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Posts Tagged ‘Vemurafenib’


New Guidelines and Meeting Information on Advanced Thyroid Cancer as Reported by Cancer Network (Meeting Highlights)

 

Reporter: Stephen J. Williams, Ph.D.

Cancer Network presents exclusive coverage on thyroid cancer from the 15th International Thyroid Congress (ITC) and 85th Annual Meeting of the American Thyroid Association (ATA), held October 18-23 in Lake Buena Vista, Florida.

Vista, Florida.
Conference Reports
ATA Updates Guidelines for Differentiated Thyroid Cancers
Release of newly revised, evidence-based clinical management guidelines for thyroid nodules and differentiated thyroid cancers were announced at the 85th Annual Meeting of the ATA.
FAM83F Protein Implicated in Papillary Thyroid Cancer and Drug Resistance
The FAM83F protein contributes to papillary thyroid cancer cell viability and doxorubicin resistance, according to a study presented at the 85th Annual Meeting of the ATA.
Autophagy Implicated in Vemurafenib Resistance in BRAF-Mutant Thyroid Cancer
Preclinical findings suggest that autophagy inhibition might prove useful in overcoming BRAF-mutant thyroid cancers resistant to vemurafenib.

 

Summary of Newly Released Guidelines on Management of Thyroid Nodules and Differentiated Thyroid Cancers

See Cancer.gov for more information on thyroid cancer

Release of newly revised, evidence-based clinical management guidelines for thyroid nodules and differentiated thyroid cancers were announced at the 15th International Thyroid Congress (ITC) and 85th Annual Meeting of the American Thyroid Association (ATA) in Lake Buena Vista, Florida, and published in Thyroid.

  • The ATA Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer authored the guidelines. The Taskforce was chaired by Bryan R. Haugen, MD, of the University of Colorado School of Medicine in Aurora, Colorado.

The updated guidelines reflect

  • advances in the interpretation of biopsy and the use of molecular-marker studies in the clinical differentiation of benign thyroid nodules from thyroid cancer,
  • risk assessment,
  • cancer screening,
  • the management of benign thyroid nodules,
  • the diagnosis and the initial and long-term management of differentiated thyroid cancer.
  • Guidelines modified for long-term management of differentiated thyroid cancer
  • additional research and recommendations needed “for clinical trials and targeted therapy.”

The United States saw an estimated 63,000 newly diagnosed cases of thyroid cancer cases in 2014, up sharply from 37,200 in 2009, when the ATA guidelines were last revised.

– See more at: http://www.cancernetwork.com/ata-2015-thyroid-cancer/ata-updates-guidelines-differentiated-thyroid-cancers?GUID=D63BFB74-A7FD-4892-846F-A7D1FFE0F131&XGUID=&rememberme=1&ts=20102015#sthash.yXbBrS2x.dpuf

 

 

 

Vemurafenib

From 2011 FDA press release on approval of vemurafenib:

FDA NEWS RELEASE

For Immediate Release: Aug. 17, 2011
Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

FDA approves Zelboraf and companion diagnostic test for late-stage skin cancer
Second melanoma drug approved this year that improves overall survival

The U.S. Food and Drug Administration today approved Zelboraf (vemurafenib), a drug to treat patients with late-stage (metastatic) or unresectable (cannot be removed by surgery) melanoma, the most dangerous type of skin cancer.

Zelboraf is specifically indicated for the treatment of patients with melanoma whose tumors express a gene mutation called BRAF V600E. The drug has not been studied in patients whose melanoma tests negative for that mutation by an FDA approved diagnostic.

Zelboraf is being approved with a first-of-a-kind test called the cobas 4800 BRAF V600 Mutation Test, a companion diagnostic that will help determine if a patient’s melanoma cells have the BRAF V600E mutation.

The BRAF protein is normally involved in regulating cell growth, but is mutated in about half of the patients with late-stage melanomas. Zelboraf is a BRAF inhibitor that is able to block the function of the V600E-mutated BRAF protein.

“This has been an important year for patients with late-stage melanoma. Zelboraf is the second new cancer drug approved that demonstrates an improvement in overall survival,” said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. “In March, we approved Yervoy (ipilimumab), another new treatment for late-stage melanoma that also showed patients live longer after receiving the drug.”

Zelboraf was reviewed under the FDA’s priority review program that provides for an expedited six-month review of drugs that may offer major advances in treatment or that provide a treatment when no adequate therapy exists. Zelboraf and the companion BRAF V600E test are being approved ahead of the drug’s Oct. 28, 2011 goal date and the companion diagnostics’ Nov. 12, 2011 goal date.

Zelboraf’s safety and effectiveness were established in a single international trial of 675 patients with late-stage melanoma with the BRAF V600E mutation who had not received prior therapy. Patients were assigned to receive either Zelboraf or dacarbazine, another anti-cancer therapy. The trial was designed to measure overall survival (the length of time between start of treatment and death of a patient).

The median survival (the length of time a patient lives after treatment) of patients receiving Zelboraf has not been reached (77 percent still living) while the median survival for those who received dacarbazine was 8 months (64 percent still living).

“Today’s approval of Zelboraf and the cobas test is a great example of how companion diagnostics can be developed and used to ensure patients are exposed to highly effective, more personalized therapies in a safe manner,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostic Device Evaluation and Safety in the FDA’s Center for Devices and Radiological Health.

The FDA’s approval of the cobas 4800 BRAF V600 Mutation Test was based on data from the clinical study that also evaluated the safety and effectiveness of Zelboraf. Samples of a patient’s melanoma tissue were collected to test for the mutation.

The most common side effects reported in patients receiving Zelboraf included joint pain, rash, hair loss, fatigue, nausea, and skin sensitivity when exposed to the sun. About 26 percent of patients developed a skin-related cancer called cutaneous squamous cell carcinoma, which was managed with surgery. Patients treated with Zelboraf should avoid sun exposure.

Zelboraf is being approved with a Medication Guide to inform health care professionals and patients of Zelboraf’s potential risks.

In July 2011, the FDA issued a new draft guidance to facilitate the development and review of companion diagnostics. The guidance, currently available for public comment, is intended to provide companies with guidance on the agency’s policy for reviewing a companion diagnostic and the corresponding drug therapy.

Melanoma is the leading cause of death from skin disease. The National Cancer Institute estimated that 68,130 new cases of melanoma were diagnosed in the United States during 2010; about 8,700 people died from the disease.

Zelboraf is marketed by South San Francisco based-Genentech, a member of the Roche Group. The cobas 4800 BRAF V600 Mutation Test is manufactured by Roche Molecular Systems in Pleasanton, Calif.

 

More Articles in this Open Access Journal on Thyroid Cancer Include

 

The Experience of a Patient with Thyroid Cancer

Thyroid Cancer: The Evolution of Treatment Options

The Relation between Coagulation and Cancer affects Supportive Treatments

 

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Author: Ziv Raviv, PhD

Introduction

Cutaneous melanoma is a type of skin cancer that originates in melanocytes, the cells that are producing melanin. While being the least common type of skin cancer, melanoma is the most aggressive one with invasive characteristics and accounts for the majority of death incidences among skin cancers. Melanoma has an annual rate of 160,000 new cases and 48,000 deaths worldwide. Melanoma affects mainly Caucasians exposed to sun high UV irradiation. Among the genetic factors that characterize the disease, BRAF mutation (V600E) is found in most cases of melanoma (80%).  Awareness toward risk factors of melanoma should lead to prevention and early detection*. There are several developmental stages (I-IV) of the disease, starting from local non-invasive melanoma, through invasive and high risk melanoma, up to metastatic melanoma. As with other cancers, the earlier stage melanoma is being detected, the better odds for full recovery are. Treatment is usually involving surgery to remove the local tumor and its margins, and when necessary also to remove the proximal lymph node(s) that drain the tumor. In high stages melanoma, adjuvant therapy is given in the form of chemotherapy (Dacarbazine and Temozolomide) and immunotherapy (IL-2 and IFN). Until recently no useful treatment was available for metastatic melanoma. However, research efforts had led to the development of two new drugs against metastatic melanoma: Vemurafenib (Zelboraf), a B-Raf inhibitor; and Ipilimumab (Yervoy), a monoclonal antibody that blocks the inhibitory signal of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Both drugs are now available for clinical use presenting good results.

Personalized therapy for melanoma

In an attempt to develop personalized therapies for malignant melanoma, a unique strategy has been taken by the group of Prof. Yardena Samuels at the NIH (now situated at the WIS) to identify recurring genetic alterations of metastatic cutaneous melanoma. The researchers approach employed the collections of hundreds of tumors samples taken from metastasized melanoma patients together with matched normal blood tissues samples. The samples are undergoing exome sequencing for the analysis of somatic mutations (namely mutations that evolved during the progress of the disease to the stage of metastatic melanoma, unlike genomic mutations that may have contribute to the formation of the disease). The discrimination of such tumor related somatic mutations is done by comparison to the exome sequencing of the patient’s matched blood cells DNA. In addition, the malignant cells derived from the removed cancer tissue of each patient are extracted to form a cell line and are grown in culture. These cells are easily cultivate in culture with no special media supplements, nor further genetic manipulations such as hTERT are needed, and are extremely aggressive as determined by various cell culture and in vivo tests. The ability to grow these primary tumor-derived cell lines in culture has a great value as a tool for studying and characterizing the biochemical, functional, and clinical aspects of the mutated genes identified.

In one study [1] Samuels and her colleagues performed this sequencing process for mutation analysis for the protein tyrosine kinase (PTK) gene family, as PTKs are frequently mutated in cancer. Using high-throughput gene sequencing to analyze the entire PTK gene family, the researchers have identified 30 somatic mutations affecting the kinase domains of 19 PTKs and subsequently evaluated the entire coding regions of the genes encoding these 19 PTKs for somatic mutations in 79 melanoma samples. The most frequent mutations were found in ERBB4, a member of the EGFR/ErbB family of receptor tyrosine kinase (RTK), were 19% of melanoma patients had such mutations. Seven missense mutations in the ERBB4 gene were found to induce increased kinase activity and transformation capability. Melanoma derived cell lines that were expressing these mutant ERBB4 forms had reduced cell growth after silencing ERBB4 by RNAi or after treatment with the ERBB inhibitor Lapatinib. Lapatinib is already in use in the clinic for the treatment of HER2 (ErbB2) positive breast cancers patients. Following this study, a clinical trial is now conducted with this drug to evaluate its effect in cutaneous metastatic melanoma patients harboring mutations in ERBB4.

In another study of this group [2], the scientists employed the exome sequencing method to analyze the somatic mutations of 734 G protein coupled receptors (GPCRs) in melanoma. GPCRs are regulating various signaling pathways including those that affect cell growth and play also important role in human diseases. This screen revealed that GRM3 gene that encode the metabotropic glutamate receptor 3 (mGluR3), was frequently mutated and that one of its mutations clustered within one position. Mutant GRM3 was found to selectively regulate the phosphorylation of MEK1 leading to increased anchorage-independent cell growth and cellular migration. Tumor derived melanoma cells expressing mutant GRM3 exhibited reduced cell growth and migration upon knockdown of GRM3 by RNAi or by treatment with the selective MEK inhibitor, Selumetinib (AZD-6244), a drug that is being testing in clinical trials. Altogether, the results of this study point to the increased violent characteristics of melanomas bearing mutational GRM3.

In a third study, melanoma samples were examined for somatic mutations in 19 human genes that encode ADAMTS proteins [3]. Some of the ADAMTS genes have been suggested before to have implication in tumorigenesis. ADAMTS18, which was previously found to be a candidate cancer gene, was found in this study to be highly mutated in melanoma. ADAMTS18 mutations were biologically examined and were found to induce an increased proliferation of melanoma cells, as well as increased cell migration and metastasis. Moreover, melanoma cells expressing these mutated ADAMTS18 had reduced cell migration after RNAi-mediated knockdown of ADAMTS18. Thus, these results suggest that genetic alteration of ADAMTS18 plays a major role in melanoma tumorigenesis. Since ADAMTS genes encode extracellular proteins, their accessibility to systematically delivered drugs makes them excellent therapeutic targets.

Conclusive remarks

The above illustrated research approach intends to discover frequent melanoma-specific mutations by employing high-throughput whole exome and genome sequencing means. For the most highly mutated genes identified, the biochemical, functional, and clinical aspects are being characterized to examine their relevancy to the disease outcomes. This approach therefore introduces new opportunities for clinical intervention for the treatment of cutaneous melanoma. In addition to the discovery of novel highly mutated genes, this approach may also help determine which pathways are altered in melanoma and how these genes and pathways interact. Finding melanoma-associated highly mutated genes could lead to personalized therapeutics specifically targeting these altered genes in individual melanomas. Along with the opportunity to develop new agents to treat melanoma, the approach takes advantage of existing anti-cancer drugs, utilizing them to treat these mutated genes melanoma individuals. In addition to their potential for therapeutics, the discovery of highly mutated genes in melanoma patients may lead to the discovery of new markers that may assist the diagnosis of the disease. The implications of these screenings findings on other types of cancer bearing common pathways similar to melanoma should be examined as well. Finally, this elegant approach should be adopted in research efforts of other cancer types.

* Special review will be published further in the cancer prevention section of Pharmaceutical Intelligence

References

1. Prickett TD, Agrawal NS, Wei X, Yates KE, Lin JC, Wunderlich JR, Cronin JC, Cruz P, Rosenberg SA, Samuels Y (2009) Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet 41 (10):1127-1132

2. Prickett TD, Wei X, Cardenas-Navia I, Teer JK, Lin JC, Walia V, Gartner J, Jiang J, Cherukuri PF, Molinolo A, Davies MA, Gershenwald JE, Stemke-Hale K, Rosenberg SA, Margulies EH, Samuels Y (2011) Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma. Nat Genet 43 (11):1119-1126

3. Wei X, Prickett TD, Viloria CG, Molinolo A, Lin JC, Cardenas-Navia I, Cruz P, Rosenberg SA, Davies MA, Gershenwald JE, Lopez-Otin C, Samuels Y (2010) Mutational and functional analysis reveals ADAMTS18 metalloproteinase as a novel driver in melanoma. Mol Cancer Res 8 (11):1513-1525

Related articles on melanoma on this open access online scientific journal:

1.  In focus: Melanoma Genetics. Curator: Ritu Saxena, Ph.D.

2.  In focus: Melanoma therapeutics. Author and Curator: Ritu Saxena, Ph.D.

3.  A New Therapy for Melanoma.  Reporter- Larry H Bernstein, M.D.

4. Thymosin alpha1 and melanoma. Author, Editor: Tilda Barliya, Ph.D.

5. Exome sequencing of serous endometrial tumors shows recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Reporter and Curator: Dr. Sudipta Saha, Ph.D.

6. How Genome Sequencing is Revolutionizing Clinical Diagnostics. Reporter: Aviva Lev-Ari, PhD, RN.

7. Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. Curator and Reporter: Stephen J. Williams, Ph.D.

 

 

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In focus: Melanoma therapeutics

 

Author and Curator: Ritu Saxena, Ph.D.

In the last post of Melanoma titled “In focus: Melanoma Genetics”, I discussed the clinical characteristics and the genetics involved in Melanoma.  This post would discuss melanoma therapeutics, both current and novel.

According to the American Cancer Society, more than 76,000 new cases and more than 9100 deaths from melanoma were reported in the United States in 2012[1] Melanoma develops from the malignant transformation of melanocytes, the pigment-producing cells that reside in the basal epidermal layer in human skin. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate.

Melanoma therapeutics

Surgical treatment of cutaneous melanoma employs specific surgical margins depending on the depth of invasion of the tumor and there are specific surgical treatment guidelines of primary, nodal, and metastatic melanoma that surgeons adhere to while treatment. Melanoma researchers have been focusing on developing adjuvant therapies for that would increase the survival post-surgery.

Chemotherapy

Among traditional chemotherapeutic agents, only dacarbazine is FDA approved for the treatment of advanced melanoma (Eggermont AM and Kirkwood JM, Eur J Cancer, Aug 2004;40(12):1825-36). Dacarbazine is a triazene derivative and alkylates and cross-links DNA during all phases of the cell cycle, resulting in disruption of DNA function, cell cycle arrest, and apoptosis. Currently, 17 clinical trials are underway to test the efficacy and effectiveness of dacarbazine against melanoma as either a single agent or in combination chemotherapy regimens with other anti-cancer chemotherapeutic agents such as cisplatin, paclitaxel. Temozolomide is a triazene analog of dacarbazine and is approved for the treatment of malignant gliomas. At physiologic pH, it is converted to a short-lived active cytotoxic compound, monomethyl triazeno imidazole carboxamide (MTIC). MTIC methylates DNA at the O6 and N7 positions of guanine, resulting in inhibition of DNA replication. Unlike dacarbazine, which is metabolized to MITC only in the liver, temozolomide is metabolized to MITC at all sites. Temozolomide is administered orally and penetrates well into the central nervous system. Temozolomide is being tested in many combination regimens for patients with melanoma metastatic to the brain (Douglas JG and Margolin K, Semin Oncol, Oct 2002;29(5):518-24).

Immunotherapy

Melanoma and the immune system are closely related. Hence, immunotherapy has been explored in the treatment of the disease. The two most widely investigated immunotherapy drugs for melanoma are Interferon (IFN)-alpha and Interleukin-2 (IL-2).

The role of IFNalpha-2b in the adjuvant therapy of patients with localized melanoma at high risk for relapse was established by the results of three large randomized trials conducted by the US Intergroup; all three trials demonstrated an improvement in relapse-free survival and two in overall survival. One of these trials, a large randomized multicenter trial performed by the Eastern Cooperative Oncology Group (ECOG), in high-risk melanoma patients showed significant improvements in relapse-free and overall survival with adjuvant IFN-α-2b therapy, compared with standard observation (ECOG 1684). The results of the study led to FDA approval of IFN-α-2b for treatment of melanoma. This study was performed on patients with deep primary tumors without lymph node involvement and node-positive melanomas. In other studies, little antitumor activity has been demonstrated in IFN-α-2b–treated metastatic stage IV melanoma.

Recombinant IL-2 showed an overall response rate of 15-20% in metastatic melanoma and was capable of producing complete and durable remissions in about 6% of patients treated. Based upon these data, the US FDA has approved the use of high-dose IL-2 for the therapy of patients with metastatic melanoma. Aldesleukin (Brand name: Proleukin) is a recombinant analog of the endogenous cytokine interleukin-2 (IL-2). It binds to and activates the IL-2 receptor (IL-2R), followed by heterodimerization of the IL-2R beta and gamma(c) cytoplasmic chains; activation of Jak3; and phosphorylation of tyrosine residues on the IL-2R beta chain, resulting in an activated receptor complex (NCI). The activated complex recruits several signaling molecules that act as substrates for regulatory enzymes associated with the complex. It is administered intravenously and stimulates lymphokine-activating killer (LAK) cells, natural killer (NK) cells and the production of cytokines such as gamma interferon (nm|OK). Several clinical trials are currently underway using Aldesleukin to determine the efficacy of combination treatment in melanoma patients.

Another anti-cancer immunotherapeuty-based mechanism involved inhibition of inhibitory signal of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a molecule on T-cells that plays a critical role in regulating natural immune responses. Ipilimumab (Brand name: Yervoy) was by FDA for melanoma treatment.  It is a human monoclonal antibody (MAb) T-cell potentiator that specifically blocks CTLA-4. It is approved for inoperable advanced (Stage III) or metastatic (Stage IV) melanoma in newly diagnosed or previously treated patients (nm|OK). The approval, March 25, 2011, was based on a randomized (3:1:1) double-blind double-dummy clinical trial (MDX010-20) in patients with unresectable or metastatic melanoma who had received at least one prior systemic treatment for melanoma. Patients were randomly assigned to receive either ipilimumab, 3 mg/kg intravenously, in combination with the tumor vaccine (n=403); ipilimumab plus vaccine placebo (n=137); or tumor vaccine with placebo (n=136). Patients treated with ipilimumab alone had a median overall survival (OS) of 10 months while those treated with tumor vaccine had a median OS of 6 months. The trial also demonstrated a statistically significant improvement in OS for patients treated with the combination of ipilimumab plus tumor vaccine compared with patients treated with tumor vaccine alone. For more information on the trial, check the clinical trials website, www.clinicaltrials.gov

Signaling pathway inhibitors

Approximately 90% of BRAF gene mutations involve valine (V) to glutamic acid (E) mutation at number 600 residue (V600E). The resulting oncogene product, BRAF (V600E) kinase is highly active and exhibits elevated MAPK pathway. The BRAF(V600E) gene mutation occurs in approximately 60% of melanomas indicating that it could be therapeutically relevant. Vemurafenib (Brand name: Zelboraf) is a novel small-molecule inhibitor of BRAF (V600E) kinase. It selectively binds to the ATP-binding site and inhibits the activity of BRAF (V600E) kinase. Vemurafebib inhibits over active MAPK pathway by inhibiting the mutated BRAF kinase, thereby reducing tumor cell proliferation (NCI). Encouraging results of phase III randomized, open-label, multicenter trial were reported recently at the 2011 ASCO meeting (Chapman PB, et al, ASCO 2011, Abstract LBA4).  The trial compared the novel BRAF inhibitor vemurafenib with dacarbazine in patients with BRAF-mutated melanoma. Previously untreated, unresectable stage IIIC or stage IV melanoma that tested positive for BRAF mutation were randomized (1:1) to vemurafenib or dacarbazine. The response rate (RR) was significantly high (48.4%) in vemurafenib treated patients as compared to 5.5% in dacarbazine among the 65% of patients evaluable for RR to date. In addition, vemurafenib was associated with significantly improved OS and PFS compared to dacarbazine in patients with previously untreated BRAF (V600E) mutation bearing patients with metastatic melanoma.

Biochemotherapy

Biochemothreapy combine traditional chemotherapy with immunotherapies, such as IL-2 and IFN-α-2b. These combination therapies seemed promising in phase II trials, however, seven large studies failed to show statistically significant increased overall survival rates for various biochemotherapy regimens in patients with stage IV metastasis (Margolin KA, et al, Cancer, 1 Aug 2004;101(3):435-8). Owing to inconsistent results of the available studies with regard to benefit including RR, OS and progression time, and consistently high toxicity rates, clinical practice guideline do not recommend biochemotherapy for the treatment of metastatic melanoma (Verma S, et al, Curr Oncol, April 2008; 15(2): 85–89).

Vaccines

The use of therapeutic vaccines is an ongoing area of research, and clinical trials of several types of vaccines (whole cell, carbohydrate, peptide) are being conducted in patients with intermediate and late-stage melanoma. Vaccines are also being tested in patients with metastatic melanoma to determine their immune effects and to define their activity in combination with other immunotherapeutic agents such as IL-2 or IFNalpha (Agarwala S, Am J Clin Dermatol, 2003;4(5):333-46). In fact, recently investigators at the Indiana University Health Goshen Center for Cancer Care (Goshen, IN) conducted a randomized, multicenter phase III trial involving 185 patients with stage IV or locally advanced stage III cutaneous melanoma. The patients were assigned into treatment groups with IL-2 alone or with vaccine (gp100) followed by IL-2. The vaccine-IL-2 group had a significantly improved OR as compared to the IL-2-only group (16% Vs. 6%) and longer progression free survival (2.2 months Vs. 1.6 months). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months Vs. 11.1 months). Thus, a combination of vaccine and immunotherapy showed a better response rate and longer progression-free survival than with interleukin-2 alone in patients with advanced melanoma (Schwartzentruber DJ, et al, N Engl J Med, 2 Jun 2011;364(22):2119-27).

Which Treatment When?

Earlier, there were essentially two main options for patients suffering from advanced melanoma, dacarbazine and IL-2. Dacarbazine, a chemotherapeutic agent produces modest improvements in survival or symptomatic benefits in most patients. Interleukin-2 -based drugs, on the other hand, induce long-term remissions in a small group of patients but are highly toxic. Recently, FDA approved ipilimumab and vemurafenib for patients with metastatic melanoma. Apart from these, therapies are also aiming at starving the tumor by inhibiting angiogenesis or depleting nutrients essential for cancer growth. Of the antiangiogenic compounds, VEGFR inhibitors SU5416 and AG-013736 demonstrated broad-spectrum antitumor activity in mice bearing xenografts of human cancer cell lines originating from various tissues, including melanoma. In addition, several trials are currently underway to test the efficacy of the drugs in combination. In the future, personalized medicine-based recommendations of novel and existing drugs for melanoma patients might be the way to go.

Reference:

  1. Eggermont AM and Kirkwood JM, Eur J Cancer, Aug 2004;40(12):1825-36
  2. Douglas JG and Margolin K, Semin Oncol, Oct 2002;29(5):518-24
  3. Chapman PB, et al, ASCO 2011, Abstract LBA4
  4. Margolin KA, et al, Cancer, 1 Aug 2004;101(3):435-8
  5. Verma S, et al, Curr Oncol, April 2008; 15(2): 85–89
  6. Agarwala S, Am J Clin Dermatol, 2003;4(5):333-46
  7. Schwartzentruber DJ, et al, N Engl J Med, 2 Jun 2011;364(22):2119-27
  8. Chudnovsky Y, et al, J Clin Invest, Apr 2005;115(4):813-24.
  9. National Cancer Institute (National Institute of Health)
  10. Clinical Trials reported on the U.S. Institute of Health
  11. New Medicine Oncology KnowledgeBase (nm|OK)

Related articles on Melanoma on this Open Access Online Scientific Journal: 

  1. In focus: Melanoma Genetics Curator- Ritu Saxena, Ph.D.
  2. Thymosin alpha1 and melanoma Author/Editor- Tilda Barliya, Ph.D.
  3. A New Therapy for Melanoma  Reporter- Larry H Bernstein, M.D.
  4. Melanoma: Molecule in Immune System Could Help Treat Dangerous Skin Cancer Reporter: Prabodh Kandala, Ph.D.
  5. Why Braf inhibitors fail to treat melanoma. Reporter: Prabodh Kandala, Ph.D.

 

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Larry H. Bernstein, MD
Leaders in Pharmaceutical Innovation
https://pharmaceuticalintelligence.com/2013/03/02/cancer-drugs-proving-worth/

 

INSIGHT – Cancer drugs proving worth earlier in testing
By Bill Berkrot and Ransdell Pierson | Reuters – Mon, Feb 25, 20

 

http://ph.news.yahoo.com/insight-cancer-drugs-proving-worth-earlier-testing-060402726–finance.html?goback=%2Egde_72923_member_217729560/

 

NEW YORK (Reuters) – Michael Weitz was out of options. The Californian had endured chemotherapy, radiation and surgery but his lung cancer still spread to his bones and brain. He was  entered into a Phase I study – the earliest stage of human testing for a new medicine – of crizotinib. The drug works for about 4 percent of advanced lung cancer patients with a mutated form of a protein called ALK.

 

Weitz, now 55,  is cancer-free after three years of taking the drug now sold by Pfizer as Xalkori after an unusually swift development process.

 

It typically has taken a decade and $1 billion to bring a new treatment to market. But in the last two years a handful of cancer drugs – including Onyx Pharmaceutical Inc’s Kyprolis for multiple myeloma, Roche’s Zelboraf for melanoma, and Pfizer’s Xalkori – were approved in about half that time because of improved genetic screening, more definitive Phase I trials and the dire need for new, effective treatments.

 

“We hope to be able to shave years off the time it takes to get final approval and save hundreds of millions of dollars per drug,” said Robert Schneider, director of translational cancer research at New York University Cancer Institute.

 

Smoking lung cancer

Smoking lung cancer (Photo credit: Wikipedia)

High rates of lung cancer (indicated in this m...

High rates of lung cancer (indicated in this map by brown colors) are highly correlated with the Stroke Belt. (Photo credit: Wikipedia)

 

 

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Reporter: Aviva Lev-Ari, PhD, RN

During Investor Day, Roche Highlights Personalized Medicine as Key Area for Future Growth

September 12, 2012

As regulators and payors around the world are demanding more evidence that healthcare products improve patient outcomes and save money, Roche this week attempted to reassure investors that its strategy to develop innovative products — with a strong focus on molecularly guided personalized medicines — will place it ahead of competitors.

Through several presentations during an investor day in London, Roche officials highlighted a number of drugs for cancer, neuropsychiatric conditions, and autoimmune diseases for which the company is investigating biomarkers that can help target treatment to specific groups of patients. The company said that more than 60 percent of the compounds in its drug pipeline are currently paired with a companion diagnostic and that it has more than 200 companion diagnostic projects underway across its pharma and diagnostic business groups.

Personalized medicines are not only a major part of Roche’s plan for future growth, but they also represent a way for the company to differentiate its products from competitors. By setting its drugs apart from other me-too treatments in the marketplace, the company is hoping that its products won’t be as heavily affected by the pricing pressures currently plaguing the pharma and biotech sectors.

“Yes, regulators are very stringent. But if I look back at our most recent launches, particularly in the US, if you have true medical innovation, then regulators are very willing to bring those medicines and novel diagnostics to the market,” Roche CEO Severin Schwan said during the investor conference. He highlighted that the US Food and Drug Administration reviewed and approved the BRAF inhibitor Zelboraf for metastatic melanoma and its companion diagnostic in record time and that the recent approval of the HER2-targeted breast cancer drug Perjeta also occurred ahead of schedule (PGx Reporter 8/17/2011 and 6/13/2012).

“Likewise, if you look at the payors, there is cost pressure,” Schwan reflected, but he noted that the “innovative nature” of its portfolio helps it to “negotiate better prices with payors.”

Despite this optimistic forecast, Roche has experienced some pushback from cost-conscious national payors in Europe. For example, in June the UK’s National Institute for Health and Clinical Excellence deemed Zelboraf, which costs more than $82,000 for a seven-month treatment, too pricey. Zelboraf, which Roche launched in the US market last year and in European countries earlier this year, netted the company around $97 million in revenue for the six months ended June 30.

In an effort to battle pushback from national payors, Roche is in discussions with European governments about value-based pricing schemes for several of its products. In this regard, high priced personalized medicine drugs are well suited to these types of arrangements. David Loew, chief marketing officer at Roche, told investors that governments are increasingly developing registries to track how individual patients are doing on various treatments. This information will help governments move from a volume-based pricing model for drugs to paying for them based on the drug’s indication.

He noted that in Germany, for example, Roche has developed a payment scheme where in colorectal cancer, patients pay a certain amount for up to 10 grams of the oncologic Avastin, receive it for free for up to 12 months, and then the scheme repeats. For personalized medicines, such as Herceptin, Perjeta, T-DM1, and Zelboraf, “we will have to think about different ways of pricing those new combinations,” Loew said.

Schwan highlighted that one of the major advantages for Roche in this difficult environment is that it has both drug and diagnostic capabilities in house. This, according to Schwan, enables Roche to have significant internal capabilities in early-phase research, and makes the company attractive for partnerships, as well. Roche currently has more than 70 new molecular entities in clinical development and since 2011 there have been 25 late-stage clinical trials that have yielded positive results. The firm plans to bring three more products into late-stage clinical trials by the end of the year and would like to move 10 products into late-stage development in 2013.

On the diagnostics side, newly hired chief operating officer Roland Diggelmann said that Roche is aiming to grow its presence in the testing market by becoming “the partner of choice” for developing companion assays and collaborating internally with Roche pharma to advance personalized medicine.

“We need to make sure that science translates into great medicines by designing trials that take smart risk into account, that really focus on ensuring that the molecules are being developed in the right diseases; to make sure we have the right dose; to make sure, whenever possible, we have the … companion diagnostic strategies,” Chief Medical Officer Hal Barron said at the meeting. “This whole strategy needs to result in a higher probability of success so that the return on investment is above the cost of capital and an important driver for our business.”

While Roche plans on identifying new product opportunities through a mix of its internal capabilities and external collaborations, growth through large mergers and acquisitions – a strategy that other large pharmaceutical companies have readily utilized to expand product portfolios – doesn’t seem to be a priority at the company. Noting that there may be opportunities for smaller M&A deals, Alan Hippe, chief financial and information technology officer, noted that at Roche, “we are not big fans of big mergers and big M&A.”

Targeting Cancer

A large portion of Roche’s personalized medicine strategy will be directed toward oncology, where the company has allocated 50 percent of its research and development budget.

In June, the FDA approved Perjeta in combination with Herceptin and decetaxel chemotherapy as a treatment for metastatic breast cancer patients whose tumors overexpress the HER2 protein. The agency simultaneously also approved two companion tests that can help doctors discern best responders to the treatment (PGx Reporter 6/13/2012).

Herceptin (trastuzumab), approved in 1998, still comprises a big chunk of Roche’s therapeutics business, contributing 11 percent of the $18.2 billion the firm netted in overall drug sales in the first half of the year. Roche is hoping to preserve earnings from this blockbuster drug — often hailed as the first personalized medicine success story — by combining it with Perjeta and linking it with a derivative of the chemotherapy maytansine, DM1.

Recently, Roche announced data from a late-stage clinical trial called EMILIA that showed that advanced breast cancer patients receiving the antibody drug conjugate trastuzumab emtansine, or T-DM1, lived “significantly” longer than those treated with a combination of Genentech’s Xeloda (capecitabine) and GlaxoSmithKline’s Tykerb (lapatinib). The patients in EMILIA had to have progressed after initial treatment with Herceptin and taxane chemotherapy.

According to Loew, the company is currently conducting a study looking at T-DM1 as a potential option for first-line metastatic breast cancer patients. In addition, Roche is also studying T-DM1 as an adjuvant treatment in early-stage breast cancer patients with residual disease; comparing T-DM1 plus Perjeta against Herceptin plus Perjeta in the adjuvant early-stage breast cancer setting; and looking at T-DM1-based chemotherapy in the neoadjuvant setting.

“So if we are successfully delivering those results, I think the HER2-positive breast cancer space has been completely changed and redefined,” Loew told investors.

At the end of the year, another study, called the Protocol of Herceptin Adjuvant with Reduced Exposure, or PHARE, is slated to report results, and the outcome could have a negative impact on Herceptin sales. PHARE is comparing whether patients given Herceptin for 12 months, which is currently the standard of care in the US, fare better than those given the drug for six months.

Industry observers have projected that Perjeta and T-DM1 could be a sufficient buffer against a scenario in which six months of Herceptin is found to be non-inferior to a year of the drug.

Barron noted that Roche is readily applying the strategy behind antibody-drug conjugates such as T-DM1 – where antibodies to attach to antigens on the surface of cancer cells to localize chemotherapy delivery and reduce adverse reactions – in 25 projects across its portfolio. He added that antibody-drug conjugates offer a promising mechanism for personalizing treatments.

In non-small cell lung cancer, Roche is studying MetMab (onartuzumab) in combination with Tarceva in patients with tumors that overexpress the Met protein. Data from this Phase III trial, called METLUNG, is expected in 2014. Data from a Phase II study looking at MetMab and Tarceva as a second-line NSCLC treatment yielded negative results when all comers were considered. However, the subgroup of patients who over-expressed Met had a “doubling” of progression-free survival and a “pronounced” effect on overall survival compared to the low-Met group.

Roche is also investigating MetMab in metastatic gastric cancer (Phase III), triple-negative breast cancer, (Phase II), metastatic colorectal cancer (Phase II), glioblastoma (Phase II), as well as in combination with Avastin in various cancer indications.

Other Areas of Personalization

Outside of oncology, Roche is exploring biomarker strategies to personalize drugs for Alzheimer’s disease and schizophrenia. Phase I data from a study involving gantenerumab, a IgG1 monoclonal antibody, suggest that the drug could potentially reduce amyloid plaque in Alzheimer’s patients’ brains.

Investigational drugs targeting beta-amyloid, which many researchers believe to be involved in the pathogenesis of Alzheimer’s disease, haven’t fared well in clinical trials. Most recently, Johnson & Johnson/Pfizer’s drug bapineuzumab, which also targeted the β-amyloid protein, failed to benefit Alzheimer’s patients who were non-carriers of APOE4 gene variations.

Wall Street analysts are hoping that Roche’s biomarker-driven strategy for gantenerumab will help it avoid a similar fate. The company is currently conducting a 770-patient trial called Scarlet Road, in which researchers will measure Tau/Aβ levels in study participants’ spinal fluid to identify early onset or prodormal Alzheimer’s patients and treat them with gantenerumab. Roche is developing a companion test to gauge Tau/Aβ levels in trial participants. Results from Scarlet Road are expected in 2015.

Roche subsidiary Genentech is testing another compound, crenezumab, to see if it can prevent Alzheimer’s in a population genetically predisposed to getting the disease. Genentech, in collaboration with Banner Alzheimer’s Institute and the National Institutes of Health, is conducting a Phase II trial investigating crenezumab in the residents of Medellin, Colombia, where people share a common ancestor and have a high prevalence of mutations in the presenelin 1 gene. Those harboring the dominant gene mutation will start to lose their memory in their mid-40s and their cognitive functions will deteriorate by age 50.

The five-year study will involve approximately 300 participants, of whom approximately 100 mutation carriers will receive crenezumab and another 100 mutation carriers will receive a placebo. In a third arm, approximately 100 participants who don’t carry the mutations will receive a placebo. Study investigators will begin recruiting patients for this study next year.

In schizophrenia, Roche is exploring bitopertin, a glycine reuptake inhibitor, in six Phase III studies slated for completion next year. Three of these studies are looking at the drug’s ability to control negative symptoms in schizophrenia, while the other three trials are studying the drug’s impact on sub-optimally controlled disease symptoms. “A companion diagnostics assay is in development to validate the hypothesis for an exploratory biomarker predicting response to therapy with bitopertin,” Roche said in a statement.

For lupus, Roche is conducting a proof of concept Phase II trial involving rontalizumab, an anti-interferon-alpha antibody, in which researchers are using a biomarker to identify patients most likely to respond to the drug. Data from this trial will be presented at a medical conference later this year.

Growing Role of Diagnostics

Daniel O’Day, who served as CEO of Roche Molecular Diagnostics until last week when he was appointed chief operating officer of the company’s pharma division, valued the worldwide diagnostics market at $53 billion. “We represent 20 percent of that, or around 10 billion Swiss francs ($11 billion),” he said in his investor day presentation.

While molecular diagnostics promise to be a growing part of Roche’s business in the coming years, these products currently only represent a single-digit percent of Roche’s overall diagnostics business. For the first half of this year, molecular diagnostics comprised around 6 percent of Roche’s diagnostics sales of $5.3 billion.

Roche’s Ventana Medical Systems subsidiary will likely play a large role in advancing Roche’s presence in the companion diagnostics space. This year, Ventana announced it was developing companion tests for a number of drug makers, including Aeterna Zentaris, Syndax Pharmaceuticals, Pfizer, and Bayer (PGx Reporter 1/18/2012).

In addition to these external collaborations, Roche officials highlighted the company’s internal diagnostics capabilities as particularly advantageous for expanding its presence in the personalized medicine space. For example, Roche developed the BRAF companion test for Zelboraf. The company is also developing a companion EGFR-mutation test for its non-small cell lung cancer drug Tarceva in the first-line setting, and a test to gauge so-called “super-responders” to the investigational asthma drug lebrikizumab being developed by Genentech.

In terms of molecular diagnostics, O’Day highlighted a test that gauges the overexpression of the p16 gene in cervical Pap test samples to gauge whether women have precancerous lesions.

Additionally, the FDA this year approved the use of Ventana’s INFORM HER2 Dual ISH DNA Probe cocktail on the BenchMark ULTRA automated slide staining platform, which allows labs to analyze fluorescent in situ hybridization and immunohistochemistry samples in one assay. According to O’Day, this test has been more successful than standard FISH tests in identifying HER2 status in difficult-to-diagnose patients. The company will be publishing data on this test soon, showing that it can “identify about 4 percent more [HER2-postiive patients] than FISH alone.”

When it comes to molecular technologies, Roche, like other pharma and biotech players, appear to be sticking to tried and tested technologies, such as IHC, FISH, and PCR, and reserving whole-genome sequencing for research use. “Today, sequencing is predominantly a research tool. And it’s a very valuable research tool in the future,” O’Day said, estimating that sequencing-based tests will “go into the clinic” in the next half decade.

Turna Ray is the editor of GenomeWeb’s Pharmacogenomics Reporter. She covers pharmacogenomics, personalized medicine, and companion diagnostics. E-mail her here or follow her GenomeWeb Twitter account at @PGxReporter.

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