Recent developments and obstacles in the treatment of melanoma with BRAF and MEK inhibitors

Accepted Manuscript Title: Recent developments and obstacles in the treatment of melanoma with BRAF and MEK inhibitors Authors: Mohd Wahid, Arshad Jawed, Raju K. Mandal, Sajad A. Dar, Naseem Akhter, Pallavi Somvanshi, Farah Khan, Mohtashim Lohani, Mohammed Y. Areeshi, Shafiul Haque PII: DOI: Reference:

S1040-8428(17)30481-X https://doi.org/10.1016/j.critrevonc.2018.03.005 ONCH 2519

To appear in:

Critical Reviews in Oncology/Hematology

Received date: Accepted date:

29-10-2017 17-3-2018

Please cite this article as: Wahid M, Jawed A, Mandal RK, Dar SA, Akhter N, Somvanshi P, Khan F, Lohani M, Areeshi MY, Haque S, Recent developments and obstacles in the treatment of melanoma with BRAF and MEK inhibitors, Critical Reviews in Oncology and Hematology (2010), https://doi.org/10.1016/j.critrevonc.2018.03.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Recent Developments and Obstacles in the Treatment of Melanoma with BRAF and MEK Inhibitors

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List of authors in order of their authorship Mohd Wahid1, Arshad Jawed1, Raju K. Mandal1, Sajad A. Dar1,2, Naseem Akhter3, Pallavi Somvanshi4, Farah Khan5, Mohtashim Lohani6, Mohammed Y. Areeshi1, Shafiul Haque1* Authors’ affiliations 1 Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan-45142, SAUDI ARABIA Division of Gynecology Oncology, Women’s Health Services, Henry Ford Hospital, Detroit, MI-48202, USA

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Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha-65431, SAUDI ARABIA 4

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Department of Biotechnology, TERI University, 10, Institutional Area, Vasant Kunj, New Delhi-110070, INDIA 5

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Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi-110062, INDIA 6

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Department of Emergency Medical Services, College of Applied Medical Sciences, Jazan University, Jazan-45142, SAUDI ARABIA

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*Corresponding author: Dr. Shafiul Haque, Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan-45142, SAUDI ARABIA Phone & Fax No: +966-173174383 E-mail: [email protected]

Running title: Melanoma treatment using BRAF and MEK inhibitors

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Highlights 

The median progression free survival in the patients administered with dabrafenib and trametinib were 5.1 and 4.8 months, respectively and in combination was increased to

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11.4 months. The overall survival rate and objective response rate for the patients administered with “dabrafenib + trametinib” have been increased by 72% 64%, respectively. 

The increments in end points were short lived. Hence, the use of BRAF and MEK

inhibitors as intermittent therapy along with heat shock protein 90 (HSP90) molecules is

ABSTRACT

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recommended.

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Metastatic melanoma is a least common form of cancer as it accounts only for 1% of all cancer cases. But, it is most deadly in nature and is haunting mankind for long emotionally as well as

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economically. The sites for the onset of the disease are pigment-producing cells of the skin, mucosa, eye etc. It has the potential to spread other sites like subcutaneous tissue, lymph nodes,

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lungs, liver, bone and brain. The United States Food & Drug Administration has approved various drug molecules from time to time. The molecules (Dabrafenib-BRAF inhibitor and Trametinib-MEK inhibitor) have proved their credentials alone and in combination as well. These molecules have demonstrated good results for various end points like median progression

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free survival, overall survival, objective response etc. The median progression free survival for patients using dabrafenib and trametinib were 5.1 and 4.8 months, respectively (administered singly). It has increased to 11.4 months in the combination treatment “dabrafenib + trametinib”,

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which is approximately 104% and 138% greater than dabrafenib and trametinib treated groups alone. Similarly, the overall survival rate and objective response rate for the patients administered with “dabrafenib + trametinib” have been increased by 72% 64%, respectively. All these increments in these parameters were for a short period of time as the molecules were unable to withstand the pressure of resistance developed in the patients. So, the current review

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suggests the use of BRAF and MEK inhibitors as intermittent therapy along with heat shock

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protein 90 (HSP90) molecules.

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Keywords: Melanoma; Chemotherapy; Vemurafenib; Dabrafenib; Trametinib; Metastatic;

1. Introduction

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progression free survival

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Unresectable; BRAF inhibitor; MEK inhibitor; Progression free survival (PFS); Median

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Melanoma is a disease haunting mankind for centuries and the proofs documented in the

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literature can be traced back to 1600s. The incidences of metastatic melanomas are growing steadily ultimately leading to increase in the mortality rate in comparison to other cancers (Hodi

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et al., 2010). The initial standard therapies for metastatic melanomas were chemotherapy like dacarbazine, interleukin 2, surgery etc., but could not perform well over the time. Nearly 50% of the patients suffering from melanomas have mutation in BRAF gene (encodes B-Raf protein, a member of Raf kinase family of growth signal transduction protein kinases). The melanoma cancers occur due to accumulation of mutations in the concerned genes leading to abnormal

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programming, cell proliferation and death. The main mutations in the BRAF genes include V600E (80–90%) and V600K (10–20%) (Davies et al., 2002; Curtin et al., 2005; Jakob et al., 2012). The treatment of metastatic melanomas patients having BRAF V600E or V600K

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mutations is progressing at a significant pace. Many potent inhibitors of BRAF were discovered with time like vemurafenib, dabrafenib etc. The first BRAF kinase inhibitor named vemurafenib (Zelboraf®) was discovered in the year 2011. It was approved by the Food and Drug Administration (FDA) in the United States for use in metastatic or unresectable melanoma in patients with a BRAF V600E mutation. Further, the additional molecules that pave the success

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path to the market after approval from US-FDA were dabrafenib (Tafinlar®) and trametinib

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(Mekinist™), wherein the dabrafenib was BRAF inhibitor and trametinib was MEK [(Mitogen-

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activated protein kinase kinase, is a kinase enzyme that phosphorylates mitogen-activated protein

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kinase (MAPK)] inhibitor.

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2. Dabrafenib (trade name Tafinlar)

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It is a potent, reversible adenosine triphosphate-competitive inhibitor. It selectively inhibits the BRAFV600E kinase. The concentration of the drug required for 50% inhibition of BRAFV600E

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kinase activity (IC50) is five times lower than that for BRAFwt or CRAF. It inhibits MAPK

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pathway in the mutated melanoma cells which results in the decreased proliferation of the cancerous cells (Laquerre et al., 2009).

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Dabrafenib was approved by the US FDA in the year 2013 for the treatment of unresectable or metastatic melanoma patients having BRAF V600E mutations as evaluated by an FDA-approved test. It was not approved/indicated for the treatment of patients with wild-type BRAF melanoma, because of the potential risk of tumor promotion (Stenger, 2014).

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The median time to achieve peak plasma concentration of dabrafenib (Tmax) is approximately 2 hours whereas the mean absolute bioavailability is about 95%. The amount of dabrafenib bound to human plasma proteins is 99.7%. The apparent volume of distribution (Vc/F) is 70.3 L.

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The dabrafenib chemically gets altered by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib. It further gets oxidized via CYP3A4 to form carboxy-dabrafenib and is excreted in bile and urine. The decarboxylation of carboxy-dabrafenib takes place to form desmethyl-dabrafenib leading to its absorption from the gut. The hydroxy- and desmethyl-dabrafenib as per their exposure time, relative potency and their pharmacokinetic properties shows their clinical effects on cancerous

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cells [Tafinlar. http://www.rxlist.com/tafinlar-drug/clinical-pharmacology.htm. (Assessed on

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15.06.2017)].

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The half-life of dabrafenib is approximately 8 hours whereas the metabolites carboxy-dabrafenib and desmethyl-dabrafenib exhibit longer half-lives accounting to almost 22 hours. The major

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route of elimination is fecal excretion (71%) and urinary excretion (23%) [Tafinlar.

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2.1. Clinical Studies

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http://www.rxlist.com/tafinlar-drug/clinical-pharmacology.htm (Assessed on 15.05.2017)].

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Dabrafenib was approved for clinical use based on the results shown in phase 3 international open-label trials. It showed significant improvements in various cancer parameters like

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progression-free survival (PFS), overall survival, hazard ratio etc (Hauschild et al., 2012). 2.2. Patients Selection and Study Design The articles demonstrating the phase 3 trials for dabrafenib indicates that the patients were enrolled from 70 sites covering 12 countries all over the world. The selected sites include

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hospitals, outpatient clinics, academic institutions etc (Hauschild et al., 2012). The patients considered eligible for study were suffering from histologically confirmed metastatic melanoma (stage IV or unresectable stage III) with BRAFV600E mutation. The patients selected were with

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no previous antitumour therapy administered for unresectable or metastatic melanoma other than interleukin 2. They were 18 years or above and Eastern Cooperative Oncology Group (ECOG) performance status was 0 (fully active and able to carry on all performance without restriction) or 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature), and adequate haematological, hepatic, renal, and cardiac function. The

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exclusion criteria was also followed while selecting the patients to be included in the clinical trial

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studies wherein no surgery, radiotherapy, or immunotherapy should have been performed within

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4 weeks; no history of HIV infection; glucose-6-dehydrogenase deficiency; and previous

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malignancy within the past 5 years.

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Almost 733 patients were enrolled for the study. The number of patients excluded from the study

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group following exclusion criteria discussed above was 483. The remaining 250 patients were randomized in two groups namely, dabrafenib and dacarbazine, respectively. The number of

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patients administered with dabrafenib was 187. The same patients were included in the intent to treat and safety population. Approximately 80 patients discontinued the treatment and remaining

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107 continued till completion of the study.

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2.3. Treatment and Efficacy The study discussed in the article by Hauschild et al., 2012 demonstrated the comparison of dabrafenib with dacarbazine whereas the current review article under this section focuses on dabrafenib alone. The eligible patients for the study were administered with oral dabrafenib 150

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mg twice-daily. The patients were stratified according to American Joint Committee on Cancer stage. The results were assessed by investigators as well as by the independent review committee (IRC). The main end point of the study to be considered was progression free survival (PFS). Out

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of the 187 patients assigned to the dabrafenib group, 88 patients discontinued the treatment (66 progression of disease, 5 adverse events, 4 investigator discretion, 5 withdrew consent). The median progression free survival for dabrafenib patients was 5.1 months (Table 1). The hazard ratio for progression is 0.30 (95% CI 0.18–0.511; p<0.0001). This indicates 70% reduction in the progression of the disease or death of the patients. The independent review committee also

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confirmed the investigator-assessed results for the progression free survival of dabrafenib to be

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6.7 months. The overall survival hazard ratio was 0.61 (95% CI 0.25–1.48) in favour of

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dabrafenib. Confirmed objective response rate was observed by independent review committee

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in 93 patients which accounts for approximately 50% of the patients assigned to dabrafenib

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treatment (95% CI 42.4–57.1). The complete response was shown by 6 patients (3%), whereas

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the number of patients showing partial response was 87 constituting around 47%. The investigator reported confirmed objective response in 99 patients (53%, 95% CI 45.5–60.3).

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The number of patients that showed the complete response was 6 which correspond to 3% of the patients assigned to dabrafenib group. The same group as per the investigator report, 93 patients

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showed partial response (almost 50%). The estimated median duration of response was 5.5 and

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5.6 months, respectively, for independent review committee and investigator assessment. The drug related adverse effects are the main deterrent obstacles for the completion of any clinical studies. Dabrafenib also demonstrated various adverse events of grade 2 or higher in almost 53% of the patients. The main adverse events were like hyperkeratosis, palmar-plantar

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erythrodysesthesia/palmar-plantar hyperkeratosis, squamous cell carcinoma/keratoacanthoma etc (Stenger et al, 2014). 3. Trametinib (trade name Mekinist)

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Trametinib was the first MEK inhibitor approved for clinical use by US FDA in the year 2013. It was approved for the patients suffering from unresectable or metastatic melanoma with BRAF V600E or V600K mutation (Chopra et al., 2015).

Trametinib is a selective reversible allosteric inhibitor of MEK1 and MEK2 having half-

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maximum inhibitory concentration or IC50 value approximately 0.7–0.9 nmol/l. The MEK1 and

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MEK2 are located downstream from BRAF kinase. These MEK1 and MEK2 proteins are

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responsible for the proliferation of melanoma cells (Thakur et al., 2013; Flaherty et al., 2012). It

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is a potent molecule with oral bioavailability, specificity and long circulating half life and small Cmax to Ctrough ratio (Gilmartin et al., 2011). The likelihood of toxicity due to long circulating half

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life with small Cmax to Ctrough ratio is more for trametinib but produces sustained MAPK pathway inhibition (LoRusso et al., 2005; Gilmartin et al., 2011; King et al., 2014; Iverson et al., 2009;

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Adjei et al., 2008; Brown et al., 2007).

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3.1. Clinical Studies

The approval of trametinib by the US FDA in the year 2013 was based on Phase III (METRIC)

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trial. These trials compared trametinib (2 mg orally once daily) with chemotherapy (DTIC 1000 mg/m2 or paclitaxel 175 mg/m2 once every 3 weeks) in a 2:1 ratio. The progression free survival (PFS) was considered as the primary end point in the treatment of patients suffering from metastatic melanoma with a V600E or V600K mutation (Flaherty et al., 2012).

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3.2. Patients Selection and Study Design The patients selected for the study had histologically confirmed, unresectable stage IIIC or IV melanoma having mutation at 600th position in the BRAF wherein the amino acid valine changed

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to either glutamic acid or lysine (V600E or V600K). The mutational status of the patients was confirmed using investigational polymerase-chain-reaction (PCR) assay performed at Response Genetics. Furthermore, all the patients enrolled for the study were more than 18 years of age and the ECOG (Eastern Cooperative Oncology Group) performance status was 0 or 1 (Oken et al., 1982; Flaherty et al., 2012). The most common exclusion criteria adopted for the study was

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negative test for the above mentioned mutations.

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The total number of patients selected for the study was 322. They were randomly assigned to

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trametinib (2 mg once daily) or intravenous chemotherapy consisting of either dacarbazine (1000

weeks.

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3.3. Treatment and Efficacy

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mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3

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The primary end point of the study was progression-free survival whereas the secondary end

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points included were overall survival, overall response rate, duration of response, and safety. The therapy was continued to the patients until disease progression, death, or withdrawal from the

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study. The patients were allowed to cross over from chemotherapy to trametinib group after the disease progression confirmation by an independent review committee. The intention to treat population showed PFS of 4.8 months with hazard ratio for progression 0.45 (95% CI, 0.33 to 0.63; p<0.001) (Flaherty et al., 2012) (Table 1). There were 35 deaths in the trametinib arm of

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the intention to treat population which accounts for approximately 16%. The 6 months overall survival rate was 81% with hazard ratio of death 0.54 (95% CI: 0.32–0.92; p = 0.01). The response rate (complete response + partial response) of the patients in the intention to treat

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population as assessed according to response evolution criteria in solid tumors (RECIST) was 22% (95% CI, 17 to 28). The median duration of response was 5.5 months (95% CI, 4.1 to 5.9). Furthermore, the data as described by Flaherty et al., 2012, showed that approximately 119 patients showed stable disease which is about 56%.

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The adverse events are considered as the important unwanted incidences in all clinical studies.

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Hence, trametinib was also not spared by the undesirable menace named adverse events/side

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effects of clinical trials. The most common adverse events in the patients administered with

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trametinib were rashes (57%), diarrhea (43%), peripheral edema (26%), fatigue (26%), and dermatitis acneiform (19%). Almost 7% of the patients showed decreased ejection fraction or

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ventricular dysfunction in trametinib group. Serious drug related grade 3 cardiac affecting events

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were also found in 2 patients leading to permanent discontinuation of the study drug.

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Dabrafenib and trametinib have shown excellent results for various parameters like progressionfree survival, overall survival, overall response rate, duration of response, and safety as single

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agents. But the threats of resistance have started haunting the patients administered with dabrafenib and trametinib as single agents. The scientists are actively working on the resistance

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around the world to find any way out. The main reason found was the reactivation of MAPK pathway which is present upstream of MEK rather than any parallel or bypass pathway (Nazarian et al., 2010; Poulikakos et al., 2011; Johannessen et al., 2010; Straussman et al., 2012). Hence, it

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was suggested to combine dabrafenib and trametinib which showed comparatively better results than when administered alone for the treatment of melanoma. 4. Dabrafenib & Trametinib Combination

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The combination of dabrafenib and trametinib was considered to enhance antitumor activity in the melanoma patients compared to dabrafenib alone. The absolute obstruction of the MAPK pathway by combining a BRAF inhibitor and MEK inhibitor was suggested to outdo BRAF inhibitor resistance that produces cell death in BRAF V600 melanoma patients (Flaherty et al.,

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2012).

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4.1. Clinical Studies

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A Phase III study by the name COMBI-V was conducted to study the combined effect of

The COMBI-V study was conducted to compare the

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patients to establish an OS benefit.

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dabrafenib and trametinib in unresectable metastatic BRAF V600E or V600K mutation positive

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combined effect of dabrafenib and trametinib in comparison vemurafenib. Dabrafenib was administered (150 mg orally twice daily) and trametinib (2 mg orally once daily) whereas

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vemurafenib was administered as 960 mg orally twice daily.

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4.2. Patients Selection and Study Design COMBI-V was an open-label, randomised phase 3 study. It was conducted to compare the

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combination of dabrafenib and trametinib therapy with vemurafenib monotherapy. It was carried out from June, 2012, to October, 2013. Around 1645 patients were screened at 193 centres all over the world. The selected patients were histologically confirmed unresectable or metastatic melanoma with BRAF Val600Glu or Val600Lys mutations and all of them were of 18 years or older (Robert et al., 2015). Out of the 1645 screened patients, 704 patients undergo

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randomization with 352 patients in each “dabrafenib + trametinib” and vemurifenib group, respectively. A total of 68 patients which accounts for approximately 10% (34 patients in each group) had BRAF V600K mutation. The number of patients that continued to receive treatment

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for at least 15 days after disease progression was 80 in the combination therapy group and 81 in the vemurafenib group as per the request from an investigator in spite of RECIST progression. 4.3. Treatment and Efficacy

The various parameters were checked for the clinical trial studies of the combination therapy that includes dabrafenib and trametinib (Robert et al., 2015). These parameters were median

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progression-free survival, overall survival and objective response rate etc. The median

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progression-free survival as assessed by Robert et al., 2015 was 11.4 months in the “dabrafenib +

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trametinib” group. The rate of overall survival was 72% (95% CI, 67 to 77; hazard ratio=0.69;

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95% CI, 0.53 to 0.89) in the combination therapy group at 12 months. Further, the additional important parameter shown by the investigators was a complete response. The complete response

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was shown by 47 patients which is about 13% of the patients in the combination therapy group.

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The partial response was shown by 179 patients (approximately 51% patients) where as the

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stable disease was shown by 92 patients (approximately 26% patients). The progressive disease in the combination therapy group was demonstrated by 22 patients which is about 6% of the

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patients in the intention to treat population. The objective response was shown by 64% of the patients (226 patients, 95% CI 59.1 to 69.4). The duration of response was approximately 13.8

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months (95% CI, 11.0 to not reached). Almost 91% patients in the treatment group suffered from various adverse events wherein 13% stopped the treatment permanently. The most common adverse events were pyrexia and decreased ejection fraction (3% for each event) in the combination-therapy group.

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5. Opinion The current revew has discussed various end points like median progression free survival, overall survival rate, objective response and median duration of response of different metastatic

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melanoma patients (Table 1). The patients were administered with dabrafenib, trametinib alone and their combination. The median progression free survival as demonstrated by the patients administered with dabrafenib and trametinib were 5.1 and 4.8 months, respectively. The median progression free survival of the metastatic patients was increased to 11.4 months in the combination treatment “dabrafenib + trametinib” which is approximately 104% and 138%

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greater than dabrafenib and trametinib treated groups alone, respectively.

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The next parameter referred as overall survival rate was not reached for the dabrafenib patients.

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The trametinib administered group demonstrated overall survival rate around 54% whereas the

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“dabrafenib + trametinib” combination group showed 72% overall survival rate after 12 months time.

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The objective response rate (complete + partial) for the dabrafenib and trametinib group was

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50% (93 out of 187 patients) and 22% (47 out of 214 patients), respectively. The same parameter

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as measured for the “dabrafenib + trametinib” combined group was found to be 64% which corresponds to 226 patients out of 351 patients. Furthermore, the median duration of response for

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the combination treatment group was also tremendously increased to 13.8 months in comparison to 5.5 months as shown by dabrafenib and trametinib group separately. Hence, the results shown

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are impressive in different valuable parameters of the metastatic melanoma patients treated by the combination. But most of the results for various end points do not seem to last long. The mentioned improvement in the results of the combination treatment group i.e., dabrafenib + trametinib can be attributed to the overcoming of resistance developed in dabrafenib and

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trametinib groups alone, respectively. The resistance developed in the patients in response to the metastatic drugs has been vigorously probed by many investigators. The reactivation of the MAPK pathway upstream of MEK was found as the major contributing factor for the resistance

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developed (Nazarian et al., 2010; Poulikakos et al., 2011; Johannessen et al., 2010; Straussman et al., 2012). The dual inhibitions of MEK and mutant BRAF kinases have shown good results in initial tumour response, have the capacity to prevent or delays MAPK-driven acquired resistance but not for too long. The outcomes have also shown the decrease in frequency and severity of the adverse events related to skin (Long et al., 2014; Robert et al., 2015; Larkin et al., 2014). The

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results obtained by using the combination of dabrafenib and trametinib have shown good

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progress in various parameters like median progression free survival, overall survival rate,

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objective response etc for the time being.

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Hence, it appears that new combinations of different drugs are warranted that could circumvent the problem of resistance developed in the patients undergoing treatment for metastatic

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melanoma. The various scientists have started trying these combinations for the treatment of

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resistant patients or to prevent the development of resistance in the new patients. The sequential

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or combinatorial therapy using BRAF and MEK inhibitors have not shown much benefit. Furthermore, it was also shown that resistance to BRAF inhibitors also imparts resistance to

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MEK inhibitors (Kim et al., 2013). The studies at preliminary stages have also suggested that intermittent therapy can prove to be as boon with BRAF inhibitor to delay the development of

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acquired resistance (Thakur et al., 2013). The other molecules named heat shock protein 90 (HSP90) inhibitors (XL888) have the potential to overcome the onset of BRAF inhibitor resistance (Paraiso et al., 2012). Hence, the current review suggests targeting multiple pathways responsible to develop the resistance in metastatic patients by using different intermittent

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combinations BRAF and MEK inhibitors along with heat shock protein molecules like HSP90/XL888.

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Conflict of Interest The authors have declared no conflicts of interests.

Acknowledgements

Authors are grateful to Jazan University, Saudi Arabia for providing the necessary facilities for

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References

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this research study.

1. Hodi, F.S., O'Day, S.J., McDermott, D.F., Weber, R.W., Sosman, J.A., Haanen, J.B.,

A

Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J.C., Akerley, W., van den Eertwegh, A.J., Lutzky, J., Lorigan, P., Vaubel, J.M., Linette, G.P., Hogg, D., Ottensmeier, C.H., Lebbé, C., Peschel, C., Quirt, I., Clark, J.I., Wolchok, J.D., Weber, J.S., Tian, J., Yellin, M.J, Nichol, G.M, Hoos, A., Urba, W.J., 2010. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 363 (8), 711-23.

15

2. Davies, H., Bignell, GR., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M.J., Bottomley, W., Davis, N., Dicks, E., Ewing, R., Floyd, Y., Gray, K., Hall, S., Hawes, R., Hughes, J., Kosmidou, V., Menzies, A., Mould, C., Parker, A., Stevens, C.,

SC RI PT

Watt, S., Hooper, S., Wilson, R., Jayatilake, H., Gusterson, B.A., Cooper, C., Shipley, J., Hargrave, D., Pritchard-Jones, K., Maitland, N., Chenevix-Trench, G., Riggins, G.J., Bigner, D.D., Palmieri, G., Cossu, A., Flanagan, A., Nicholson, A., Ho, J.W.C., Leung, S.Y., Yuen, S.T., Weber, B.L., Seigler, H.F., Darrow, T.L., Paterson, H., Marais, R., Marshall, C.J., Wooster, R., Stratton, M.R., Futreal, PA., 2002. Mutations of the BRAF gene in human

Curtin, J.A., Fridlyand, J., Kageshita, T., Patel, H.N., Busam, K.J., Kutzner, H., Cho, K.H.,

N

3.

U

cancer. Nature. 417, 949–54.

A

Aiba, S., Bröcker, E.B., LeBoit, P.E., Pinkel, D., Bastian, B.C., 2005. Distinct sets of genetic

Jakob, J.A., Bassett, R.L.Jr., Ng C.S., Curry, J.L., Joseph, R.W., Alvarado, G.C., Rohlfs,

D

4.

M

alterations in melanoma. N Engl J Med. 353, 2135–47.

TE

M.L., Richard, J., Gershenwald, J.E., Kim, K.B., Lazar, A.J., Hwu, P., Davies, M.A., 2012. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer.

Laquerre, S., Arnone, M., Moss, K., Yang, J., Fisher, K., Kane‐ Carson, L.S., Smitheman,

CC

5.

EP

118(16): 4014–4023.

K., Ward, J., Heidrich, B., Rheault, T., Adjabeng, G., Hornberger, K., Stellwagen, J.,

A

Waterson, A., Han, C., Mook Jr. R.A., Uehling, D., King, A.J., 2009. A selective RAF kinase inhibitor induces cell death and tumor regression of human cancer cell lines encoding B-RAFV600E mutation [abstract]. Mol Cancer Ther. 8(12 Suppl 1): Abstract B88.

16

6.

Stenger, M., 2014. Dabrafenib in advanced melanoma with BRAF V600E mutation. JCSO. 12, 48-49.

7.

Tafinlar.

http://www.rxlist.com/tafinlar-drug/clinical-pharmacology.htm.

(Assessed

on

8.

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15.05.2017). Hauschild, A., Grob, J.J., Demidov, L.V., Jouary, T., Gutzmer, R., Millward, M., Rutkowski, P., Blank, C.U., Miller, W.H. Jr., Kaempgen, E., Martín-Algarra, S., Karaszewska, B., Mauch, C., Chiarion-Sileni, V., Martin, A.M., Swann, S., Haney, P.,

U

Mirakhur, B., Guckert, M.E., Goodman, V., Chapman, P.B., 2012. Dabrafenib in BRAF-

N

mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled

Thakur, M.D., Stuart, D.D., 2013. The evolution of melanoma resistance reveals therapeutic

M

9.

A

trial. Lancet. 380, 358-365.

D

opportunities. Cancer Res. 73, 6106-6110.

TE

10. Chopra, N., Nathan, P.D., 2015. Trametinib in metastatic Melanoma. Expert Rev Anticancer

EP

Ther. 15(7): 749-60.

11. Flaherty, K.T., Robert, C., Hersey, P., Nathan, P., Garbe, C., Milhem, M., Demidov, L.V.,

CC

Hassel, J.C., Rutkowski, P., Mohr, P., Dummer, R., Trefzer, U., Larkin, J.M., Utikal, J., Dreno, B., Nyakas, M., Middleton, M.R., Becker, J.C., Casey, M., Sherman, L.J., Wu, F.S.,

A

Ouellet, D., Martin, A.M., Patel, K., Schadendorf, D., METRIC Study Group., 2012. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 367, 107-114.

17

12. Gilmartin, A.G., Bleam, M.R., Groy, A., Moss, K.G., Minthorn, E.A., Kulkarni, S.G., Rominger, C.M., Erskine, S., Fisher, K.E., Yang, J., Zappacosta, F., Annan, R., Sutton, D., Laquerre, S.G., 2011. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and

SC RI PT

activation with favourable pharmacokinetic properties for sustained in vivo pathway inhibition. Cancer Ther Preclin. 17(5), 989-1000.

13. LoRusso, P.M., Adjei, A.A., Varterasian, M., Gadgeel, S., Reid, J., Mitchell, D.Y., Hanson, L., DeLuca, P., Bruzek, L., Piens, J., Asbury, P., Van, B.K., Herrera, R., Sebolt-Leopold, J., Meyer, M.B., 2005. Phase I and pharmacodynamics study of the oral MEK inhibitor CI-

N

U

1040 in patients with advanced malignancies. J Clin Oncol. 23(23), 5281-593.

A

14. King, J.W., Nathan, P.D., 2014. Role of the MEK inhibitor trametinib in the treatment of

M

metastatic melanoma. Future Oncol. 10(9), 1559-1570. 15. Iverson, C., Larson, G., Lai, C., Yeh, L.T., Dadson, C., Weingarten, P., Appleby, T., Vo, T.,

D

Maderna, A., Vernier, J.M., Hamatake, R., Miner, J.N., Quart, B., 2009. RDEA119/BAY

TE

869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer.

EP

Cancer Res. 69(17), 6839-6847.

CC

16. Adjei, A.A., Cohen, R.B., Franklin, W., Morris, C., Wilson, D., Molina, J.R., Hanson, L.J., Gore, L., Chow, L., Leong, S., Maloney, L., Gordon, G., Simmons, H., Marlow, A.,

A

Litwiler, K., Brown, S., Poch, G., Kane, K., Haney, J., Eckhardt, S.G., 2008. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 26(13), 2139-2146.

18

17. Brown, A.P., Carlson, T.C., Loi, C.M., Graziano, M.J., 2007. Pharmacodynamic and toxicokinetic evaluation of the novel MEK inhibitor, PD0325901, in the rat following oral and intravenous administration. Cancer Chemother Pharmacol. 59(5), 671-679.

SC RI PT

18. Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T, Carbone, P.P., 1982. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 5, 649-655.

19. Nazarian, R., Shi, H., Wang, Q., Kong, X., Koya, R.C., Lee, H., Chen, Z., Lee, M.K., Attar,

U

N., Sazegar, H., Chodon, T., Nelson, S.F., McArthur, G., Sosman, J.A., Ribas, A., Lo, R.S.,

N

2010. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS

A

upregulation. Nature. 468, 973–977.

M

20. Poulikakos, P.I., Persaud, Y., Janakiraman, M., Kong, X., Ng, C., Moriceau, G., Shi,H., Atefi, M., Titz, B., Gabay, M.T., Salton, M., Dahlman, K.B., Tadi,

M.,

Wargo,

J.A.,

D

Flaherty,K.T., Kelley, M.C., Misteli, T., Chapman, P.B., Sosman, J.A., Graeber, T.G.,

TE

Ribas, A., Lo, R.S., Rosen, N., Solitet, DB., 2011. RAF inhibitor resistance is mediated by

EP

dimerization of aberrantly spliced BRAF(V600E). Nature. 480, 387–390.

CC

21. Johannessen, C.M., Boehm, J.S., Kim, S.Y., Thomas, S.R., Wardwell, L., Johnson, L.A., Emery, C.M., Stransky, N., Cogdill, A.P., Barretina, J., Caponigro, G., Hieronymus, H.,

A

Murray, R.R., Salehi-Ashtiani, K., Hill, D.E., Vidal, M., Zhao, J.J., Yang, X., Alkan, O., Kim, S., Harris, J.L., Wilson, C.J., Myer, V.E., Finan, P.M., Root, D.E., Roberts, T.M., Golub, T., Flaherty, K.T., Dummer, R., Weber, B.L., Sellers, W.R., Schlegel, R., Wargo, J.A., Hahn, W.C., Garraway, L.A., 2010. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 468, 968–972.

19

22. Straussman, R., Morikawa, T., Shee, K., Barzily-Ronki, M., Du, J., Davis, A., Gould, J., Flaherty, K.T., Ogino, S., Wargo, J.A., Golub, T.R., 2012. Tumor microenvironment contributes to innate RAF-inhibitor resistance through HGF secretion. Proceedings of the

SC RI PT

103rd Annual Meeting of the American Association for Cancer Research; Chicago, Illinois; March 31–April 4. (4837).

23. Flaherty, K.T., Infante, J.R., Daud, A., Gonzalez, R., Kefford, R.F., Sosman, J., Hamid, O., Schuchter, L., Cebon, J., Ibrahim, N., Kudchadkar, R., Burris III, H.A., Falchook, G., Algazi, A., Lewis, K., Long, G.V., Puzanov, I., Lebowitz, P., Singh, A., Little, S., Sun, P.,

U

Allred, A., Ouellet, D., Kim, K.B., Patel, K., Weberet, J., 2012. Combined BRAF and MEK

A

N

Inhibition in Melanoma with BRAF V600 Mutations. N Engl J Med. 367(18), 1694-1703.

M

24. Robert, C., Karaszewska, B., Schachter, J., Rutkowski, P., Mackiewicz, A., Stroiakovski, D., Lichinitser, M., Dummer, R., Grange, F., Mortier, L., Chiarion-Sileni, V., Drucis, K.,

D

Krajsova, I., Hauschild, A., Lorigan, P., Wolter, P., Long, G.V., Flaherty, K., Nathan, P.,

TE

Ribas, A., Martin, A., Sun, P., Crist, W., Legos, J., Rubin, S.D., Little, S.M., Schadendorf, D., 2015. Improved Overall Survival in Melanoma with Combined Dabrafenib and

EP

Trametinib. N Engl J Med. 372, 30-39.

CC

25. Long, G.V., Stroyakovskiy, D., Gogas, H., Levchenko, E., Braud, F.D., Larkin, J., Garbe, C., Jouary, T., Hauschild, A., Grob, J.J., Sileni, V.C., Lebbe, C., Mandala, M., Millward, M.,

A

Arance, A., Bondarenko, I., Haanen, J.B.A.G., Hansson, J., Utikal, J., Ferraresi, V., Kovalenko, N., Mohr, P., Probachai, V., Schadendorf, D., Nathan, P., Robert, C., Ribas, A., DeMarini, D.J., Irani, J.G., Casey, M., Ouellet, D., Martin, A., Le, N., Patel, K., Keith

20

Flaherty, K., 2014. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 371, 1877–1888. 26. Larkin, J., Ascierto, P.A., Dreno, B., Atkinson, V., Liszkay, G., Maio, M., Mandala, M.,

SC RI PT

Demidov, L., Stroyakovskiy, D., Thomas, L., Cruz-Merino, L.D.L., Dutriaux, C., Garbe, C., Sovak, M.A., Chang, I., Choong, N., Hack, S.P., McArthur, G.A., Ribas, A., 2014. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 371,

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1867–1876.

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Biographies

Shafiul Haque earned his PhD in biotechnology from Jamia Millia Islamia, New Delhi, India

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and achieved excellent blend of managerial skills by completing MBA, PG Diploma in Pharma Regulatory Affairs, and Certificate Course on Intellectual Property Rights. He worked for BioRad laboratories as an Application Specialist (genomics & proteomics) for EMEA region & West India. He did his Post-doctoral research from the University of Helsinki, Finland. Later, he worked as a Research Consultant for King Saud University, Riyadh (Saudi Arabia) and from the

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last four years, he is the Head of the Research & Scientific Studies Unit, College of Nursing & Allied Health Sciences, Jazan University, Saudi Arabia. His areas of interest are cancer biology,

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genetics, bioprocess, bioinformatics, medical education, and infectious diseases.

Mohd Wahid completed his doctoral reasearch in biochemistry from Jamia Millia Islamia, New Delhi, India. He achieved outstanding fusion of techno-legal knowledge by completing PG Diplomas in Pharmaceutical Regulatory Affairs and in Intellectual Property Laws. Dr. Wahid was a manager in R&D center of Dr. Reddy’s Laboratories Ltd., Hyderabad (India) and

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supervised different projects dealing with therapeutic proteins/antibodies development, and also

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actively participated in their clinical trials. Also, he worked as an Intellectual Property Manager

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in Glenmark Research Centre, Mumbai (India) for the development of New Biological Entities

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(NBEs). Presently, Dr. Wahid is working as an Asst. Professor of biochemistry in the College of

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Nursing & Allied Health Sciences, Jazan University, Saudi Arabia. His research expertise

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included infectious diseases, immunology, and cancer biology.

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Figures and table

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Table 1. Results of various end-points using dabrafenib and trametinib, separately and their combination for the treatment of metastatic melanoma patients

Parameters

Dabrafenib

Median progression free survival (mo)

5.1

Hazard ratio 0.30

Overall survival rate

NR

--

Trametinib

p-value

CI

<0.0001

--

95% 0.180.511 --

p-value

CI

4.8

Hazard ratio 0.45

<0.001

81% at 6

54

0.01

95%, 0.33 to 0.63 95%,

Dabrafenib + Trametinib Hazard p-value ratio

CI

11.4

72% at

0.69

0.005

22

95%,

months

Complete response (%) Partial response (%)

Median duration of response (mo)

93 patients (50%) 6 patients (3%) 87 patients (47%) 5.5

--

<0.001

47 patients (22%) 4 patients (2%)

--

<0.001

--

95% 42.4– 57.1 --

--

--

--

--

--

--

--

--

--

--

--

--

--

43 patients (20%) 5.5

--

--

--

--

0.53 to 0.89 --

--

--

--

--

--

--

95%, 4.1 to 5.9

--

--

95%, 11.0 to not reached

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Note: NR=not reached; mo=month(s); CI=confidence interval

12 months 226 patients (64%) 47 patients (13%) 179 patients (51%) 13.8

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Objective response

0.32 to 0.92 95%, 17 to 28

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