafenib, dabrafenib, trametinib, and vemurafenib. Even though
the less common side effects of DTIC are less severe than the ones from dabrafenib + trametinib, the
survival rate of patients taking DTIC is much lower than patients taking the latter. All in all, the drug that
is both effective and efficient is dabrafenib + trametinib.
Materials and Methods:
This paper is not experiment based but more research based and hence did not require any materials. In
order to collect data for the survival rates, response rate duration, response rate percentages and progression
free survival, phase II and phase III data from clinical trials were gathered and complied from health
institutions. The information for side effects were either gathered from health institutions, cancer societies
or from the companies that have produced the drugs. This information was then gathered to create graphs
or tables that easily depicted the results that were collected.
References:
1. "Genes and Mapped Phenotypes." National Center for Biotechnology Information. U.S.
National Library of Medicine, 11 Aug. 2014. Web. 17 Aug. 2014.
2. "BRAF Gene." Genetics Home Reference. U.S. National Library of Medicine, Dec. 2012.
Web. 17 Aug. 2014.
3. Li, Xia. "BRAF Mutations: Prognostic and Therapeutic Markers in Human Cancers." BRAF
Mutations: Prognostic and Therapeutic Markers in Human Cancers. Austin Publishing
Group, 20 Mar. 2014. Web. 17 Aug. 2014.
4. "Medical Devices." Cobas® 4800 BRAF V600 Mutation Test. U.S. Food and Drug
Administration, 06 Sept. 2013. Web. 17 Aug. 2014.
5. "Common Drugs and Medications to Treat Malignant Melanoma with BRAF V600E
Mutation." WebMD. WebMD, n.d. Web. 17 Aug. 2014.
6. "Trametinib and Dabrafenib." Drugs. U.S. Food and Drug Administration, 14 Jan. 2014.
Web. 17 Aug. 2014.
7. Ribas, Antoni. "Tumor Immunotherapy Directed at PD-1." New England Journal of
Medicine 366.26 (2012): 2517-519. Web.
8. "DTIC (dacarbazine)." Aim at Melanoma. AIM at Melanoma Foundation, n.d. Web. 17 Aug.
2014.
9. "Sorafenib." (Nexavar) Chemotherapy Drug Information. Scott Hamilton CARES Initiative,
n.d. Web. 17 Aug. 2014.
10. "Vemurafenib." American Cancer Society, 27 Aug. 2013. Web. 17 Aug. 2014.
11. Ascierto, Paolo A., John M. Kirkwood, Jean-Jacques Grob, Ester Simeone, Antonio M.
Grimaldi, Michele Maio, Giuseppe Palmieri, Alessandro Testori, Francesco M. Marincola,
and Nicola Mozzillo. "The Role of BRAF V600 Mutation in Melanoma." National Center
for Biotechnology Information. U.S. National Library of Medicine, 09 July 2012. Web. 17
Aug. 2014.
12. "Treatment Options for Unresectable Stage III, Stage IV, and Recurrent
Melanoma." National Cancer Institute. N.p., n.d. Web. 17 Aug. 2014.
13. "FDA Approval for Vemurafenib." Cancer Drug Information. National Cancer Institute, 03
July 2014. Web. 17 Aug. 2014.
14. "Mekinist (trametinib)." GlaxoSmithKline. Centerwatch, May 2013. Web. 17 Aug. 2014.
15. "MEKINIST (trametinib)." Aim at Melanoma. AIM at Melanoma Foundation, n.d. Web. 17
Aug. 2014.
16. "Trametinib." Drugs. U.S. Food and Drug Administration, 30 May 2013. Web. 17 Aug.
2014.
17. Kim, K. B., R. Kefford, A. C. Pavlick, J. R. Infante, A. Ribas, J. A. Sosman, L. A. Fecher, M.
Millward, G. A. Mcarthur, P. Hwu, R. Gonzalez, P. A. Ott, G. V. Long, O. S. Gardner, D.
Ouellet, Y. Xu, D. J. Demarini, N. T. Le, K. Patel, and K. D. Lewis. "Phase II Study of the
MEK1/MEK2 Inhibitor Trametinib in Patients With Metastatic BRAF-Mutant Cutaneous
Melanoma Previously Treated With or Without a BRAF Inhibitor." Journal of Clinical
Oncology 31.4 (2013): 482-89. Web.
18. Sosman, Jeffrey A., MD. "Molecularly Targeted Therapy for Metastatic Melanoma." Wolters
Kluwer Health, 11 Aug. 2014. Web. 17 Aug. 2014.
19. "Phase II, Open-label Study of Dabrafenib plus Trametinib in Patients with BRAF Mutationpositive Melanoma Brain Metastases: A GSK-sponsored Trial."ASC Universtiy. American
Society of Clinical Oncology, n.d. Web. 17 Aug. 2014.
20. Ribas, Antoni. "Tumor Immunotherapy Directed at PD-1." New England Journal of
Medicine 366.26 (2012): 2517-519. Web.
21. "Clinical Trial Results." Metastatic Melanoma Treatment. N.p., n.d. Web. 18 Aug. 2014.
22. Chapman, Paul B. "Vemurafenib and Ipilimumab to Be Tried Together."Medscape. The Skin
Cancer Foundation, 2011. Web. 18 Aug. 2014.
23. Fellner, Chris. "Ipilimumab (Yervoy) Prolongs Survival In Advanced Melanoma."National
Center for Biotechnology Information. U.S. National Library of Medicine, Sept. 2012. Web.
18 Aug. 2014.
24. "Ipilimumab Improves Outcomes in Advanced Melanoma." CancerConnect.
CancerConsultants, n.d. Web. 24 Aug. 2014.
25. "DTIC." Drug Information. The Scott Hamilton CARES Initiative, n.d. Web. 24 Aug. 2014.
26. "Side Effects." Trametinib. Drugs, n.d. Web. 24 Aug. 2014.
27. "Dabrafenib." Drug Information. The Scott Hamilton CARES Initiative, n.d. Web. 24 Aug.
2014.
28. "FDA Approves Mekinist in Combination with Tafinlar for Advanced Melanoma."News &
Events. U.S. Food and Drug Administration, 10 Jan. 2014. Web. 24 Aug. 2014.
29. "Side Effects of a Metastatic Melanoma Treatment." Metastatic Melanoma Treatment.
Bristol-Myers Squibb, n.d. Web. 24 Aug. 2014.
Figure captions:
Figure 1: Bar graph showing the response rate percentage of DTIC and melanoma combating kinase
inhibitors.
Figure 2: Bar graph showing the response rate duration of DTIC and melanoma combating kinase
inhibitors.
Figure 3: Bar graph showing the progression free duration of DTIC and melanoma combating kinase
inhibitors.
Figure 4: Bar graph showing the median overall survival rate of patients taking BRAF V600E metastatic
melanoma combating medication.
Figure 5: Data table comparing the common side effects, less common side effects, and other side effects
of DTIC and melanoma combating kinase inhibitors with other remarks when necessary.