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Advances in Targeted Therapies against Lung Cancer

Lung cancer was the leading cause of cancer death worldwide in 2012 according to WHO (World Health Organization, 2012) and the second most commonly diagnosed cancer in both men and women. Smoking is the most convincing risk factor that contributes to the development of lung cancer; other risk factors include exposure to radon, asbestos, radioactive ores, inhaled chemicals and air pollution. There are two main types of lung cancer, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) with NSCLC accounting for 85% of lung cancer cases.  The standard therapy includes surgery, chemotherapy, and radiation therapy alone or in combination. Unfortunately, the prognosis of patients with lung cancer has been poor with these conventional therapeutic approaches. The recent development of targeted therapies has made some advances in achieving a more personalized treatment and resulting in improved life quality for patients.  Below is a list of the current targeted therapies and their intended molecular and/or pathological indications. EGFR (epidermal growth factor receptor) mutations. EGFR mutation is diagnosed mostly by sequencing of the tumor samples with EGFR gene amplification detected by FISH (fluorescence in situ hybridization).  Depending on the nature of the mutations, the available EGFR-TKIs (tyrosine kinase inhibitors) include Tarceva ( Erlotinib ), Iressa ( Gefitinib ), Gilotrifs (Afatinib, previously Tomtovok and Tovok). Third generation irreversible EGFR-TKIs such as Rociletinib (CO-1686, received FDA Breakthrough Therapy Designation in 2014), Avitinib (developed by Hangzhou ACEA Pharmaceutical Research), Dasatinib, WZ-4002, Dacomitinib and AZD-9291 are in early or late clinical trial stage. K-ras mutations. K-ras mutations occur in about 25-35% NSCLC patients and correlates with history of smoking.  Currently, no drug has been approved for inhibition of mutant K-Ras gene product.  However, direct sequencing of K-ras gene in tumor samples should help with the development of an individualized therapy. EML4-ALK rearrangement. Chromosomal translocation resulting the fusion of ALK (anaplastic lymphoma kinase) and EML4 (echinoderm microtubule-associated protein-like 4) gene is observed in about 5% NSCLC cases.  This fusion is commonly detected by FISH on tumor samples.  Available targeted therapies include Xalkori ( Crizotinib ) and Zykadia ( Ceritinib ).  Second generation of ALK-TKIs include alectinib, LDK-378 and AP-26113, which are still in various clinical trial phases. BRAF mutations. Direct sequencing of BRAF gene is the method of detection currently.  Two BRAF-specific inhibitors, Zelboraf ( Vemurafenib ) and Tafinlar (Dabrafenib ) have been approved by the FDA for treatment of metastatic melanoma.  Clinical trials in lung patients with BRAF mutations are needed. MET amplification. MET amplification can lead to acquired resistance to EGFR-TKIs.  MET amplification is detected by FISH and Cometriq (Cabozatinib) is the FDA approved drug targeting this genomic change for some cancers.  But clinical data for treatment of NSCLC is not available at this time. Targeting of angiogenesis. Bevacizumab (Avastin) is a monoclonal antibody against VEGF-A (vascular endothelial factor-A) and is an option for treatment of lung cancer. There is no specific companion diagnosis for prediction of efficacy for Avastin. Blocking immune checkpoints has received a lot attention recently.  Drugs that are in various clinical development stages for treatment of lung cancer include CTLA-4 inhibitors Yervoy (ipilimumab) and tremelimumab (formerly ticilimumab, CP-675,206), PD-1 inhibitors Opdivo (nivolumab, received FDA approval in March 2015) and Keytruda (pembrolizumab, received Breakthrough Therapy Designation in 2014), and PD-L 1 inhibitors MPDL-3280A (received Breakthrough Therapy Designation earlier this year) and MED14736).  Biomarkers for selection of patients are also in development; such as determination of PD-L1 expression by immunohistochemistry (IHC) is being developed as a companion diagnosis for the use of PD-1 inhibitors.  Therapeutic vaccines targeting lung cancer that are currently in clinical trials include L-BLP25, HyperAcute (tergenpumatucel-L) and TG4010 etc. Other antibodies targeting various proteins involved in cancer and in various clinical stages for the treatment of lung cancer include Bavituximab (against phosphatidylserine), Patritumab (anti-HER3), Rilotumumab (anti-hepatocyte growth factor), Cixutumumab (anti-insulin-like growth factor-1 receptor), Erbitus (anti-EGFR receptor, also called Cetuximab), IMMU-132 (an antibody drug conjugate) and Demcizumab (anti-Delta-like ligand 4, also called OMP-21M18). “With the advances of molecular diagnostic technologies and the development of various targeted therapies, lung cancer management is marching towards a more personalized approach to reduce suffering and improve quality of life,” commented Dr. Mao Mao, Senior Vice President of Translational Bioscience and Diagnostics at WuXi AppTec.   Related Links & References: Haghgoo SM, Allameh A, Mortaz E, Garssen J, Folkerts G, Barnes PJ, Adcock IM. Pharmacogenomics and targeted therapy of Cancer: Focusing on Non-small cell lung Cancer.  Eur J Pharmacol. 2015 Feb 25. pii: S0014-2999(15)00136-3. Anagnostou VK, Brahmer JR. Cancer Immunotherapy: A Future Paradigm Shift in the Treatment of Non-Small Cell Lung Cancer.  Clin Cancer Res. 2015 Mar 1;21(5):976-984.

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The First True Anti-Aging Drug?

A clinical trial sponsored by Novartis could potentially unlock the secret of the molecular “fountain of youth” and holds the promise of an effective anti-aging drug.  The clinical trial conducted in New Zealand and Australia is a randomized, observer-blind, placebo-controlled trial that enrolled over 200 healthy volunteers age 65 or over.  The objective of the study was to investigate whether RAD001, an analog of rapamycin could improve immune functions in the elderly as assessed by response to influenza vaccination.  The results, which were recently published in  the prestigious Science Translational Medicine , show that indeed RAD001 enhanced the immune response to the influenza vaccine by about 20% in this healthy senior population..  The data from this trial demonstrate that RAD0001 can ameliorate immunosenescence, the decline of immune system functions as people ages, by increasing the antibody titers to influenza and reducing the percentage of certain population of T lymphocytes, whose number increases with age. Rapamycin was first approved by the FDA in 1999 as an immunosuppressant to prevent organ transplant rejection and is also used as a slow releasing coating in conjunction with coronary stents to prevent restenosis following balloon angioplasty.   Currently, many clinical trials are being conducted to investigate its therapeutic effects in several types of cancers and various other diseases.  In regard to anti-aging studies, resveratrol, a compound found in grapes and red wine, is also being studies by GlaxoSmithKline for its anti-aging function in certain populations.  However, rapamycin, having been shown consistently to counteract aging and age-related diseases in several mouse populations and other animals, represents the most promising candidate disrupting aging-related disease progression. With an approval history by the FDA and an excellent safety profile, research communities are hopeful that a fine-tuned dosing regimen will be developed for rapamycin to aid humans to age gracefully with a good quality of life.   Related Links:

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Genentech’s New Combination Chemotherapy Prolonged Breast Cancer Patient Lives for Extra 16 Months

A phase III clinical trial sponsored by Genentech using a combination of chemotherapy drugs showed unprecedented results in patients with metastatic HER2-positive breast cancer.  The outcome of this study is published in the February issue of the prestigious New England Journal of Medicine.  The trial enrolled over 800 patients with metastatic HER2-positive breast cancer and randomly assigned them to treatment group (pertuzumab + trastuzumab + docetaxel) or control group (placebo + trastuzumab + docetaxel).  The treatment group extended lives by close to 16 months compared to the control group, a result that is so impressive that “doctors have rushed to make it standard therapy”.  In addition, pertuzumab treatment group did not present more side effects in comparison to the control group. Pertuzumab (Perjeta) and trastuzumab (Herceptin) are both humanized monoclonal antibodies developed by Genentech to combat HER2-positive cancer cells.  These two antibodies target different HER2 epitopes, consequently the combination of these two antibodies results in more comprehensive signaling blockade.  Preclinical experiments showed that combining pertuzumab and trstuzumab led to greater activity than that with either antibody alone.  Importantly, combination therapy with these two antibodies and docetaxel resulted in higher efficacy among patients receiving neoadjuvant therapy in another clinical trial, which provided the basis for Perjeta’s first FDA approval in 2013 for use in combination with Herceptin and docetaxel in patients with HER2-positive early breast cancer.  With this exciting and unprecedented result, Perjeta and Herceptin combination is poised to become the most powerful targeted therapy for HER2-positive cancers, a type of cancer notorious for aggressiveness and therapy-resistance. Genentech, based in San Francisco, California is a member of the Roche Group.  HER2 (human epidermal growth factor receptor 2) is an oncogene and it is over-expressed in about 20% breast cancers.  Breast cancer in women is the second most common type of cancer in the US.  According to the American Cancer Society, about 231,840 new cases of invasive breast cancer will be diagnosed in women and about 40,290 women will die from breast cancer in 2015 in the US.  Worldwide, breast is one of the 5 most common sites diagnosed with cancer.   Related Links:

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FDA Approves Lenvima for Treatment of Progressive Radioiodine-refractory Differentiated Thyroid Cancer (RR-DTC)

FDA announced this February the approval of lenvima (lenvatinib), a novel investigative chemotherapy for patients with progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC).  Lenvima is developed by Eisai Co., Ltd headquartered in Tokyo, Japan.  This approval is one day after the publication of Eisai’s phase III multi-nation clinical trial in the New England Journal of Medicine (NEJM), which showed significant progression-free survival (PFS) in lenvima group compared to placebo control group (median PFS 18.3 months with lenvima vs. 3.6 months with placebo). Differentiated thyroid cancer is the most common type of thyroid cancer representing about 95% of all thyroid cancers.  Some of differentiated thyroid cancers are radioiodine-refractory (RR-DTC) and treatment options for this group of patients are limited, which presents a significant unmet medical need.  Eisai’s lenvima is an oral RTK (receptor tyrosine kinase) inhibitor selectively targeting multiple different molecules including VEGFR, FGFR, RET, KIT and PDGFR, some of which are involved in tumor angiogenesis and proliferation of thyroid cancer. Lenvima was granted Orphan Drug Designation for thyroid cancer by regulatory authorities in Japan, the United States and Europe.  In addition, Lenvima was granted priority review status in the United States and accelerated assessment in Europe.  Currently Eisai is conducting several trials of lenvima attempting to treat several solid tumors, including hepatocellular carcinoma, renal cell carcinoma and non-small cell lung cancer.  Depending on the results of these trial, lenvima could become an oncology blockbuster.   Related Links:

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A New Hope for Glioblastoma

Celldex’s investigational immunotherapy rindopepimut received Breakthrough Therapy Designation from the FDA Celldex Therapeutics, headquartered in Hampton, New Jersey announced on February 23 that the US Food and Drug Administration (FDA) has granted its rindopepimut Breakthrough Therapy Designation for the treatment of adult patients with EGFRvIII-positive (epidermal growth factor receptor variant III-positive) glioblastoma (GBM).  The FDA’s decision is based largely on data from several Phase II clinical trials involving newly diagnosed or recurrent EGFRvIII-positive GBM.  Across all phase II studies, rindopepimut prolonged overall survival well beyond what has been observed in the corresponding patient populations historically, marking an important milestone for this difficult to treat disease.  And importantly, these studies also demonstrate that rendopepimut is well tolerated in patients. Rindopepimut is an investigational immunotherapeutic vaccine that targets EGFRvIII.  EGFRvIII is a mutated form of the epidermal growth factor receptor (EGFR) that is only expressed in cancer cells and the expression of this form of EGFR promotes cancer growth.  EGFRvIII is present in about 25-40% of GBM tumors and EGFRvIII-positive GBM is typically associated with poor prognosis than the overall GBM population. According to Anthony Marucci, Co-founder, President and Chief Executive Officer of Celldex Therapeutics, Glioblastoma patients have extremely limited treatment options, with only three new drugs approved in more than twenty years. The FDA’s decision to grant Breakthrough Designation underscores rindopepimut’s therapeutic potential, and brings new hope to patients with glioblastoma.   Related Links:

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