Features Practice Changers Recent advances that are redefining oncology Jane de Lartigue ince President Richard Nixon declared war Small-molecule inhibitors on cancer more than 40 years ago, there have The most easily “druggable” targets for small-molecule Sbeen significant increases in the number of inhibitors (SMIs) are kinases, particularly cell surface people who survive cancer. Alongside advances in tyrosine kinase receptors, which initiate signaling cas- screening, detection, and diagnosis, the develop- cades that drive important cellular processes. SMIs dif- ment of targeted anticancer agents has been a fer from mAbs in that they are administered orally major contributory factor to this success. We rather than intravenously, are less specific, and require highlight some of the key developments that have more frequent dosing. shaped oncological practice in recent decades and Imatinib was the first agent of this kind and those that will likely have a significant impact in was also the first to target a specific molecular the near future (Figure 1). defect in cancer cells; a chromosomal translocation (Philadelphia chromosome) that resulted in the Top 5 therapeutic developments formation of the BCR-ABL fusion protein, a ty- Monoclonal antibodies rosine kinase that is always active and therefore Monoclonal antibodies (mAbs) are designed to oncogenic. This defect is present in almost all specifically kill cancer cells by targeting tumor- patients with chronic myelogenous leukemia, so associated antigens on their surface (Table 1). The imatinib therapy results in a complete hematologic first drug of this kind to be approved by the Food response in 98% of patients. Imatinib has also and Drug Administration (FDA) was rituximab. revolutionized the treatment of gastrointestinal stromal tumors, a rare abdominal cancer that was This anti-CD20 mAb has revolutionized the treat- 2 ment of B-cell lymphomas (on which the CD20 virtually untreatable before its approval. There are at least 90 tyrosine kinases in the human antigen is expressed), producing response rates over 4 90% in combination with the CHOP (cyclophos- genome and many of these have now been targeted phamide, doxorubicin, vincristine, prednisolone) with inhibitors that are either approved (Table 2)orin chemotherapy regimen.1 various stages of development. There have also been notable advances in the Conjugated drugs use of mAbs in the treatment of solid tumors. Chemotherapy and radiotherapy remain impor- Trastuzumab reduces recurrence rates by half tant components of treatment for many types of when used in combination with chemotherapy in cancer, but their efficacy is limited by systemic the 20%-30% of women with metastatic breast toxicity and lack of tumor specificity. Conjugated cancers that overexpress the HER2 (human epi- agents combine the potent cytotoxic abilities of dermal growth factor receptor) protein. HER2- traditional therapies with the specificity of a mAb targeted therapy continues to provide break- (Figure 2). throughs; in 2012, pertuzumab, which has a Currently, there are 4 antibody–drug conjugates synergistic effect when combined with trastu- (ADCs) that have been approved by the FDA; 2 con- zumab, was approved. jugated to chemotherapeutic agents, and 2 to radiother- mAbs work via several different cellular mecha- apeutic agents. The most recent approval came in 2013 nisms, of which researchers are now gaining a better for ado-trastuzumab emtansine (T-DM1), which con- understanding, and increasingly effective agents with jugates the HER2 mAb trastuzumab to the cytotoxic 2,3 fewer side effects are being developed. agent emtansine. T-DM1 was approved for patients with HER2-positive metastatic breast cancer previ- ously treated with trastuzumab and a taxane, following Commun Oncol 2013;10:178-185 © 2013 Frontline Medical Communications DOI: 10.12788/j.cmonc.0036 the demonstration that median overall survival in pa- 178 COMMUNITY ONCOLOGY Ⅲ June 2013 www.CommunityOncology.net Practice Changers tients receiving the conjugate was in- A creased by more than 5 months, com- The first an-angiogenic agent, a mAb targeng VEGF, pared with patients receiving a The radiotherapeuc anbody bevacizumab, is approved for ibritumomab uxetan is the treatment of CRC. combination of capecitabine and approved for the treatment of 5 NHL. lapatinib. Erlonib becomes the second Genentech alone has over 25 ADCs EGFR-targeted small molecule The oncogenic BRAF mutaon inhibitor available for the in the pipeline, and these are rapidly be- is idenfied and found to be an treatment of NSCLC. important driver of certain malignancies, including coming an important component of PIK3CA melanoma. Mutaons in the gene cancer treatment, particularly as re- Trastuzumab approved for the and EGFR gene are idenfied treatment of HER2-posive and shown to be important searchers begin to improve their design breast cancer drivers of colon and lung cancer, to maximize efficacy and limit toxic side respecvely. 6,7 A second radiotherapeuc anbody, I-131 tositumomab effects. The mAb alemtuzumab An an-EGFR mAb, enters the market for NHL. becomes available for the Pannitumumab, is approved for treatment of CLL. the treatment of metastac CRC Identification of defects that drive and becomes the first agent to different cancers The first agent targeng the demonstrate the use of KRAS as First-ever targeted agent EGFR, gefinib revoluonizes a predicve biomarker. Imanib for the treatment of approved; rituximab for the the treatment of NSCLC. CML gains the fastest FDA Cancer-causing genetic changes are treatment of B-cell approval in US history. It is the malignancies referred to as “driver” events because first agent to target a specific The human genome is decoded Mutaons in the ABL gene are they confer a growth advantage to can- molecular defect – the paving the way for the idenficaon idenfied. The first conclusive evidence of Philadelphia chromosome. of new genec defects driving cancer cer cells and can be directly linked to cancer stem cells is published. and improving diagnosis and the development of a cancer. Genome treatment. sequencing technology has allowed re- 1998 2001 2004 2006 searchers to uncover many of these 1997 2002 2003 events. The most frequently altered B gene in human cancer is p53. Other The first therapeuc cancer An androgen receptor inhibitor, common mutations occur in the kinase vaccine, Sipleucel-T, is enzalutamide is approved for approved for the treatment of the treatment of late-stage enzymes that are essential to intracellular advanced prostate cancer. prostate cancer. signaling pathways. Driver events also occur in the form of chromosomal rear- Breast cancer survival is further The first inhibitor of mTOR , improved by the introducon of rangements and gene overexpression, everolimus is granted approval a second HER2-targeng mAb, by the FDA for the treatment of pertuzumab, to be used in with 2 significant examples being the advanced RCC. combinaon with trastuzumab. EML4-ALK fusion gene in non–small- The first an-cancer agent targeng a cell lung cancer, and overexpression of A second EGFR-targeted mAb, developmental pathway, the hedgehog cetuximab, is approved for the inhibitor vismodegib is approved for the HER2 gene in breast cancer. treatment of KRAS wild type paents with basal cell carcinoma. The identification of driver events CRC. has been instrumental in developing tar- A record number of Americans The first anbody-drug conjugate, Ofatumumab is the first non- are shown to be surviving T-DM1, is approved by the FDA for geted therapies and assessing which pa- radiotherapeuc mAb targeng cancer according to NCI and the treatment of breast cancer. It tients benefit the most, and a number of CD20 to be approved for the CDC data. combines the HER2 mAb with a treatment of CLL. cytotoxic agent (DM1). Ipilimumab, a mAb targeng tests have been approved by the FDA CTLA4, becomes the first cancer for this purpose (Table 3). Continual as- agent to target the immune Acvang mutaons in the The transforming EML4-ALK system, in order to help HER2 gene are idenfied, which sessment of the cancer genome is also fusion gene is idenfied as an paents with metastac could mean that HER2-negave important driver of lung cancer. melanoma. paents also benefit from important as subsequent mutations HER2-targeted agents. can develop in response to targeted therapy that may drive resistance.8 2012 2007 2009 2010 2011 2013 Inhibiting angiogenesis Tumors require oxygen and nutrients FIGURE 1 Timeline of developments in targeted therapies, beginning with the FDA’s approval of rituximab in 1997 through 2013 to date, with the approval of T-DM1 for breast cancer. from their surrounding environment to Abbreviations and definitions: ABL, gene that encodes abelson murine leukemia viral oncogene homolog 1; be able to grow and they initially obtain BRAF, gene that encodes B-Raf kinase; CDC, Centers for Disease Control and Prevention; CLL, chronic them through diffusion. However, they lymphocytic leukemia; CML, chronic myelogenous leukemia; CRC, colorectal carcinoma; CTLA4, cytotoxic T-lymphocyte antigen-4; EGFR, epidermal growth factor receptor; EML4-ALK, fusion between echinoderm are unable to grow beyond 2 mm with- microtubule-associated protein-like 4 and anaplastic lymphoma kinase genes; FDA, Food and Drug Admin- out stimulating the growth of new blood istration; KRAS, gene encoding a member of the Ras family of kinases; mAb, monoclonal antibody; NCI, vessels (a process called angiogenesis) to National Cancer Institute; NHL, non-Hodgkin lymphoma; NSCLC,