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Targeted therapies in cancer
CANCER TREATMENT
Targeted therapies in cancer
therapies have changed cancer care, with tailoring to an individual patients’ tumour, new approaches to dosing and disease assessment, and an increasing burden on health economics. Rather than a disease specific approach, these novel therapies may be of benefit in multiple cancer types. There are three main categories of targeted therapies: small molecule inhibitors, monoclonal antibodies and immunotherapies, each of which will be discussed in turn.
Harriet S Walter Samreen Ahmed
Abstract
Small molecule kinase inhibitors
Cytotoxic chemotherapy has traditionally provided the backbone of medical care for cancer. While chemotherapy remains the treatment of choice for many types of cancer, so-called ‘targeted therapies’ are now increasingly available within the clinic across a broad range of tumour types. Targeted therapies can inhibit specific molecular targets implicated in cancer or single oncogenic drivers, rather than affecting cell division or DNA synthesis. While often better tolerated, they can be associated with adverse events, which require specialist multidisciplinary management. Targeted therapies have changed cancer care, with tailoring to an individual patients’ tumour, new approaches to dosing and disease assessment, but with an increasing burden on health economics. Rather than a disease-specific approach, these novel therapies may be of benefit in multiple cancer types. There are three main categories of targeted therapies: small molecule inhibitors, monoclonal antibodies and immunotherapies, which will be considered in this article.
Kinases are important targets in cancer due to their involvement in multiple signal transduction processes, which become dysregulated and have the potential to drive cancer.1 The ability to design highly selective small molecule inhibitors to individual kinases, which inhibit downstream signalling pathways. With an acceptable side effect profile and potential for high response rates, they provide significant opportunity for therapeutic intervention. There are a small number of molecularly defined cancers that are driven by a single gene, which can be targeted by specific small molecule inhibitors, some of which have provided a superior clinical benefit to cancer patients over standard chemotherapy. However, despite these successes, there remains much to be learnt on how best to utilize kinase inhibitors and in what order. Kinase activation in cancer Oncogenic activation of protein and lipid kinases occurs as a consequence of often multiple types of genetic and epigenetic changes. This may result in increased activity of the kinase, overexpression, or the loss of negative regulation. Most frequently, genetic alterations found in cancer are somatically acquired and can result in constitutively upregulated kinase activity, and oncogene addiction.1 An example is the BRAF V600E mutation, targetable in a number of different cancer types including melanoma, colorectal, papillary thyroid, lung and hairy cell leukaemia. Genomic instability can also result in elevated kinase activity through amplification of large chromosomal regions or complex chromosomal re-arrangements such as translocation or deletion, resulting in over-expression or expression of a chimeric kinase or deregulated expression respectively.1 The receptor tyrosine kinases EGFR, HER2/ERRB2 and CDK4 and CDK6, serine/threonine kinases are frequently over-expressed as a result of gene amplification. Kinase inhibitors targeting kinase fusions, for example, BCR-ABL1 in chronic myeloid leukaemia and ALK fusions in lung cancer, have shown remarkable clinical results and provide an ideal target because of their oncogenic dependency. Other mechanisms of kinase activation include overexpression due to epigenetic change, activation of a kinase transcription factor, inactivating mutations of negative regulators, alternative splicing, splice mutations, overexpression of a ligand or upstream positive regulator. These diverse and multiple processes of kinase activation present numerous important opportunities for the identification of new therapeutic targets and treatment opportunities.
Keywords Immunotherapies; monoclonal antibodies; small molecule inhibitors; targeted therapies
Introduction Cytotoxic chemotherapy has traditionally provided the backbone of medical care for cancer. Chemotherapy targets rapidly dividing cells, including cancer cells and normal tissues thus producing a predictable toxicity profile. Since the 1990s, we have seen significant changes and advances in the management of cancer. While chemotherapy remains the treatment of choice for many types of cancer, so called ‘targeted therapies’ are now increasingly available within the clinic across a broad range of tumour types. Targeted therapies, like chemotherapy, can inhibit cancer growth and the development of metastatic disease. However, their mechanism of action differs from traditional cytotoxic chemotherapy. Targeted therapies can inhibit specific molecular targets implicated in cancer or single oncogenic drivers, rather than affecting cell division or DNA synthesis. While often better tolerated, they can be associated with adverse events, which require specialist multidisciplinary management. Targeted
Harriet S Walter MBChB MSc MRCP is a Specialist Trainee in Medical Oncology and a Cancer Research UK Clinical Trials Fellow, University Hospitals Leicester and University of Leicester, UK. Conflicts of interest: none declared.
Types of kinase inhibitor binding sites Protein kinases catalyse the transfer of the terminal phosphate of ATP to substrates containing a serine, threonine or tyrosine
Samreen Ahmed MBChB MD FRCP is Professor in Medical Oncology, University Hospitals Leicester, UK. Conflicts of interest: none declared.
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Please cite this article in press as: Walter HS, Ahmed S, Targeted therapies in cancer, Surgery (2017), https://doi.org/10.1016/ j.mpsur.2017.12.010
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lapatinib, which inhibits both HER2 and EGFR and has been used in metastatic breast cancer in patients who have progressed following treatment with Herceptin.
residue. Most kinase inhibitors are ATP competitive and have a conserved activation loop. The classification of these molecules depends on the region of interaction in the kinase and reversibility of the inhibition (Table 1). There are multiple examples of kinases inhibitors in the clinical setting that have produced clinically meaningful results.
Combination therapy Combination therapy has been a method of improving not only efficacy, but also delaying the onset to resistance. Many combination therapies are now currently used within the clinic or in clinical trials. A good example if this is in melanoma, where combination therapies target the MAPK pathway at different points using a BRAF V600E inhibitor and MEK1/MEK2 inhibitor together (Figure 1). This combination has been used in clinical trials to improve outcome compared with those receiving a single agent V600E inhibitor. Drug combinations targeting parallel kinase pathways and combined inhibition of kinases that regulate cell cycle checkpoints and phase transitions are being explored. However, combination therapy may result in increased and unanticipated toxicity. Furthermore the questions often arise as to which drug to combine with which drug and how? The combination of kinase inhibitors with other therapies is also being explored and utilized in the clinic including chemotherapy and immunotherapy combinations. The concept behind combination therapy is the idea of directly targeting the tumour and reducing its immunosuppressive influences in order to shift the local microenvironment towards a pro-inflammatory state and enhance the activity of the immune activators.7
Imatinib mesylate Perhaps the most well-described example is that of the BCR-ABL1 inhibitor, imatinib mesylate, in Philadelphia chromosome positive chronic myeloid leukaemia (CML). Imatinib targets the inactive confirmation of the tyrosine kinase region of the BCRABL fusion protein, which is a result of the translocation and fusion of chromosome 9 region q34 that contains ABL to chromosome 22 region q11. This results in unregulated ABL tyrosine kinase. Imatinib therapy in CML has resulted in durable responses, with an 8 year survival rate of 85%.3 Imatinib is also used in the treatment of gastrointestinal stromal tumours (GIST), where the c-KIT protein is mutated. Vascular endothelial growth factor The vascular endothelial growth factor (VEGF) family consists of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and placental growth factor (PIGF).4 There are three individual receptor VEGFR-1, VEGFR-2, VEGFR-3, which are transmembrane receptors. On ligand binding, they dimerise and become activated through transphosphorylation. Many small molecule inhibitors of the VEGF family are in clinical use or trials. Sunitinib, used in the treatment of renal cell cancer, GIST and pancreatic neuroendocrine tumours, is largely a VEGF inhibitor, although it also targets PDGFRs and other receptor tyrosine kinase inhibitors. Common side effects include impaired wound healing, hypertension, skin rash and thrombosis.
Monoclonal antibodies Monoclonal antibodies can be used to target cancer-specific antigens found not just on the surface of cancer cells, but also within the surrounding tumour stromal and vascular cells.8 Antibodies induce cell death through several mechanisms: antibody-dependent cytotoxicity, immune-mediated killing mechanisms and indirect effects on the stroma or vasculature. The Fc function of antibodies is particularly important, and while most antibodies are intact immunoglobulin molecules (IgG), increasingly novel constructs and the delivery of conjugated cytotoxic drugs using these. Examples of the different types of tumour-associated antigens targeted by antibodies are shown below in Table 2.8 Monoclonal antibodies are now used extensively within the fields of oncology and haematology and many have gained FDA and EMA approval with widespread use in the clinics. Specific examples used widely are described below.
EGFR and HER2 The epidermal growth factor receptor is a transmembrane receptor, involved in multiple cell processes. On binding of ligand to the extracellular domain, receptor dimerization occurs and activation of the kinase domain and downstream signalling pathways. HER2 is overexpressed in breast cancer and drives cell proliferation, angiogenesis and invasion.5 Small molecule inhibitors, for example erlotinib and gefitinib, that target the EGFR ATP binding site are used for the treatment of advanced NSCLC in the presence of activating mutations within the tyrosine kinase domain of EGFR.6 A further example is
Comparison between the different types of kinase inhibitors2 Type of inhibitor
Type of binding
Binding site
ATP competitive
Selectivity
Examples
Type 1
Reversible
ATP site
Yes
Low
Type 2 Type 3 Type 4 Covalent
Reversible Reversible Reversible Irreversible
ATP site and DFG pocket Allosteric Allosteric ATP site
No No No No
High Very high Very high Low
Gefitinib Vemurafenib Imatinib Selumetinib ON012380 Ibrutinib Afatinib
Table 1
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Rituximab CD20 is expressed broadly across non-Hodgkin lymphomas.9 Targeting CD20 with rituximab results improved outcomes for patients treated in combination with chemotherapy, for example cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) and also when received in the maintenance setting. Rituximab, on binding to CD20, results in both antibody dependent cell mediated cytotoxicity and complement dependent cytotoxicity.
Dual blockade within the MAPK pathway in melanoma RTK
Bevacizumab Bevacizumab targets VEGF, a secreted glycoprotein, upregulated within the tumour micro-environment.10 Signalling through the VEGF receptors (VEGFR-1, VEGFR-2 and VEGFR-3) activates the Raf-1-MEK-ERK pathway and the PKC-dependent pathway, involved in proliferation, differentiation and apoptosis. Examples of the clinical use of bevacizumab in combination with chemotherapy include colorectal, breast, lung and glioblastoma. Side effects include the risk of hypertension, proteinuria, poor wound healing, bleeding, perforation and thrombosis.
RAS
Vemurafenib Dabrafenib
BRAF
Trametinib Cobimetinib Selumetinib
MEK 1/2
RAF 1
Trastuzumab emtansine (T-DM1) Antibodyedrug conjugates consist of a cytotoxic drug covalently linked to a monoclonal antibody enabling activity against a tumour specific antigen. TDM-1 is one of the first antibody drug conjugates (ADC) used in clinical practice. It is indicated in advanced HER2-positive breast cancers having progressed on earlier trastuzumab-based treatment. TDM-1 consists of trastuzumab, linked to a highly toxic chemotherapy drug (DM1) that inhibits microtubule assembly.11 The clinical development of DM1 was halted early due to toxicity despite promising in vitro activity. However, delivering DM1 intracellularly to target cancer cells specifically has enabled this drug to be used in the clinical setting with manageable toxicity. Upon binding to HER2, the trastuzumab component of T-DM1 exerts its antitumour effects. The HER2eT-DM1 complex is then endocytosed and undergoes degradation with release of the active DM1.
ERK 1/2
Figure 1
Trastuzumab (Herceptin) HER2 is upregulated in approximately 15e20% of breast cancers.5 Trastuzumab is a monoclonal antibody specific to the ectodomain of HER2, and on binding inhibits receptor dimerization, thus preventing downstream signalling through the phospholipase C-y (PLC-y), PI3K and Ras/MAPK pathways. Trastuzumab has shown benefit in breast cancer in the early and metastatic setting, resulting in improved survival when used alone or in conjunction with chemotherapy.
Categories of tumour-associated antigens targetable with antibodies8 Type of antigen
Example of antigen
Example of therapeutic antibody against this target
Tumour types expressing antigen
Haematopoietic differentiation antigens Glycoproteins expressed by solid tumours Glycolipids
CD20 CEA Gangliosides (such as GD2, GD3 and GM2) Le VEGF EGFR ERBB2
Rituximab, obinutuzumab labetuzumab 3F8, ch14.18 and KW-2871
Non-Hodgkin’s lymphoma Breast, colon and lung tumours Neuroectodermal tumours
Hu3S193 and IgN311 Bevacizumab Cetuximab, panitumumab Trastuzumab and pertuzumab
FAP
Sibrotuzumab and F19
Breast, colon, lung and prostate tumours Tumour vasculature e.g. colon, breast, lung Glioma, lung, colon, head and neck tumours Breast, colon, lung, ovarian and prostate tumours Colon, breast, lung, pancreas and head and neck tumours
Carbohydrates Targets of anti-angogenic mABS Growth and differentiation signalling
Stromal and extracellular matrix antigens
Table 2
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4, an inhibitory receptor, expressed on the surface of activated and regulatory T cells.14 It binds to B7.1 and B7.2, which are present on antigen presenting cells and when bound, it downregulates T-cell activation through cell cycle arrest, T-cell anergy or tolerance. Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody, gained FDA approval in 2011 as first-line therapy for metastatic melanoma. Treatment-related AEs are mostly mild to moderate with single agent immune checkpoint blockade, but can occur at any point during treatment, frequently following at least 4 weeks of treatment but often after many months. Toxicity may also occur following treatment discontinuation. Establishing the correct diagnosis, grade of toxicity, initiating treatment with steroids where appropriate and withholding further immunotherapy is essential. The most common toxicities include dermatitis, enterocolitis, pneumonitis, endocrinopathies, liver abnormalities and uveitis, which may be life threatening without prompt recognition and correct management. Most toxicities will respond to steroids but often high doses and tapering courses are required. Persistence or refractories to steroids may require additional use of immunosuppressive therapies such as antitumour necrosis factor therapy. Often a multidisciplinary team is required to optimize management of toxicities, including endocrinologists, dermatologists, ophthalmologists and gastroenterologists. While prompt and appropriate treatment of toxicity with steroids is mandated, it should be recognized that efficacy of immunotherapies may be compromised in patients receiving steroids concurrently. Currently no predictive markers are available to guide which patients will get therapeutic benefit from ipilimumab or predict toxicity. In contrast to cytotoxic therapies and other targeted therapies, response to immunotherapies may take several months and in some patients’ pseudoprogression may be seen. PD-I inhibition has also been recognized as an important immunotherapy target expressed by antigen stimulated T cells, which inhibit T cell proliferation, cytokine release and cytotoxicity.15 It has two known ligands, PD-L1 and PD-L2. Pre-clinical data have shown that inhibition of the interaction between PD-1 and PD-L1, enhances T cell responses and antitumour activity. Antibodies targeting PD-1 and PD-L1 have been approved for use within the clinical setting. Nivolumab, an anti-PD-1 antibody, has been licenced for use in melanoma, renal cell and lung cancer and is in clinical trials in other solid tumours. PD-L1 antibodies such as pembrolizumab have been licenced in lung cancer and is now available for the line treatment of advanced PD-L1 positive disease and melanoma. Significant responses that are durable have been observed with PD-L1 and PD-1 antibodies. Interestingly toxicity appears less than with CTLA-4 antibodies. The search for new targets continues and identified potential targets include lymphocyte activation gene 3 (LAG3) and T cell immunoglobulin and mucin domain-containing 3 (TIM3) protein.
Trastuzumab emtansine offers both the potential benefits of trastuzumab and the unique targeted delivery of chemotherapy, which may result in improved efficacy and fewer adverse events (AEs).
Immunotherapy Cancer cells develop multiple ways to evade the immune system, through local immune evasion, tolerance, disruption of T-cell signalling and immune editing.12 This results in cancer cells that are more resistant to apoptosis and less immunogenic. Despite prior disappointing results, recent exciting developments in the field have brought new hope to the clinic and revolutionized the field. Current immunotherapy strategies include stimulation of effector mechanisms and counteracting of inhibitory mechanisms. Approaches include the use of vaccines, adoptive cellular therapy, and targeted antibody therapy. Cancer vaccines The concept of using cancer vaccines came from the recognition that patients possess CD8þ and CD4þ T cells that are able to recognize tumour antigens. Early attempts at using therapeutic vaccines were hindered by a failure to recognize that cancer induces tolerance and therefore to be effective, cancer vaccines must overcome this. Dendritic cells, which are extremely efficient at presenting antigen and inducing T-cell immunity, have been used as a mechanism to overcome this immune tolerant environment. To date, considerable problems with the development and use of cancer vaccines remain. Perhaps the greatest limiting factor in the development of cancer vaccines has been the identification of the ideal tumour antigen, which is both specific to cancer cells and immunogenic. However, this is compounded by our increasing knowledge of the complexity of the tumour microenvironment and inter and intra-tumoural heterogeneity. Oncolytic virus therapy Oncolytic virus therapy relies on the use of native or engineered viruses to replicate in and kill cancer cells.13 Subsequent cell death results in release of tumour associated antigens and specific CD8þ T-cell responses. Approaches to reduce the risk of clearance of the virus from the body, preventing activity, have included the use of covalent conjugation of the viral coat with polyethylene glycol and polymer coating, which prevents antibody binding and neutralization. Examples of vectors trialled are herpes simplex virus and vaccinia virus, genetically engineered to be non-pathogenic and other non-pathogenic viruses such as Seneca valley virus (picornavirus). In October 2015, talimogene laherparepvec was the first oncolytic immunotherapy approved for the use of metastatic melanoma by the FDA. Improved responses were seen that were durable and resulted in improved overall survival over the control arm. Limitations of oncolytic therapy potentially surround their use in immune compromised individuals and local administration, which may limit their use in metastatic disease.
Combining immune checkpoint inhibitors Immunotherapy agents are now being trialled in combination with both chemotherapy and small molecule inhibitors but also with other immunotherapies. The combination of anti-CTLA-4 and anti-PD-1 immunotherapies have shown higher response rates in melanoma than single-agent therapy, however, at a cost
Immune checkpoint blockade Significant and rapid progress has been seen in the use of immunotherapies to block inhibitory immune pathways over the past few years. The initial target for immunotherapies was CTLA-
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CANCER TREATMENT
of increased toxicity.16 Trials of combination immunotherapies are ongoing with examples in renal cell carcinoma, NSCLC, triple negative breast cancer and bladder cancer. Combining immunotherapy with chemotherapy, may boost the effect of immunotherapies through the release of tumour neoantigens, and through modification of the tumour microenvironment.12 Similarly with small molecule inhibitors, the potential benefit of immunotherapy may be increased in combination with targeted therapies.
true, with rates similar to other solid tumours. Wound dehiscence is potentially a particular concern for patients with CNS tumours because previous radiotherapy and frequent, lengthened administration of corticosteroids already increases this risk. The half-lives of bevacizumab and tyrosine kinase inhibitors are substantially different; thus, precise recommendations regarding the timing of surgery after neoadjuvant therapy depend on the tumour type and therapy used.
Barriers to the use of targeted therapies Chimeric antigen T (CAR T) cells CAR T cells are constructed from T cells removed from a patient and modified to express a receptor that recognizes and targets cancer cells. The CAR consists of the variable regions of an antibody, a linker and intracellular signalling chain composed of the CD3z signalling domain of the T-cell receptor (TCR) and costimulatory molecules.17 In haematological malignancies, response rates of over 80% have been seen using the B-cell antigen CD19 as a target. In solid tumours, a lack of a specific target purely found on cancer cells has hindered progress. Clinical applicability has been limited by significant toxicity, largely due to severe cytokine release syndrome, resulting in death in some cases. Furthermore the resource and time required to construct CAR T therapies for each patient may limit their clinical widespread utility.
The heterogeneity and ability of tumours to evolve has limited the ability of targeted therapies to date within the clinical setting. However, outside of an improved understanding of tumour biology there are additional considerations in the development of targeted therapies that have been well described.20 First, our approach to the treatment of cancer has largely been focused on the site of origin. Increasing knowledge of the molecular characteristics of cancer has meant that we can no longer rely on a site specific classification for the management and treatment of cancer. For example, patients with HER2 positive breast cancer should receive trastuzumab where clinically appropriate. Concerns with improved access to molecular and genetic testing, are linked to additional costs, the requirement for bioinformatics support and improved IT systems. Second, our current design of clinical trials does not lend itself to acceleration of drug development nor allow for drugs to gain approval readily in small patient populations, where the % of patients with a specific actionable mutation may be just 1e2% of the population. We need to see increasing trials with umbrella- and baskettype designs that allow for multiple drugs, or multiple tumour types, to be tested within one trial based on molecular classifications. Third, ensuring patient safety with emerging and at times unpredicted toxicity remains a key concern for clinicians. Lastly, the cost of targeted treatments, with many requiring continuous administration for many years, may prohibit there integration into clinical practice. A
Specific potential toxicities and their management VEGF-targeted therapies are associated with poor wound healing, bowel perforation, arterial thrombosis and increased risk of bleeding.18 The use of VEGF-targeted therapies in the perioperative period requires careful consideration based on estimated drug half life. A recommended interval of 6-week minimum between cessation of bevacizumab and surgery is often recommended. In the context of liver metastases, most centres would advocate an interval of 6e8 weeks between bevacizumab therapy and surgery, typically continuing chemotherapy alone until 3e4 weeks presurgery. In the neoadjuvant and adjuvant setting, overall and wound complication rates with the use of bevacizumab in combination with chemotherapy vary. This may relate in part to the fact that data on wound complications associated with VEGF-targeted therapies emanate from studies done in different clinical settings, and an absence of uniform definitions for wound complications. In patients with a gastrointestinal perforation secondary to bevacizumab, there are no definitive treatment recommendations. Bevacizumab-related perforations have been reported to be associated with a 30-day mortality rate of 12.5% and a 60-day mortality rate of 25% in a study by Badgwell et al., in a variety of tumours.19 Site of perforation could not be identified in a number of patients and surgical intervention was not required in all cases. More importantly, management of gastrointestinal perforation should take into account both patient related factors including prognosis and extent of disease, as well as the possible options for non-operative intervention, including drain placement and role of antibiotics. Safety concerns regarding risk of bleeding were raised in the safe use of bevacizumab in lung cancer. Interestingly, concerns of haemorrhage and stroke in primary CNS tumours did not hold
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REFERENCES 1 Gross S, Rahal R, Stransky N, Lengauer C, Hoeflich KP. Targeting cancer with kinase inhibitors. J Clin Investig 2015 May; 125: 1780e9. 2 Martin TA, Jiang WG. Anti-cancer agents in medicinal chemistry (Formerly current medicinal chemistry - anti-cancer agents). Anticancer Agents Med Chem 2010 Jan; 10: 1. 3 Cornelison AM, Kantarjian H, Cortes J, Jabbour E. Outcome of treatment of chronic myeloid leukemia with second-generation tyrosine kinase inhibitors after imatinib failure. Clin Lymphoma Myeloma Leuk 2011 Jun; 11(suppl 1): 101. 4 Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for antiand pro-angiogenic therapies. Genes Cancer 2011 Dec; 2: 1097e105. 5 Prat A, Perou CM. Deconstructing the molecular portraits of breast cancer. Mol Oncol 2011 Feb; 5: 5e23. 6 Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 2009 Jan; 9: 28e39. 7 Muller AJ, Scherle PA. Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors. Nat Rev Cancer 2006 Aug; 6: 613e25.
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8 Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer 2012 Mar 22; 12: 278e87. 9 Plosker GL, Figgitt DP. Rituximab: a review of its use in nonHodgkin’s lymphoma and chronic lymphocytic leukaemia. Drugs 2003; 63: 803e43. 10 Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer 2013 Dec; 13: 871e82. 11 Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat 2011 Jul; 128: 347e56. 12 Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov 2015 Aug; 14: 561e84. 13 Goldufsky J, Sivendran S, Harcharik S, et al. Oncolytic virus therapy for cancer. Oncolytic Virother 2013 Sep 23; 2: 31e46.
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14 Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996 Mar 22; 271: 1734e6. 15 Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26: 677e704. 16 Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013 Jul 11; 369: 122e33. 17 Yu S, Li A, Liu Q, et al. Chimeric antigen receptor T cells: a novel therapy for solid tumors. J Hematol Oncol 2017 Mar 29; 10: 9. 18 [Internet]. Avastin safety information, 2017 [updated July]. 19 Badgwell BD, Camp ER, Feig B, et al. Management of bevacizumab-associated bowel perforation: a case series and review of the literature. Ann Oncol 2008 Mar; 19: 577e82. 20 Jameson JL, Longo DL. Precision medicineepersonalized, problematic, and promising. N Engl J Med 2015 Jun 4; 372: 2229e34.
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Targeted therapies in cancer
therapies have changed cancer care, with tailoring to an individual patients’ tumour, new approaches to dosing and disease assessment, and an increasing burden on health economics. Rather than a disease specific approach, these novel therapies may be of benefit in multiple cancer types. There are three main categories of targeted therapies: small molecule inhibitors, monoclonal antibodies and immunotherapies, each of which will be discussed in turn.
Harriet S Walter Samreen Ahmed
Abstract
Small molecule kinase inhibitors
Cytotoxic chemotherapy has traditionally provided the backbone of medical care for cancer. While chemotherapy remains the treatment of choice for many types of cancer, so-called ‘targeted therapies’ are now increasingly available within the clinic across a broad range of tumour types. Targeted therapies can inhibit specific molecular targets implicated in cancer or single oncogenic drivers, rather than affecting cell division or DNA synthesis. While often better tolerated, they can be associated with adverse events, which require specialist multidisciplinary management. Targeted therapies have changed cancer care, with tailoring to an individual patients’ tumour, new approaches to dosing and disease assessment, but with an increasing burden on health economics. Rather than a disease-specific approach, these novel therapies may be of benefit in multiple cancer types. There are three main categories of targeted therapies: small molecule inhibitors, monoclonal antibodies and immunotherapies, which will be considered in this article.
Kinases are important targets in cancer due to their involvement in multiple signal transduction processes, which become dysregulated and have the potential to drive cancer.1 The ability to design highly selective small molecule inhibitors to individual kinases, which inhibit downstream signalling pathways. With an acceptable side effect profile and potential for high response rates, they provide significant opportunity for therapeutic intervention. There are a small number of molecularly defined cancers that are driven by a single gene, which can be targeted by specific small molecule inhibitors, some of which have provided a superior clinical benefit to cancer patients over standard chemotherapy. However, despite these successes, there remains much to be learnt on how best to utilize kinase inhibitors and in what order. Kinase activation in cancer Oncogenic activation of protein and lipid kinases occurs as a consequence of often multiple types of genetic and epigenetic changes. This may result in increased activity of the kinase, overexpression, or the loss of negative regulation. Most frequently, genetic alterations found in cancer are somatically acquired and can result in constitutively upregulated kinase activity, and oncogene addiction.1 An example is the BRAF V600E mutation, targetable in a number of different cancer types including melanoma, colorectal, papillary thyroid, lung and hairy cell leukaemia. Genomic instability can also result in elevated kinase activity through amplification of large chromosomal regions or complex chromosomal re-arrangements such as translocation or deletion, resulting in over-expression or expression of a chimeric kinase or deregulated expression respectively.1 The receptor tyrosine kinases EGFR, HER2/ERRB2 and CDK4 and CDK6, serine/threonine kinases are frequently over-expressed as a result of gene amplification. Kinase inhibitors targeting kinase fusions, for example, BCR-ABL1 in chronic myeloid leukaemia and ALK fusions in lung cancer, have shown remarkable clinical results and provide an ideal target because of their oncogenic dependency. Other mechanisms of kinase activation include overexpression due to epigenetic change, activation of a kinase transcription factor, inactivating mutations of negative regulators, alternative splicing, splice mutations, overexpression of a ligand or upstream positive regulator. These diverse and multiple processes of kinase activation present numerous important opportunities for the identification of new therapeutic targets and treatment opportunities.
Keywords Immunotherapies; monoclonal antibodies; small molecule inhibitors; targeted therapies
Introduction Cytotoxic chemotherapy has traditionally provided the backbone of medical care for cancer. Chemotherapy targets rapidly dividing cells, including cancer cells and normal tissues thus producing a predictable toxicity profile. Since the 1990s, we have seen significant changes and advances in the management of cancer. While chemotherapy remains the treatment of choice for many types of cancer, so called ‘targeted therapies’ are now increasingly available within the clinic across a broad range of tumour types. Targeted therapies, like chemotherapy, can inhibit cancer growth and the development of metastatic disease. However, their mechanism of action differs from traditional cytotoxic chemotherapy. Targeted therapies can inhibit specific molecular targets implicated in cancer or single oncogenic drivers, rather than affecting cell division or DNA synthesis. While often better tolerated, they can be associated with adverse events, which require specialist multidisciplinary management. Targeted
Harriet S Walter MBChB MSc MRCP is a Specialist Trainee in Medical Oncology and a Cancer Research UK Clinical Trials Fellow, University Hospitals Leicester and University of Leicester, UK. Conflicts of interest: none declared.
Types of kinase inhibitor binding sites Protein kinases catalyse the transfer of the terminal phosphate of ATP to substrates containing a serine, threonine or tyrosine
Samreen Ahmed MBChB MD FRCP is Professor in Medical Oncology, University Hospitals Leicester, UK. Conflicts of interest: none declared.
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Please cite this article in press as: Walter HS, Ahmed S, Targeted therapies in cancer, Surgery (2017), https://doi.org/10.1016/ j.mpsur.2017.12.010
CANCER TREATMENT
lapatinib, which inhibits both HER2 and EGFR and has been used in metastatic breast cancer in patients who have progressed following treatment with Herceptin.
residue. Most kinase inhibitors are ATP competitive and have a conserved activation loop. The classification of these molecules depends on the region of interaction in the kinase and reversibility of the inhibition (Table 1). There are multiple examples of kinases inhibitors in the clinical setting that have produced clinically meaningful results.
Combination therapy Combination therapy has been a method of improving not only efficacy, but also delaying the onset to resistance. Many combination therapies are now currently used within the clinic or in clinical trials. A good example if this is in melanoma, where combination therapies target the MAPK pathway at different points using a BRAF V600E inhibitor and MEK1/MEK2 inhibitor together (Figure 1). This combination has been used in clinical trials to improve outcome compared with those receiving a single agent V600E inhibitor. Drug combinations targeting parallel kinase pathways and combined inhibition of kinases that regulate cell cycle checkpoints and phase transitions are being explored. However, combination therapy may result in increased and unanticipated toxicity. Furthermore the questions often arise as to which drug to combine with which drug and how? The combination of kinase inhibitors with other therapies is also being explored and utilized in the clinic including chemotherapy and immunotherapy combinations. The concept behind combination therapy is the idea of directly targeting the tumour and reducing its immunosuppressive influences in order to shift the local microenvironment towards a pro-inflammatory state and enhance the activity of the immune activators.7
Imatinib mesylate Perhaps the most well-described example is that of the BCR-ABL1 inhibitor, imatinib mesylate, in Philadelphia chromosome positive chronic myeloid leukaemia (CML). Imatinib targets the inactive confirmation of the tyrosine kinase region of the BCRABL fusion protein, which is a result of the translocation and fusion of chromosome 9 region q34 that contains ABL to chromosome 22 region q11. This results in unregulated ABL tyrosine kinase. Imatinib therapy in CML has resulted in durable responses, with an 8 year survival rate of 85%.3 Imatinib is also used in the treatment of gastrointestinal stromal tumours (GIST), where the c-KIT protein is mutated. Vascular endothelial growth factor The vascular endothelial growth factor (VEGF) family consists of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and placental growth factor (PIGF).4 There are three individual receptor VEGFR-1, VEGFR-2, VEGFR-3, which are transmembrane receptors. On ligand binding, they dimerise and become activated through transphosphorylation. Many small molecule inhibitors of the VEGF family are in clinical use or trials. Sunitinib, used in the treatment of renal cell cancer, GIST and pancreatic neuroendocrine tumours, is largely a VEGF inhibitor, although it also targets PDGFRs and other receptor tyrosine kinase inhibitors. Common side effects include impaired wound healing, hypertension, skin rash and thrombosis.
Monoclonal antibodies Monoclonal antibodies can be used to target cancer-specific antigens found not just on the surface of cancer cells, but also within the surrounding tumour stromal and vascular cells.8 Antibodies induce cell death through several mechanisms: antibody-dependent cytotoxicity, immune-mediated killing mechanisms and indirect effects on the stroma or vasculature. The Fc function of antibodies is particularly important, and while most antibodies are intact immunoglobulin molecules (IgG), increasingly novel constructs and the delivery of conjugated cytotoxic drugs using these. Examples of the different types of tumour-associated antigens targeted by antibodies are shown below in Table 2.8 Monoclonal antibodies are now used extensively within the fields of oncology and haematology and many have gained FDA and EMA approval with widespread use in the clinics. Specific examples used widely are described below.
EGFR and HER2 The epidermal growth factor receptor is a transmembrane receptor, involved in multiple cell processes. On binding of ligand to the extracellular domain, receptor dimerization occurs and activation of the kinase domain and downstream signalling pathways. HER2 is overexpressed in breast cancer and drives cell proliferation, angiogenesis and invasion.5 Small molecule inhibitors, for example erlotinib and gefitinib, that target the EGFR ATP binding site are used for the treatment of advanced NSCLC in the presence of activating mutations within the tyrosine kinase domain of EGFR.6 A further example is
Comparison between the different types of kinase inhibitors2 Type of inhibitor
Type of binding
Binding site
ATP competitive
Selectivity
Examples
Type 1
Reversible
ATP site
Yes
Low
Type 2 Type 3 Type 4 Covalent
Reversible Reversible Reversible Irreversible
ATP site and DFG pocket Allosteric Allosteric ATP site
No No No No
High Very high Very high Low
Gefitinib Vemurafenib Imatinib Selumetinib ON012380 Ibrutinib Afatinib
Table 1
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Rituximab CD20 is expressed broadly across non-Hodgkin lymphomas.9 Targeting CD20 with rituximab results improved outcomes for patients treated in combination with chemotherapy, for example cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) and also when received in the maintenance setting. Rituximab, on binding to CD20, results in both antibody dependent cell mediated cytotoxicity and complement dependent cytotoxicity.
Dual blockade within the MAPK pathway in melanoma RTK
Bevacizumab Bevacizumab targets VEGF, a secreted glycoprotein, upregulated within the tumour micro-environment.10 Signalling through the VEGF receptors (VEGFR-1, VEGFR-2 and VEGFR-3) activates the Raf-1-MEK-ERK pathway and the PKC-dependent pathway, involved in proliferation, differentiation and apoptosis. Examples of the clinical use of bevacizumab in combination with chemotherapy include colorectal, breast, lung and glioblastoma. Side effects include the risk of hypertension, proteinuria, poor wound healing, bleeding, perforation and thrombosis.
RAS
Vemurafenib Dabrafenib
BRAF
Trametinib Cobimetinib Selumetinib
MEK 1/2
RAF 1
Trastuzumab emtansine (T-DM1) Antibodyedrug conjugates consist of a cytotoxic drug covalently linked to a monoclonal antibody enabling activity against a tumour specific antigen. TDM-1 is one of the first antibody drug conjugates (ADC) used in clinical practice. It is indicated in advanced HER2-positive breast cancers having progressed on earlier trastuzumab-based treatment. TDM-1 consists of trastuzumab, linked to a highly toxic chemotherapy drug (DM1) that inhibits microtubule assembly.11 The clinical development of DM1 was halted early due to toxicity despite promising in vitro activity. However, delivering DM1 intracellularly to target cancer cells specifically has enabled this drug to be used in the clinical setting with manageable toxicity. Upon binding to HER2, the trastuzumab component of T-DM1 exerts its antitumour effects. The HER2eT-DM1 complex is then endocytosed and undergoes degradation with release of the active DM1.
ERK 1/2
Figure 1
Trastuzumab (Herceptin) HER2 is upregulated in approximately 15e20% of breast cancers.5 Trastuzumab is a monoclonal antibody specific to the ectodomain of HER2, and on binding inhibits receptor dimerization, thus preventing downstream signalling through the phospholipase C-y (PLC-y), PI3K and Ras/MAPK pathways. Trastuzumab has shown benefit in breast cancer in the early and metastatic setting, resulting in improved survival when used alone or in conjunction with chemotherapy.
Categories of tumour-associated antigens targetable with antibodies8 Type of antigen
Example of antigen
Example of therapeutic antibody against this target
Tumour types expressing antigen
Haematopoietic differentiation antigens Glycoproteins expressed by solid tumours Glycolipids
CD20 CEA Gangliosides (such as GD2, GD3 and GM2) Le VEGF EGFR ERBB2
Rituximab, obinutuzumab labetuzumab 3F8, ch14.18 and KW-2871
Non-Hodgkin’s lymphoma Breast, colon and lung tumours Neuroectodermal tumours
Hu3S193 and IgN311 Bevacizumab Cetuximab, panitumumab Trastuzumab and pertuzumab
FAP
Sibrotuzumab and F19
Breast, colon, lung and prostate tumours Tumour vasculature e.g. colon, breast, lung Glioma, lung, colon, head and neck tumours Breast, colon, lung, ovarian and prostate tumours Colon, breast, lung, pancreas and head and neck tumours
Carbohydrates Targets of anti-angogenic mABS Growth and differentiation signalling
Stromal and extracellular matrix antigens
Table 2
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4, an inhibitory receptor, expressed on the surface of activated and regulatory T cells.14 It binds to B7.1 and B7.2, which are present on antigen presenting cells and when bound, it downregulates T-cell activation through cell cycle arrest, T-cell anergy or tolerance. Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody, gained FDA approval in 2011 as first-line therapy for metastatic melanoma. Treatment-related AEs are mostly mild to moderate with single agent immune checkpoint blockade, but can occur at any point during treatment, frequently following at least 4 weeks of treatment but often after many months. Toxicity may also occur following treatment discontinuation. Establishing the correct diagnosis, grade of toxicity, initiating treatment with steroids where appropriate and withholding further immunotherapy is essential. The most common toxicities include dermatitis, enterocolitis, pneumonitis, endocrinopathies, liver abnormalities and uveitis, which may be life threatening without prompt recognition and correct management. Most toxicities will respond to steroids but often high doses and tapering courses are required. Persistence or refractories to steroids may require additional use of immunosuppressive therapies such as antitumour necrosis factor therapy. Often a multidisciplinary team is required to optimize management of toxicities, including endocrinologists, dermatologists, ophthalmologists and gastroenterologists. While prompt and appropriate treatment of toxicity with steroids is mandated, it should be recognized that efficacy of immunotherapies may be compromised in patients receiving steroids concurrently. Currently no predictive markers are available to guide which patients will get therapeutic benefit from ipilimumab or predict toxicity. In contrast to cytotoxic therapies and other targeted therapies, response to immunotherapies may take several months and in some patients’ pseudoprogression may be seen. PD-I inhibition has also been recognized as an important immunotherapy target expressed by antigen stimulated T cells, which inhibit T cell proliferation, cytokine release and cytotoxicity.15 It has two known ligands, PD-L1 and PD-L2. Pre-clinical data have shown that inhibition of the interaction between PD-1 and PD-L1, enhances T cell responses and antitumour activity. Antibodies targeting PD-1 and PD-L1 have been approved for use within the clinical setting. Nivolumab, an anti-PD-1 antibody, has been licenced for use in melanoma, renal cell and lung cancer and is in clinical trials in other solid tumours. PD-L1 antibodies such as pembrolizumab have been licenced in lung cancer and is now available for the line treatment of advanced PD-L1 positive disease and melanoma. Significant responses that are durable have been observed with PD-L1 and PD-1 antibodies. Interestingly toxicity appears less than with CTLA-4 antibodies. The search for new targets continues and identified potential targets include lymphocyte activation gene 3 (LAG3) and T cell immunoglobulin and mucin domain-containing 3 (TIM3) protein.
Trastuzumab emtansine offers both the potential benefits of trastuzumab and the unique targeted delivery of chemotherapy, which may result in improved efficacy and fewer adverse events (AEs).
Immunotherapy Cancer cells develop multiple ways to evade the immune system, through local immune evasion, tolerance, disruption of T-cell signalling and immune editing.12 This results in cancer cells that are more resistant to apoptosis and less immunogenic. Despite prior disappointing results, recent exciting developments in the field have brought new hope to the clinic and revolutionized the field. Current immunotherapy strategies include stimulation of effector mechanisms and counteracting of inhibitory mechanisms. Approaches include the use of vaccines, adoptive cellular therapy, and targeted antibody therapy. Cancer vaccines The concept of using cancer vaccines came from the recognition that patients possess CD8þ and CD4þ T cells that are able to recognize tumour antigens. Early attempts at using therapeutic vaccines were hindered by a failure to recognize that cancer induces tolerance and therefore to be effective, cancer vaccines must overcome this. Dendritic cells, which are extremely efficient at presenting antigen and inducing T-cell immunity, have been used as a mechanism to overcome this immune tolerant environment. To date, considerable problems with the development and use of cancer vaccines remain. Perhaps the greatest limiting factor in the development of cancer vaccines has been the identification of the ideal tumour antigen, which is both specific to cancer cells and immunogenic. However, this is compounded by our increasing knowledge of the complexity of the tumour microenvironment and inter and intra-tumoural heterogeneity. Oncolytic virus therapy Oncolytic virus therapy relies on the use of native or engineered viruses to replicate in and kill cancer cells.13 Subsequent cell death results in release of tumour associated antigens and specific CD8þ T-cell responses. Approaches to reduce the risk of clearance of the virus from the body, preventing activity, have included the use of covalent conjugation of the viral coat with polyethylene glycol and polymer coating, which prevents antibody binding and neutralization. Examples of vectors trialled are herpes simplex virus and vaccinia virus, genetically engineered to be non-pathogenic and other non-pathogenic viruses such as Seneca valley virus (picornavirus). In October 2015, talimogene laherparepvec was the first oncolytic immunotherapy approved for the use of metastatic melanoma by the FDA. Improved responses were seen that were durable and resulted in improved overall survival over the control arm. Limitations of oncolytic therapy potentially surround their use in immune compromised individuals and local administration, which may limit their use in metastatic disease.
Combining immune checkpoint inhibitors Immunotherapy agents are now being trialled in combination with both chemotherapy and small molecule inhibitors but also with other immunotherapies. The combination of anti-CTLA-4 and anti-PD-1 immunotherapies have shown higher response rates in melanoma than single-agent therapy, however, at a cost
Immune checkpoint blockade Significant and rapid progress has been seen in the use of immunotherapies to block inhibitory immune pathways over the past few years. The initial target for immunotherapies was CTLA-
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of increased toxicity.16 Trials of combination immunotherapies are ongoing with examples in renal cell carcinoma, NSCLC, triple negative breast cancer and bladder cancer. Combining immunotherapy with chemotherapy, may boost the effect of immunotherapies through the release of tumour neoantigens, and through modification of the tumour microenvironment.12 Similarly with small molecule inhibitors, the potential benefit of immunotherapy may be increased in combination with targeted therapies.
true, with rates similar to other solid tumours. Wound dehiscence is potentially a particular concern for patients with CNS tumours because previous radiotherapy and frequent, lengthened administration of corticosteroids already increases this risk. The half-lives of bevacizumab and tyrosine kinase inhibitors are substantially different; thus, precise recommendations regarding the timing of surgery after neoadjuvant therapy depend on the tumour type and therapy used.
Barriers to the use of targeted therapies Chimeric antigen T (CAR T) cells CAR T cells are constructed from T cells removed from a patient and modified to express a receptor that recognizes and targets cancer cells. The CAR consists of the variable regions of an antibody, a linker and intracellular signalling chain composed of the CD3z signalling domain of the T-cell receptor (TCR) and costimulatory molecules.17 In haematological malignancies, response rates of over 80% have been seen using the B-cell antigen CD19 as a target. In solid tumours, a lack of a specific target purely found on cancer cells has hindered progress. Clinical applicability has been limited by significant toxicity, largely due to severe cytokine release syndrome, resulting in death in some cases. Furthermore the resource and time required to construct CAR T therapies for each patient may limit their clinical widespread utility.
The heterogeneity and ability of tumours to evolve has limited the ability of targeted therapies to date within the clinical setting. However, outside of an improved understanding of tumour biology there are additional considerations in the development of targeted therapies that have been well described.20 First, our approach to the treatment of cancer has largely been focused on the site of origin. Increasing knowledge of the molecular characteristics of cancer has meant that we can no longer rely on a site specific classification for the management and treatment of cancer. For example, patients with HER2 positive breast cancer should receive trastuzumab where clinically appropriate. Concerns with improved access to molecular and genetic testing, are linked to additional costs, the requirement for bioinformatics support and improved IT systems. Second, our current design of clinical trials does not lend itself to acceleration of drug development nor allow for drugs to gain approval readily in small patient populations, where the % of patients with a specific actionable mutation may be just 1e2% of the population. We need to see increasing trials with umbrella- and baskettype designs that allow for multiple drugs, or multiple tumour types, to be tested within one trial based on molecular classifications. Third, ensuring patient safety with emerging and at times unpredicted toxicity remains a key concern for clinicians. Lastly, the cost of targeted treatments, with many requiring continuous administration for many years, may prohibit there integration into clinical practice. A
Specific potential toxicities and their management VEGF-targeted therapies are associated with poor wound healing, bowel perforation, arterial thrombosis and increased risk of bleeding.18 The use of VEGF-targeted therapies in the perioperative period requires careful consideration based on estimated drug half life. A recommended interval of 6-week minimum between cessation of bevacizumab and surgery is often recommended. In the context of liver metastases, most centres would advocate an interval of 6e8 weeks between bevacizumab therapy and surgery, typically continuing chemotherapy alone until 3e4 weeks presurgery. In the neoadjuvant and adjuvant setting, overall and wound complication rates with the use of bevacizumab in combination with chemotherapy vary. This may relate in part to the fact that data on wound complications associated with VEGF-targeted therapies emanate from studies done in different clinical settings, and an absence of uniform definitions for wound complications. In patients with a gastrointestinal perforation secondary to bevacizumab, there are no definitive treatment recommendations. Bevacizumab-related perforations have been reported to be associated with a 30-day mortality rate of 12.5% and a 60-day mortality rate of 25% in a study by Badgwell et al., in a variety of tumours.19 Site of perforation could not be identified in a number of patients and surgical intervention was not required in all cases. More importantly, management of gastrointestinal perforation should take into account both patient related factors including prognosis and extent of disease, as well as the possible options for non-operative intervention, including drain placement and role of antibiotics. Safety concerns regarding risk of bleeding were raised in the safe use of bevacizumab in lung cancer. Interestingly, concerns of haemorrhage and stroke in primary CNS tumours did not hold
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