Targeted cancer therapy
Targeted cancer therapy interferes with particular molecules, pathways or processes in carcinogenesis and tumour growth, aiming to harm malignant cells more selectively than normal tissue. It rests on what sets a cancer cell apart from a normal one, on the tumour markers and subtypes that decide who receives which drug, on how each class of agent acts and how resistance to it arises, and on the companion diagnostics that select the patients a drug works in.
What sets cancer cells apart
Carcinogenesis is the process by which normal cells become cancer cells. To metastasise is for a tumour to spread to areas of the body not in direct contact with it, and metastases are the tumours that result, generally through the lymphatic and blood systems.
Hanahan and Weinberg's influential 2000 paper The Hallmarks of Cancer proposed that most if not all cancers acquire the same set of functional capabilities during their development, albeit through various mechanistic strategies. It described six hallmarks that set cancer cells apart: evading apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, sustained angiogenesis, limitless replicative potential, and tissue invasion and metastasis. Their 2011 update added two more: deregulating cellular energetics, meaning that cancer cells can use metabolic pathways in ways normal cells do not, and avoiding immune destruction, meaning that they can sabotage the immune cells sent to attack them. It also described two enabling characteristics of cancer: genome instability and mutation, and tumour-promoting inflammation, a characteristic of the tumour microenvironment. Because the number of parallel signalling pathways supporting a given hallmark must be limited, Hanahan and Weinberg observe that it may become possible to target all of them therapeutically and so prevent the development of adaptive resistance.
The hallmarks have been tremendously influential, but a 2010 commentary questioned the emphasis on them, noting that five of the six original hallmarks are also characteristic of benign tumours. Benign tumours can grow extremely large but do not kill, because they do not spread to other parts of the body. On the commentary's argument only the capability for tissue invasion and metastasis is unique to malignant cells, and it is invasion and metastasis that are responsible for most cancer mortality. It also held that the terms cancer and tumour are too often used interchangeably, and that keeping the difference in mind might help focus attention on the mechanisms of malignancy itself. In 2011 Hanahan and Weinberg, for their part, envisioned significant advances in understanding invasion and metastasis during the coming decade.
A tumour is not a pure lump of cancer cells growing in isolation but is like a dirty snowball, full of white cells, cytokines, blood vessels and scaffold tissue as well as malignant cells, a mixture called the tumour microenvironment. Much more was learned after 2000 about how cancer cells interact with and subvert non-malignant cells to serve their own ends, and by 2012 many researchers believed that targeting the microenvironment was a promising new line of attack against cancer.
Selectivity
Surgery, chemotherapy and radiation therapy are very effective in most cases but by their nature imprecise. At surgery it is difficult to be sure that all cancer cells have been removed, that is, that clean margins have been achieved, and nearly impossible to detect microscopic cancer cells that have already spread through the lymphatic or circulatory system. Clean margins is a histopathological definition describing the surgical margins as free of cancer cells. Traditional treatments also often fail to disable all malignant cells, because they are too toxic for patients or because small clusters of drug-resistant malignant cells seed throughout the body.
Chemotherapy and radiation therapy target rapidly dividing cells, which include healthy proliferating cells such as hair follicles, bone marrow and the lining of the mouth, so alopecia, anaemia or mucositis may develop. Another serious side effect, neutropenia, can predispose a patient to dangerous infections. Because chemotherapy and radiation therapy are imprecise and indiscriminate, oncologists have long searched for ways to kill tumour cells but spare normal cells.
Alopecia is loss or absence of hair, which usually grows back, and anaemia is a less than normal amount of red blood cells, which often leaves the patient weak and tired. Mucositis is inflammation of the lining of the mouth and digestive tract, and oral mucositis impairs eating, swallowing and talking. Neutropenia is a low blood count of granulocytes, the white cells that fight infections.
Targeted cancer therapies use drugs that block the growth and spread of cancer by interfering with specific molecules, pathways or processes in carcinogenesis and tumour growth. Their goal is to specifically interrupt some aspect of the cancer cell's life cycle while not interfering with normal cells. They attack tumours specifically and either do not harm normal tissues or harm them less than traditional cancer therapies, and selecting the correct targets can make an important difference to a patient's clinical outcome. Targeted therapies are often gene-based or protein-based, typically have fewer side effects than traditional therapies, and many have been shown to be extremely effective in treating specific forms of cancer. By 2007 several categories had been identified, including antiangiogenesis factors and monoclonal antibodies; some had been approved for marketing, and many others were in nonclinical or clinical development.
Targeted therapies are not new or unique to oncology: they have an established use in several clinical settings, including asthma (anti-tumour necrosis factor) and osteoporosis (bone-targeting nanocapsules of liposomes). Hormone therapies, such as antiestrogens like tamoxifen in breast cancer and inhibitors of testosterone production like leuprolide in prostate cancer, have been used successfully for decades. New targeted therapies are meant to differ in preferentially targeting the tumour rather than normal tissue, and in being designed around the molecular targets principally responsible for the malignant phenotype of a given cancer. Phenotype is how an organism looks, determined to a large extent by genotype, the identity of the alleles it carries at one or more positions on the chromosomes.
Tumour markers
Tumour markers are molecules, proteins or processes that differ from the norm in malignant cells, tissues or fluids in patients with cancer. They include circulating markers, proteins most often found in the blood but sometimes in urine or tissue samples, and genetic markers, derived from cancer-associated genes or from DNA extracted from tumours with chromosomal instability. In 2007 markers were being explored for diagnosis, prognosis and treatment, but very few were reliable and definitive for cancer, and rather than diagnosing it they were most often used to track the course of a cancer after it develops. Tumour markers show that cancer therapy can be made selective, targeting the overproduction of molecules involved in carcinogenesis.
Some commonly used circulating markers pair alpha-fetoprotein with testicular and liver cancers (diagnosis and tracking); carcinoembryonic antigen with gastrointestinal, colorectal and breast cancers (tracking); human chorionic gonadotropin with gestational trophoblastic and germ-cell tumours (tracking); monoclonal immunoglobulin protein (M) with multiple myeloma (diagnosis and tracking); prostate-specific antigen with prostate cancer (diagnosis and tracking); CA-125 with ovarian cancer and CA-19.9 with pancreatic and gastrointestinal cancers (tracking).
Some genetic markers, somatic mutations or chromosomal translocations, are associated with specific cancers: APC at 5q21 with familial adenomatous polyposis and colorectal cancer; BCL2 at 18q21 with non-Hodgkin lymphomas and acute leukaemias; BCL6 at 3q27 with lymphomas, particularly the transformation of follicular lymphoma to diffuse large-cell lymphoma; BCL1/PRAD1/CCND1 at 11q13 with lymphoma and breast and head-and-neck cancers; BCR-ABL from t(9;22)(q34;q11) with chronic myeloid leukaemia; FLT3 at 13q12 with acute myeloid leukaemia (in 70–100% of patients); HER-2/neu at 17q21 with breast and endometrial cancers; and MYC at 8q24 with lymphoma, small-cell lung, ovarian and breast cancers and childhood neuroblastoma.
Further genetic markers are PTEN at 10q23.3, associated with melanoma, glioma and renal-cell, hepatocellular, cervical, head-and-neck, breast and prostate cancers; REL at 2p15;14, with lymphomas including a subset of Hodgkin and diffuse large-cell lymphoma; RET at 10q11.2, with multiple endocrine neoplasia type 2 and familial medullary thyroid cancer; and TP53 at 17p13.1, with almost all tumour types, especially cancers of the colon, rectum, breast, lung, oesophagus, stomach, liver, ovary and urinary bladder. The BCL1 gene codes for cyclin D1, a marker that enables a differential diagnosis of mantle-cell lymphoma, a particularly aggressive form of lymphoma, and is positive in more than 80% of cases.
How targeted agents act
Targeted cancer therapies work by interfering with the growth and division of cancer cells, and different therapies act at different points during the growth and development of those cells. Some act on proteins involved in signalling, and by blocking the signals that instruct cancer cells to divide in an unregulated manner they can help stop the growth of a tumour.
A receptor is generally a protein on the cell surface or in its interior with an affinity for a specific chemical group, molecule or virus, and a ligand is a molecule or ion that can bind to and interact with a protein. An agonist binds selectively to a specific receptor and triggers a response in a cell, whereas an antagonist is a ligand that inhibits the function of an agonist. Epidermal growth factor is a polypeptide hormone that stimulates cell proliferation, especially of epithelial cells, by binding to receptor proteins on the cell surface. Fusion proteins are generated in the laboratory or within cancer cells by linking gene fragments, for example after chromosomal translocation, or their protein products. Antisense oligonucleotides are synthetic DNA or RNA designed to interact with mRNA before it is translated, preventing disease-associated proteins from being made. Ribozymes are RNA enzymes that catalyse site-specific cleavage of RNA.
Most cells carry proto-oncogenes, which oversee cell growth and other functions by producing growth factors, growth factor receptors or intracellular signalling molecules. A proto-oncogene that is broken or damaged becomes an oncogene, a gene whose activation is associated with the transformation of normal cells into cancer cells, and it instructs the cell to multiply rapidly, a hallmark of malignant cells. In 2007 approximately 100 of the approximately 30,000 genes mapped in human DNA were known to be proto-oncogenes, and over the previous three decades more than 300 genes and their protein products had been identified as directly or indirectly associated with the development of cancer. Oncogene inhibitors then included tyrosine kinase, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors, and several of the targeted agents approved in the United States, such as imatinib, erlotinib and trastuzumab, were oncogene inhibitors. Both small molecules and monoclonal antibodies can act as oncogene inhibitors, and so can antisense oligonucleotides, though in 2007 no antisense oligonucleotide had been approved for clinical use in cancer therapy. Other oncogene inhibitors, interfering with other growth factor receptor families or with intracellular targets such as specific transcription factors, were under study.
Targeted therapies can act on tumour cells or on immune cells. Gefitinib and cetuximab block the EGFR signalling pathway on tumour cells, which interferes with the tumour signals that result in tumour growth, proliferation and migration. Immunotherapies such as pembrolizumab instead bind to lymphocytes, interfering with the programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint signalling pathway and so preventing tumour cells from deactivating the immune response.
Apoptosis is a genetically determined, normal process of cell self-destruction that eliminates DNA-damaged, superfluous or unwanted cells. Cancer cells evade it and continue to survive, which increases the size of a tumour and allows it to metastasise. A key to this evasion is an increase in proteins, particularly Bcl-2, and drugs that inhibit Bcl-2 production promote apoptosis. Apoptosis-inducing therapies block enzymes that help cancer cells survive and work to make them more vulnerable to chemotherapy. Other drugs, in nonclinical development in 2007, can trigger apoptosis by binding to so-called death receptors on cell membranes, but they are also potentially very toxic to some normal cells.
A tumour can become clinically relevant, growing larger than 1 cubic millimetre, only if it has a supply of nutrients and oxygen and a way to remove waste products and carbon dioxide, that is, only if it develops a blood supply. That process is angiogenesis, first defined by Folkman: the development of new blood vessels (capillaries) that allow tumour cells to access nutrients for their growth. A blood supply also allows tumour cells to spread and develop into distant metastases. In a healthy person angiogenesis occurs during normal tissue growth and repair and in pregnancy, and its dysregulation, the inappropriate growth of new blood vessels, occurs in rheumatoid arthritis, cirrhosis, cardiovascular disease, diabetic retinopathy and cancer. Angiogenesis is driven by proangiogenesis factors, which stimulate the production of new capillaries, overcoming the effects of antiangiogenesis factors, which inhibit it. The former include VEGF, seemingly the primary factor, the fibroblast growth factor family, platelet-derived endothelial cell growth factor and tumour necrosis factor α and β; the latter include endostatin, angiostatin, interferons and thrombospondin-1 and -2. Antiangiogenesis is the inhibition of blood vessel formation.
Of the proangiogenesis factors discovered by 2007, the VEGF family was the best studied. VEGF is secreted by almost all cell types and overexpressed in most malignant tumours, and when it binds a receptor it can increase endothelial cell production, increase endothelial cell survival by inhibiting apoptosis, and reprogramme gene expression. Antiangiogenic products target VEGF or its receptors, reduce VEGF expression on cell membranes with fusion proteins, decrease receptor expression and activation with ribozymes, or inhibit tyrosine kinase to reduce receptor activation and downstream signalling. They can be monoclonal antibodies or small molecules, such as bevacizumab, which targets VEGF. In 2007 antiangiogenesis research had only about five years of clinical studies behind it, and early studies had shown that antiangiogenic agents can have significant toxicities. They continued to be pursued in spite of these toxicities, as many researchers believed control of angiogenesis to be one of the most promising targeted therapies, particularly after primary cancer surgery such as mastectomy or hemicolectomy. Targeting angiogenesis in this adjuvant setting may make it possible to delay or even prevent the growth of micrometastases throughout the body.
A monoclonal antibody is derived from a single cell in large quantities for use against a specific antigen. Treatment with monoclonal antibodies had become more common by 2007 as several received marketing approval: rituximab, alemtuzumab and gemtuzumab for some leukaemias and lymphomas, and trastuzumab and cetuximab for solid tumours. Some block the interaction of important proteins or the binding of a ligand, such as a growth factor, to a receptor, which alters signalling within the cell; others kill tumour cells directly, alone or carrying cytotoxic agents or radioisotopes.
Tumour subtypes
That cancer is not one disease but many has been known for some time, but only in the decade before 2012 did researchers begin to realise how many. Lung cancer was by then one of the few diseases to have entered the era of personalised medicine, in which treatment is selected according to the genetic makeup of the cancer. It has two main types, small cell and non-small cell, and non-small cell lung cancer accounts for about 80%. Non-small cell lung cancer subdivides into adenocarcinoma and squamous cell carcinoma, and the type matters for both prognosis and treatment selection. Even that classification is not enough: adenocarcinoma of the lung is analysed for an activating mutation of the epidermal growth factor receptor, because patients with such a mutation are much more likely to respond to tyrosine kinase inhibitors that target the receptor. The approval of crizotinib was expected to bring pressure to test for its target, the EML4-ALK translocation, as well. Advanced lung cancer is inoperable, so all of this must be gathered from small biopsy samples, and access to tissue for testing is a major issue in both clinical practice and clinical trials.
These targeted agents suit only some patients. In findings presented in 2011, only 17% of lung adenocarcinomas had an EGFR mutation and 7% had the EML4-ALK mutation. A further 22% had a KRas mutation, for which no drug was then approved, and 46% had none of the mutations known to drive lung cancer, so were not then treatable with targeted agents.
Lymphoma is a heterogeneous group of disorders that originate in lymphocytes, the major components of the immune system. It has two major divisions, Hodgkin lymphoma and the non-Hodgkin lymphomas, and is made up of more than a dozen distinct diseases. Prognosis and treatment differ across the types, and in diagnosis staging matters, as does the presence or absence of certain symptoms.
By 2012 the term personalised medicine had been criticised as more a marketing term than a scientifically meaningful description of using measurements and biomarkers to allocate patients to groups that respond to specific therapies. A 2012 journal editorial held the term stratified medicine, as Cancer Research UK uses it, to be more appropriate, because the process is a stratification into more and smaller groups of patients matched to more and more specific therapies, with the goal of a truly personalised medicine where N = 1.
Approved agents and the cancers they treat
By 2007 patients with some common cancers were benefiting from targeted therapies approved for marketing by regulatory agencies. Other treatment modalities are available and effective for these cancers, and many other targeted therapies were then in various stages of clinical development.
The targeted agents approved by the FDA by 2007 included bevacizumab (Avastin), a monoclonal antibody that targets VEGF, for colorectal cancer; bortezomib (Velcade), an inhibitor of the 26S proteasome, for multiple myeloma; cetuximab (Erbitux), a monoclonal antibody that targets EGFR, for colorectal cancer; erlotinib (Tarceva), an inhibitor of EGFR and tyrosine kinase, for non-small-cell lung cancer; gefitinib (Iressa), also an inhibitor of EGFR and tyrosine kinase, for non-small-cell lung, prostate and head-and-neck cancers; imatinib (Gleevec), a small molecule that inhibits tyrosine kinase, for chronic myeloid leukaemia and gastrointestinal stromal tumours; rituximab (Mabthera, Rituxin), against the CD20 antigen, for some B-cell non-Hodgkin lymphomas; and trastuzumab (Herceptin), a monoclonal antibody that binds the HER-2/neu receptor, for breast and non-small-cell lung cancer.
Breast cancers often contain receptors for estrogen, progesterone or both, and such receptor-positive cancers require one or both hormones to grow. The more receptors a tumour contains, the more sensitive it is to estrogens or progesterone given for other conditions, so these should be avoided in women with receptor-positive breast cancer. Tumours with an abundance of these receptors are often less virulent, and their patients often have a better prognosis than patients whose tumours have few receptors. Tamoxifen is an estrogen blocker that is a partial agonist/antagonist, and patients who take it after initial treatment have less chance of recurrence or of spread to the contralateral breast or distant sites. In 2007 the advice was that tamoxifen should be taken for 5 years or less, in sequence with other estrogen inhibitors such as aromatase inhibitors, because after 5 years initially responsive tumours may become greatly resistant to it, negating its effects on tumour reduction, serum cholesterol and bone density. When tamoxifen must be stopped, an aromatase inhibitor such as anastrozole can be used, and aromatase inhibitors lower the amount of estrogen produced outside the ovaries, such as in muscle and fat.
Breast cancer cells also express HER-2, and those that overexpress it can be extremely virulent. HER-2 is not an estrogen-receptor gene but a member of the EGFR superfamily whose ligand was not known in 2007, and it could turn out to be a receptor coactivator rather than a true surface receptor. Trastuzumab, an anti-HER-2 humanised monoclonal antibody, was designed to disrupt the tumour cell's ability to multiply by disabling the errant HER-2 gene; it had been used in early-stage and advanced metastatic breast cancer and was being investigated in the adjuvant setting.
Surgery is the preferred treatment for localised colorectal cancer, and in 2007 two monoclonal antibodies were marketed for advanced or metastatic disease. The FDA approved bevacizumab with 5-fluorouracil for the initial treatment of metastatic colorectal cancer, where it acts as an antiangiogenic therapy, attacking the tumour's new blood vessels and so cutting off its supply of nutrients. Cetuximab, directed against HER-1/EGFR, can also cause the immune system to recognise the cancer cells as foreign and attack them, and is given alone or with chemotherapy.
Non-small-cell lung cancer generally grows more slowly than small-cell, and because the lungs are so vascular, lung cancers are prone to metastases and difficult to treat. Gefitinib and erlotinib target the EGFR mutation and can cause apoptosis, block the action of tyrosine kinase, or both. Photodynamic therapy was approved by the FDA in 1998 for early-stage non-small-cell lung cancer: a photosensitising agent, porfimer sodium, is injected and absorbed by the cancer cells, which are destroyed when exposed to a special laser light about 48 hours later.
Imatinib in chronic myeloid leukaemia
Imatinib was one of the first targeted agents developed, a dramatic success for the first wave of molecularly targeted therapies, and it established a new paradigm for cancer treatment. Its starting point was a precursor of low potency and poor specificity identified in the late 1980s, from which imatinib was synthesised as a potent inhibitor of BCR-ABL, a fusion protein tyrosine kinase found in chronic myeloid leukaemia (CML). CML is a clonal haematopoietic stem-cell disorder with chronic, accelerated and blast phases, and its progression is marked by accumulating abnormalities that eventually leave the cells unable to differentiate normally. Chief among them is BCR-ABL, formed by the reciprocal translocation between chromosomes 9 and 22 known as the Philadelphia chromosome. BCR-ABL is crucial to the pathogenesis of CML, activating intracellular signalling pathways that alter cell proliferation, adhesion and survival, and it was an ideal target in the high proportion of patients carrying the abnormality.
In the initial phase 1 trial, in chronic-phase patients for whom interferon-alpha had failed, complete haematologic response occurred in 53 of 54 patients (98%) and was maintained in 51 of 53 (96%). The drug was extremely well tolerated, and its half-life of 13 to 16 hours permitted once-daily oral dosing. Studies in accelerated-phase and blast-crisis CML and in relapsed or refractory Philadelphia-positive acute lymphocytic leukaemia obtained response rates of 55% in both groups, but these responses tended not to be durable. Patients in blast crisis did better, 18% having remission and continuing treatment for up to a year, while nearly all patients with the lymphoid phenotype relapsed between one and four months. Phase 2 studies in interferon-refractory, accelerated-phase and blast-crisis disease confirmed the pattern of response and formed the basis for accelerated FDA approval of imatinib for first-line treatment of CML in December 2002.
Despite high haematologic and cytogenetic response rates, primary refractoriness and acquired resistance were by 2007 increasingly seen in CML, particularly in advanced disease. The mechanisms identified were point mutations within critical regions of the ABL kinase domain and overexpression of BCR-ABL, mainly through gene amplification. X-ray crystallographic studies showed that imatinib's selectivity and efficacy come from binding and locking BCR-ABL in its inactive, auto-inhibited conformation. Mutations seem to cause resistance by inducing a transition to the active state, in which imatinib cannot bind, or by disturbing critical contact points between imatinib and BCR-ABL, and resistance often coincides with reactivation of kinase activity in the leukaemic clone. Targeting BCR-ABL and its downstream pathways therefore remains a valid strategy. Different mutants display different degrees of resistance: some confer a highly resistant phenotype, suggesting that imatinib be stopped and a different approach tried, while others may be overcome simply by increasing the dose. In 2007 a higher dose of imatinib, imatinib with chemotherapy, and more potent inhibitors able to bind the mutant forms were being evaluated. Routine testing of the BCR-ABL sequences present in the tumour was increasingly being incorporated into clinical practice to enable rational, individualised management. Imatinib's development is an example of how individualised anticancer therapy promises more impressive results than the one-size-fits-all approach of the premolecular era.
Resistance and combinations
Even where a targeted agent works, responses are relatively short-lived and relapse in advanced disease is almost inevitable. The cause is the cancer cell's ability to change: when one pathway is blocked, genetic instability means that clones which have circumvented the blockage soon develop and thrive, helped by a signalling network so complex and redundant that several pathways can lead to the same result. So by 2012 it was increasingly recognised that targeted agents, with rare exceptions, would be most useful in combinations rather than as the single magic bullet once hoped for. A 2007 overview of targeted therapies held firmly that new ones, probably in combinations suited to each individual cancer, would be developed only when researchers began to think differently about cancer therapeutics, biopharmaceutical companies committed the resources to develop products unlike those available, and patients willingly took part in new kinds of clinical trial.
Companion diagnostics and predictive biomarkers
In 2011 the US Food and Drug Administration approved vemurafenib for metastatic melanoma and crizotinib for non-small cell lung cancer, each with a companion diagnostic identifying the patients likely to respond. Approximately 40% to 60% of melanomas carry mutations of the BRAF gene, which makes the B-RAF protein involved in cell signalling and growth. Vemurafenib is a potent inhibitor of the BRAF V600E mutation. BRIM3, the phase III trial used for approval, enrolled only patients whose tumours were V600E-positive and had a 48% response rate, with two complete and 104 partial responses. Traditional chemotherapeutic agents such as dacarbazine give response rates of 15% to 20% in metastatic melanoma.
About 3% of all patients with non-small cell lung cancer express the ALK fusion gene. PROFILE 1005, a phase II trial, enrolled only ALK-positive patients and had an overall response rate of 57%, with one complete and 46 partial responses, and tumour shrinkage in 63 of 76 patients (83%). Traditional chemotherapy gives very low response rates in this disease.
Because some patients respond well to immune checkpoint inhibitors and others do not, researchers investigate which proteins might indicate treatment effect, and predictive biomarkers represent a major advance toward precision or personalised therapies. In 2019 most anti-PD-1 monoclonal antibody approvals specified treatment for patients with higher tumour expression of PD-L1, with thresholds of at least 1% and at least 50% based on statistical significance and the manual immunohistochemical methods then current. In 2017 the FDA approved pembrolizumab on the basis not of where a tumour originated but of a genetic biomarker, microsatellite instability–high or mismatch repair deficiency, which immunohistochemical testing picks up in some solid tumours. Tumour mutational burden, the number of somatic mutations in tumour tissue, may be a more accurate biomarker than PD-L1, and researchers believe that high-burden tumours harbour neoantigens that activated T cells can readily target. A 2017 meta-analysis of 27 cancer types showed a clear and significant correlation between tumour mutational burden and objective response rate to anti-PD-1 or anti-PD-L1 therapy, regardless of PD-L1 expression. In a systematic review of 150 patients on checkpoint inhibitor monotherapy, those whose tumours had at least 20 mutations per megabase had response rates of 58% against 20% for those with low to intermediate burden, with hazard ratios of 0.34 for progression-free and 0.33 for overall survival.
In July 2019 the European Medicines Agency's human medicines committee recommended Vitrakvi (larotrectinib) for marketing authorisation in the EU, for adults and children with solid tumours that carry an NTRK gene fusion, whose disease has spread or cannot be surgically removed and who have no other satisfactory treatment options. It was the first so-called histology-independent cancer treatment recommended for approval in the EU, meaning that it can be used to treat non-haematological tumours, those that do not begin in the blood or bone marrow, with this fusion regardless of where in the body the tumour originated. The fusion should be confirmed by a validated test before treatment begins. The fusion arises when NTRK genes, which encode specific proteins, are abnormally fused to a gene, producing proteins that can cause cancer cells to grow, and the drug blocks their action and so inhibits the growth of the cancer. Such fusions are seen very frequently in certain rare cancers of adults and children and rarely in some of the commonest cancer types.
In one 2012 assessment, the term personalised medicine is conceptually useful in oncology but does not speak to the biologic complexity that confounds efforts to predict response to targeted therapy. The same assessment holds that cancer cells have primary and secondary resistance mechanisms, and that curing a cancer may take more than one companion diagnostic test combined with several targeted therapies. The same assessment predicted that pathologists will play a central role in tumour profiling for therapy decisions, and that cancers will begin to be classified by the genes promoting a tumour's growth rather than by anatomical location.
Progress and outlook
By 2012 advances had been more prominent in some cancers than in others: tyrosine kinase inhibitors had turned chronic myeloid leukaemia from a fatal disease into a chronic, manageable condition, while head and neck cancer had seen no significant treatment breakthrough in thirty years.
Robert Weinberg judged, as quoted in 2012, that advanced solid tumours of the colon, pancreas and lungs were formidable enemies that nobody yet knew how to stop. He thought it realistic that ten years on some would be stopped in their tracks and caused to shrink, perhaps not disappearing entirely but kept at a small size that leaves the patient fully normal in lifestyle, creating a chronic if tolerable disease.