Cancer Treatment Today » New Drugs

Afinitor with octreotide for eenuroendocrine cancer – pro

M Levin, MD — Sun, 15 Dec 2013 14:17:59 +0000

Both Afinitor (everolimus) and octreotide are FDA approved for neuroendocrine cancer. The phase III RADIANT-2 trial conducted in 429 patients with advanced neuroendocrine tumors (NETs) previously established that the addition of everolimus to long-acting octreotide led to a clinically meaningful 5.1-month delay in disease progression compared with octreotide alone. However, this value just missed the prespecified boundary for statistical significance (prespecified p value ≤ 0.0246; actual p value = 0.026).

Closer inspection of the data revealed that more patients with a poor prognosis were randomly assigned to the experimental arm versus the control arm, potentially attenuating the observed benefit of everolimus. Future studies will attempt to confirm the benefit of combining these two drugs.

Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group.Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study.Lancet. 2011 Dec 10;378(9808):2005-12. doi: 10.1016/S0140-6736(11)61742-X. Epub 2011 Nov 25.

http://gicasym.org/radiant-2-reanalysis-everolimus-might-be-more-beneficial-against-advanced-nets-previously-recognized

Everolimus is beneficial

Octreotide is beneficial

SPrycel for melanoma – pro

M Levin, MD — Thu, 10 Oct 2013 16:35:26 +0000

Sprycel (dasatinib) is an attractive drug for use in melanoma because it affects mutations that re sometimes expressed in melanoma cells, A recent phase II study (Kluger et al) found that it had minimal activity in melanoma, except in patients with the C-KIT mutations. Thirty-nine patients were enrolled, 36 of whom were evaluable for activity and toxicity. Five, 4, and 3 patients had acral-lentiginous, ocular, or mucosal primaries, respectively. Two patients had confirmed partial responses lasting 64 and 24 weeks (RR 5%). One patient with an exon-13 c-kit mutation had a partial response, whereas disease in another patient with an exon-11 c-kit mutation progressed. The study suggests that identifying predictive biomarkers is important for future development of dasatinib in melanoma alone or in combination trials. There si an ongoing trial: Dasatinib in Treating Patients With Locally Advanced or Metastatic Mucosal Melanoma, Acral Melanoma, or Vulvovaginal Melanoma That Cannot Be Removed By Surgery, NCT00700882

Kluger HM, Dudek AZ, McCann C, Ritacco J, Southard N, Jilaveanu LB, Molinaro A, Sznol M. A phase 2 trial of dasatinib in advanced melanoma. Cancer. 2011 May 15;117(10):2202-8.

BC. Bastian, Targeting Activated KIT Signaling for Melanoma Therapy

JCO September 10, 2013 vol. 31 no. 26 3288-3290

Ferriprox for sickle cell – pro

M Levin, MD — Wed, 17 Jul 2013 18:25:17 +0000

FERRIPROX® (deferiprone) is an iron chelator indicated for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. The approval in second line is reasonable both because the studies for approval were done in second line and because Ferroprox may be inferior to Exjade in first line (Cemak et al). This is not an innocuous drug; the most serious side effect seen in about two percent of patients treated with Ferriprox was the development of agranulocytosis, a serious and potentially life-threatening reduction in the number of granulocytes (a type of white blood cell that fights infection). The therapy is being approved under the FDA’s accelerated approval program, designed to provide patients with earlier access to promising new drugs followed by further studies to confirm the drug’s clinical benefit. The accelerated approval program allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on an endpoint that is reasonably likely to predict a clinical benefit to patients, or on an effect on a clinical endpoint other than survival or irreversible morbidity (illness).

ApoPharma has agreed to several post-marketing requirement and commitments. One commitment includes further study of the use of Ferriprox in patients with sickle cell disease who have transfusional iron overload. One such study is: Absorption, Metabolism, and Excretion of a Single Dose of Ferriprox® in Patients With Sickle Cell Disease, NCT01835496.

For Lay version see here

At this time, there is not sufficient literature support for the use of Ferriptox in sickle cell disease.

Cermak, Jaroslav,2011, http://www.eventure-online.com/eventure/publicAbstractView.do?id=161926&congressId=4634

Ferriprox, Prescribing Information, 2013

Erbitux for gastric cancer – pro

M Levin, MD — Wed, 29 May 2013 02:13:57 +0000

Epidermal growth factor receptor (EGFR) is over-expressed in a significant proportion of esophageal and gastric carcinomas and there has been significant interest in targeting it. Unfortunately, it has not yet shown much progress. A phase II study by Chan et al showed minimal clinical activity of cetuximab. A recent phase III trial, EXPAND (Erbitux in Combination With Xeloda and Cisplatin in Advanced Esophagogastric Cancer), involved 904 patients in 24 countries in Asia Pacific, Europe, and Latin America, and in Japan. Patients had unresectable advanced cancer of the stomach or gastroesophageal junction, and had received no previous chemotherapy or radiotherapy. Patient outcome was similar between treatment groups and the primary and secondary endpoints were not met; progression-free survival was 4.4 versus 5.6 months and overall survival was 9.4 versus 10.7 months with cetuximab combination and control treatment, respectively. Overall response rates were 29% with cetuximab and 30% with control. Cetuximab is not listed by NCCN on p. GAST-E.

Moehler M, Galle PR, Gockel I, et al. The multidisciplinary management of gastrointestinal cancer. Multimodal treatment of gastric cancer. Best Pract Res Clin Gastroenterol. 2007;21(6):965-981.

Pinto C, Di Fabio F, Siena S, et al. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol. 2007;18(3):510-517.

J.A.Chan et al, A multicenter phase II trial of single-agent cetuximab in advanced esophageal and gastric adenocarcinoma

Jan Kulig et al, Targeted therapy for gastric cancer–current status J Oncol Pharm Pract (2013) 19(1): 75-81

For Erbitux in other cancers besides colon cancer, see here, here and here

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Atelvia and gastrointestinal toxicity – pro

M Levin, MD — Thu, 25 Apr 2013 14:02:03 +0000

Risedronic acid(Atelvia) is a bisphosphonate used to strengthen bone, treat or prevent osteoporosis, and treat Paget’s disease of bone. It is recommended that risedronate be taken with the body upright, and followed by a glass of water. Moreover, it is recommended that no food or drink other than water be taken for 2 hours before and 30 minutes after taking risedronate. Risedronate has a faster esophageal transit time and a different chemical chain which results in less gastrointestinal side-effects than other drugs in this class. The dosage instructionssay that risedronate can be taken with less water than other drugs in the class. It is taken weekly but risedronate is also available as a 75mg tablet to be taken on two consecutive days each month (2CDM) in order to optimize patient adherence. These factors may make it preferred for use in the elderly.

M.R McLung et al, Efficacy and safety of a novel delayed-release risedronate 35 mg once-a-week tablet. Osteoporos Int. 2012 January; 23(1): 267–276.

McClung MR, Balske A, Burgio DE, Wenderoth D, Recker RR.
Treatment of postmenopausal osteoporosis with delayed-release risedronate 35 mg weekly for 2 years.Osteoporos Int. 2013 Jan;24(1):301-10.

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For more on Zometa in osteoporosis and for Forteo see here

Cyclosporine for aplastic anemia – pro

M Levin, MD — Tue, 23 Apr 2013 23:32:54 +0000

Aplastic anemia in younger patients is generally immune mediated and is treated with immunosupression. When there is no sibling donor, cyclosporine(CSA) is recommended, usually in combination with other drugs but it can also be used alone(1). First-line treatment approaches include immunosuppressive treatment using the combination of antithymocyte globulin and cyclosporine A for patients without a sibling donor and HLA identical sibling transplant for patients younger than age 40 with a donor(2). Despite a theoretical rationale for its use, sirolimus did not improve the response rate in patients with severe aplastic anemia when compared to standard h-ATG/CsA(3). CsA is usually dosed on day 1 to a target trough level between 200 and 400 ng/mL, starting at a dose of 10 mg/kg per day (in children, 15 mg/kg per day).

1.http://aphcon.org/aplastic-anemia-treatment-guidelines.html, 2013

2. Jakob R. Passweg et al, Aplastic Anemia: First-line Treatment by Immunosuppression and Sibling Marrow Transplantation ASH Education Book December 4, 2010 vol. 2010 no. 1 36-42

3.Scheinberg P, Wu CO, Nunez O, et al.(2009) Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study. Haematologica 94:348354.

4.Phillip Scheinberg1and Neal S. Young, .How I treat acquired aplastic anemia Blood August 9, 2012 vol. 120 no. 6 1185-1196

For Lay version see here

Promacta for Aplastic Anemia

Red cell growth factors for Aplastic Anemia

Megace ES and Megace; What does bioequivalence mean? – pro

M Levin, MD — Sun, 24 Feb 2013 05:15:10 +0000

The advantage is in the concentrated dose that Megace ES offers in contrast to Megace. Megace ES (megestrol acetate) oral suspension is indicated for the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS).

The recommended adult initial dosage of Megace ES (megestrol acetate) oral suspension is 625 mg/day (5 mL/day or one teaspoon daily). The equicaletn Megace dose it 800 mg and requires 20 ml. Megace ES 625 mg/5 mL and megestrol acetate oral suspension 800 mg/20 mL are bioequivalent in a fed state.
A bioavailability study directly comparing the rate and extent of absorption of Megace ES and megestrol acetate oral suspension revealed that the Cmax** level with the original formulation was 1,364 ng/mL in fed patients and 187 ng/mL in unfed patients. In contrast, the Cmax level with Megace ES was 1,517 ng/mL in fed patients and 1,041 ng/mL in unfed patients. Further, in unfed patients Megace ES achieved 5 times greater peak plasma levels than megestrol acetate oral suspension. Additionally, the study demonstrated that a lower volume of Megace ES achieved maximum blood concentration more rapidly than the currently available oral suspension products.

However, the two products were nto directly compared in regard to clinical effectiveness and it is not known if this pharmacokinetic advantages translate into any clinical advantage.

Jamie H. Von Roenn, MD; Donald Armstrong, MD; Donald P. Kotler, MD; David L. Cohn, MD; Nancy G. Klimas, MD; N. S. Tchekmedyian, MD; Lawrence Cone, MD; Patrick J. Brennan, MD; and Sigmund A. Weitzman, MD, Megestrol Acetate in Patients with AIDS-related Cachexia , Ann Intern Med. 15 September 1994;121(6):393-399

Michelle H. Oster, PhD, RD; Sheila R. Enders, BS; Steven J. Samuels, PhD; Lawrence A. Cone, MD; Thomas M. Hooton, MD; Henry P. Browder, PhD; and Neil M. Flynn, MD
Megestrol Acetate in Patients with AIDS and Cachexia Ann Intern Med. 15 September 1994;121(6):400-408

Food Effect Working Group of the Biopharmaceutics Coordinating Committee, Office of Pharmaceutical Science. Guidance for industry: food-effect bioavailability and fed bioequivalence studies. Food and Drug Administration, Center for Drug Evaluation and Research Web site. http://www.fda.gov/cder/guidance/5194fnl.pdf. Published December 2002

MegaceES, Prescribing Information, 2013

Food and Drug Administration, Center for Drug Evaluation and Research. Electronic Orange Book: Approved Drug Products With Therapeutic Equivalence Evaluations. 28th ed. Rockville, MD: Food and Drug Administration, Center for Drug Evaluation and Research; 2008.

For Lay version see here

Marinol for cachexia

Thalidmide for cachexia

Octreotide for pancreatic fistula – pro

M Levin, MD — Sun, 24 Feb 2013 04:31:03 +0000

The principal effects of octreotide include inhibition of growth hormone (GH), glucagon, and insulin. However, there are other effects that have been attemtped to be exploited to therapeutic ends, including to help heal pancreatic and gastreointeistinal fistulas. Among themare reduction of splanchnic blood flow, and inhibition of release of several gastrointestinal hormones, including serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide.

Graham et al. conducted a prospective study of prophylactic long-acting octreotide to prevent postoperative pancreatic fistula (POPF) in high-risk patients undergoing
pancreaticoduodenectomy. The authors concluded that prophylactic use of depot octreotide in high-risk patients does not result in reduced incidence of POPF.

A recent Cochrane review of somatostatin analogues (SSAs) for pancreatic surgery concluded that SSAs reduce perioperative complications but do not reduce perioperative mortality. In those undergoing pancreatic surgery for malignancy, they shorten hospital stay. Further adequately powered trials with low risk of bias are necessary. Based on the current available evidence, somatostatin and its analogues are recommended for routine use in patients undergoing pancreatic resection for malignancy. There is currently no evidence to support their routine use in pancreatic surgeries performed for other indications.

In a meta-analysis by Zeng et al., eight studies were reviewed to evaluate the efficacy of somatostatin and its analogues in the prevention of postoperative complications after
pancreaticoduodenectomy. The use of somatostatin or its analogues did not significantly benefit for reducing the incidence of pancreatic fistula (odds ratio [OR] 95% confidence interval [CI], 0.64-1.37; p=0.73), total pancreas-specific postoperative complications (OR 95% CI, 0.63-1.42; p=0.79), delayed gastric emptying (OR 95% CI, 0.50-1.78; p=0.86), total complication (OR 95% CI, 0.73-1.70; p=0.61), mortality (OR 95% CI, 0.59-7.72; p=0.97) and length of postoperative hospital stay (weighted mean difference 95% CI, -7.74 to 4.47; p=0.60). The use of somatostatin and its analogues does not significantly reduce postoperative complications after pancreaticoduodenectomy.

Several clinical trials have evaluated the use of octreotide to prevent the development of pancreatic fistula after pancreatic surgery with conflicting recommendations. A recent review on surgicalcreiticalcare.net concluded that : “There is insufficient evidence to conclude that octreotide reduces fistula closure rates or time to closure. Octreotide therapy
may be useful when there is reason to believe that a reduction in fistula output would facilitate patient management. However, its use for the purpose of fistula closure or the use of doses greater than those evaluated in clinical trails cannot be recommended.”

Graham JA, Johnson LB, Haddad N, et al. A prospective study of prophylactic long-acting
octreotide in high-risk patients undergoing pancreatticoduodenectomy. The American Journal of
Surgery. 2011;201(4):481-485.

Gurusamy KS, Koti R, Fusai G, Davidson BR. Somatostatin analogues for pancreatic surgery.
Cochrane Database of Systematic Reviews 2010, Issue 2.

Zeng Q, Zhang Q, Han S, et al. Efficacy of somatostatin and its analogues in prevention of
postoperative complications after pancreaticoduodenectomy: a meta-analysis of randomized
controlled trials. Pancreas. 2008 Jan;36(1):18-25.

OCTREOTIDE IN THE PREVENTION AND TREATMENT OF
GASTROINTESTINAL AND PANCREATIC FISTULAS – http://www.surgicalcriticalcare.net/Guidelines/octreotide%202009.pdf

For Lay version see here

Octreotide fir angiodyslpasia and for angiodysplasis and GI bleeding

Zofran – patterns of use – pro

M Levin, MD — Mon, 11 Feb 2013 16:18:38 +0000

Ondansetron (Zofran) had been FDA approved for two decades and highly effective for nausea and vomiting. It is indicated for:
Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m2.
Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.
Prevention of nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen.
Prevention of postoperative nausea and/or vomiting.

Because of its expense (greater than $100/dose), for many years it was only used for patients undergoing cancer chemotherapy or after surgical procedures. As the cost dropped (now under a $1 a dose), it is came to be used in many hospital and outpatient settings. A growing area of use is empiric use in nursing homes. The drug is so effective, that some physicians consider using it as needed less morbid that performing a workup to determine the etiology of nausea in these patients.

This strategy needs more data to be considered well supported. Zofran is not a completely innocuous drug. The U.S. Food and Drug Administration (FDA) recently informed healthcare professionals and the public that preliminary results from a recently completed clinical study suggest that a 32 mg single intravenous dose of ondansetron (Zofran, ondansetron hydrochloride, and generics) may affect the electrical activity of the heart (QT interval prolongation), which could pre-dispose patients to develop an abnormal and potentially fatal heart rhythm known as Torsades de Pointes. Consequenlty, GlaxoSmithKline (GSK) has announced changes to the Zofran drug label to remove the 32 mg single intravenous dose. While the 8 mg dose is presumably free of this complication, one remains uncomfortable about empiric use of Zofran in any clinical situation and such a strategy needs to be validated with clinical trials.

Several other uses have been preliminarily explored. During the past decade ondansetron has been increasingly used in the United States for Nausea and Vomiting of Pregnancy (NVP), owing to the lack of a drug indicated by the FDA for this condition; some concern had been voiced about potential increased incidence of cleft palate in the offspring of mothers who took Zofran during pregnancy. A 2006 double-blind, randomized controlled trial indicated that ondansetron may have value in the treatment of schizophrenia, as an adjunct to haloperidol. Another, albeit small, open-label trial had found ondansetron to be useful in treating antipsychotic-induced tardive dyskinesia in people with schizophrenia. Early studies have also examined ondansetron as a possible treatment for psychosis resulting from advanced Parkinson’s disease. Hewlett and others performed an open label study that suggested that it can decrease symptoms of OCD. Zofran appears to decrease the craving for alcohol, especially in early-onset alcoholics. Researchers at the Stanford University School of Medicine have demonstrated that ondansetron might be useful and effective for treating withdrawal symptoms of opioid addictions. Ondansetron has been useful in irritable bowel syndrome with diarrhea (IBS-D). Two small, placebo-controlled trials showed that ondansetron was found to be as effective as pethidine (meperidine, Demerol) to decrease post-anethsia shivering, when given prior to anesthesia.

In early January of 2012, the Food and Drug Administration approved the first generic versions of Zofran (Ondansetron) Tablets, Orally Disintegrating Tablets and Oral Solution which are indicated to prevent nausea and vomiting associated with surgery, radiotherapy and cancer chemotehrapy. This si a part of the FDA initiative to reduce drug costs by expediting approvals of generics. The indication is narrower than that of brand Zofran, which also includes postoperative nausea.

Several alternatives exist for opioid induced nausea(OINV). , although currently there are no drugs specifically approved for opioid induced nausea. They include the less expensive compazine and metocopropamide and others. A recent guidelines says that the drug of choice for preventing OINV is droperidol.

Several alternatives exist, although currently there are no drugs specifically approved for opioid induced nausea(OINV). They include the less expensive compazine and metocopropamide and others. A recent guideline says that the drug of choice for preventing OINV is droperidol.
Gómez-Arnau JI, Aguilar JL, Postoperative nausea and vomiting and opioid-induced nausea and vomiting: guidelines for prevention and treatment. Rev Esp Anestesiol Reanim. 2010 Oct;57(8):508-24.

Lohitnavy M, Chaijittiprasert K, Polnok S, Lohitnavy O, Taytiwat P. Bioequivalence study of ondansetron tablet in healthy Thai male volunteers. J Med Assoc Thai. 2002 Jul;85(7):808-13.

Frank Porreca, and Michael H. Ossipov, Nausea and Vomiting Side Effects with Opioid Analgesics during Treatment of Chronic Pain: Mechanisms, Implications, and Management Options PAIN MEDICINE Volume 10 • Number 4 • 2009

Salvucci AA, Squire B, Burdick M, et al. Ondansetron is safe and effective for prehospital treatment of nausea and vomiting by paramedics. Prehosp Emerg Care 15(1): 34-8, Jan 2011.

Chu LF, Liang DY, Li X, Sahbaie P, Dʼarcy N, Liao G, Peltz G, David Clark J (February 2009). “From mouse to man: the 5-HT3 receptor modulates physical dependence on opioid narcotics”. Pharmacogenet. Genomics 19 (3): 193–205

Zofran, Prescribing Information, 2012

Zhang ZJ, Kang WH, Li Q, Wang XY, Yao SM, Ma AQ (2006). “Beneficial effects of ondansetron as an adjunct to haloperidol for chronic, treatment-resistant schizophrenia: a double-blind, randomized, placebo-controlled study”. Schizophrenia Research 88 (1–3): 102–10. Zullino DF, Eap CB, Voirol P (2001). “Ondansetron for tardive dyskinesia”. Am J Psychiatry 158 (4): 657–8. .

Sirota P, Mosheva T, Shabtay H, Giladi N, Korczyn AD (2000). “Use of the selective serotonin 3 receptor antagonist ondansetron in the treatment of neuroleptic-induced tardive dyskinesia”. Am J Psychiatry 157 (2): 287–9.

Zoldan J, Friedberg G, Livneh M, Melamed E (1995). “Psychosis in advanced Parkinson’s disease: treatment with ondansetron, a 5-HT3 receptor antagonist”. Neurology 45 (7): 1305–8.

Hewlett WA, Schmid SP, Salomon RM (2003). “Pilot trial of ondansetron in the treatment of 8 patients with obsessive compulsive disorder”. J Clin Psychiatry 64 (9): 1025–30.

Corrêa Filho JM, Baltieri DA. A pilot study of full-dose ondansetron to treat heavy-drinking men withdrawing from alcohol in Brazil. Addict Behav. 2013 Apr;38(4):2044–2051

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Does Zelboraf work for other than BRAF-E mutations – pro

M Levin, MD — Fri, 08 Feb 2013 15:44:11 +0000

Zelboraf is anti BRAF kinase inhibitor. ZELBORAF™ is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test.

More than 30 mutations of the BRAF gene associated with human cancers have been identified. The most common one is BRAFE, a substitution of valine (V) glutamate (E) at codon 600, and it is referred to as BRAF600E. Other mutations which have been found are R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, K600E, A727V, etc. and most of these mutations are clustered to two regions: the glycine-rich P loop of the N lobe and the activation segment and flanking regions. These mutations change the activation segment from inactive state to active state, Preclinical evidence is that most of these mutations stimulate enhanced B-Raf kinase activity toward MEK. A few mutants have reduced activity toward MEK but adopt a conformation that activates wild-type C-RAF, which then signals to ERK.

With this in mind, other BRAF mutations than E should also respond to Zelboraf. There is some evidence for that in individual cases, for example for the BRAFK mutation as well as for BRAFR. In the Chapman study, on which the FDA approval was based, there were ten patients with BRAFK and they showed some response. Ten patients in the vemurafenib group were later found to have BRAF V600K mutations; of these patients, 4 had a partial response (40%). Being that there are so many different BRAF mutations, it is not reasonable to require large studies performed for each mutation subtype.

Zelboraf, Prescribing Information, 2012
Flaherty K. “Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer”. 2009 ASCO Annual Meeting Abstract, J Clin Oncol 27:15s, 2009 (suppl; abstr 9000).

Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (August 2010). “Inhibition of mutated, activated BRAF in metastatic melanoma”. N. Engl. J. Med. 363 (9): 809–19.

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, Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation, N Engl J Med 2011; 364:2507-2516

For Lay version see here

About Zelboraf