Oncology Basics. Essentials. Hormonal/Endocrine Therapy, Immunotherapy and Targeted Therapy. Tutorial 4. Oncology Practise Essentials

Transcription

1 Part 2: Pharmacology of Cancer Chemotherapy Immunotherapy and Targeted Therapy

2 The pharmacology of the large family of anticancer drugs is the subject of this tutorial. It will give you the background to discuss treatments knowledgeably with patients and to understand, assess, and manage basic toxicities. Goals and Objectives Describe the mechanism of action of the following classes of cancer drugs: Hormonal agents/endocrine therapy Immunotherapy Targeted therapies List the indications of the above classes of cancer drugs. Describe the unique properties of the above classes of cancer drugs. 46

3 Hormonal Agents/Endocrine therapy Endocrine therapy is another therapeutic option for cancers in which growth can be stimulated by gonadal hormones (e.g. breast, prostate and endometrial cancers). Antagonizing these hormones can diminish growth of these cancers. The indication for use is often based on testing for tumour hormone receptors. In breast cancer, patients whose tumours are both estrogen receptor (ER) positive and progesterone receptor (PR) positive respond well to hormonal therapy. Fortunately, hormonal agents are generally associated with much lower rates of toxicity than cytotoxic agents. Corticosteroid hormones are also useful in treating cancers, including hematologic malignancies (e.g. lymphomas, lymphocytic leukemias and multiple myeloma) and prostate cancer. They are also used in supportive care management such as in the prevention of nausea and vomiting caused by emetogenic agents. Antiestrogens Tamoxifen acts as an estrogen antagonist in breast cancer cells, but appears to have estrogen agonist effects in the endometrium, bone and lipids. Because of its combined estrogen agonist/ estrogen antagonist effects, tamoxifen is classified as a selective estrogen receptor modulator (SERM). It is used in both pre- and post-menopausal women due to its MOA on estrogen receptors. Tamoxifen is used to prevent the recurrence of breast cancer in ER-/PR-positive breast cancer patients. In the adjuvant setting, tamoxifen is usually given for five years, or it may be given sequentially with an aromatase inhibitor for a total of 5 years of hormonal treatment. Treatment beyond 5 years is currently undergoing investigation. In the metastatic setting, it is given until disease progression is evident. Tamoxifen can increase the risk for thromboembolic events (e.g. stroke, pulmonary embolism and deep vein thrombosis; 2 to 5%) and endometrial cancer. Aromatase Inhibitors The primary source of estrogen in post-menopausal women is from the peripheral conversion of androstenedione into estrone and estradiol, that occurs mainly in adipose tissue. The conversion process is mediated by the enzyme aromatase. Thus, aromatase inhibitors reduce the levels of circulating estrogens. They are used primarily in post-menopausal, ER-/PR-positive breast cancer patients. In select patients who are contraindicated to tamoxifen, aromatase inhibitors may be used in combination with ovarian suppression (surgical or pharmacological) because aromatase inhibitors have no effect on estrogen secreted by the ovaries.. Anastrozole and letrozole are nonsteroidal compounds that act by reversible, competitive inhibition of aromatase. These triazole compounds have no intrinsic hormonal activity. 47 acpho.org

4 Exemestane is a steroidal compound which forms a covalent bond with aromatase, resulting in irreversible inhibition. Luteinizing Hormone Releasing Hormone (LHRH) analogs LHRH analogs initially stimulate an increase in the release of luteinizing hormone (LH), resulting in a transient elevation in serum androgen in men, and serum estradiol in women. Chronic administration, however, leads to the down-regulation of LHRH receptors in the pituitary gland, causing decreased production of LH and, ultimately, the sex hormones (androgen, estradiol). Decreasing the testicular production of androgen in men reduces the growth of androgendependent prostate cancer. Reducing the production of estradiol by the ovaries decreases the growth of estrogen-dependent breast cancer. In pre-menopausal breast cancer patients, the decrease in estrogen levels simulates an oophorectomy. In men, the decrease in testosterone simulates castration. Leuprolide, buserelin and goserelin are LHRH analogs used to treat prostate cancer. Goserelin is an LHRH analog used to treat breast cancer in pre- and peri -menopausal, ER/PR receptor positive breast cancer patients. LHRH analogs are administered by injection. The initial elevation of androgen in men and estradiol in women can cause a flare response in patients with advanced/metastatic disease for the first few weeks of therapy. In women, this manifests as pain and/or hypercalcemia. In men, this manifests as increased bone pain and urinary symptoms. In prostate cancer patients, flare response is minimized by giving antiandrogen treatment for one month beginning at the time of the initial LHRH injection. Progestins Megestrol is a synthetic progestin with the same physiological effect as progesterone. The exact mechanism of action on cancer cells is unknown, but it is thought to suppress the release of LH from the pituitary gland. Megestrol is used to treat endometrial cancer and cancer cachexia. Antiandrogens Bicalutamide, flutamide and nilutamide are three antiandrogens available for the treatment of prostate cancer. These nonsteroidal agents competitively inhibit the binding of androgens to the androgen receptor. Antiandrogens can reduce the symptoms from the flare phenomenon associated with LHRH agonist therapy. 48 acpho.org

5 Corticosteroid Hormones Dexamethasone is a synthetic glucocorticoid with no mineralocorticoid activity. Glucocorticoids are cytotoxic to leukemia, myeloma and lymphoma cells, likely due to the induction of apoptosis. The action of dexamethasone is not cell-cycle phase-specific. Dexamethasone is part of the GDP regimen for lymphoma. Prednisone is a synthetic glucocorticoid with minimal mineralocorticoid activity. It is included in many regimens, including CHOP for non-hodgkin s lymphoma. In addition to the treatment of leukemia, myeloma and lymphoma, prednisone is combined with docetaxel or mitoxantrone for the treatment of hormone-refractory prostate cancer. Immunotherapy Tretinoin is a naturally occurring derivative of vitamin A (retinol). Vitamin A and its metabolites are called retinoids, and play an important role in many biologic processes, including cellular differentiation. Many cells express retinoic acid receptors (RAR s) which, once activated by retinoid binding, regulate the expression of genes that control cellular growth and differentiation. Tretinoin binds to the retinoic acid receptor. Interferons (IFNs) are a family of proteins produced by nucleated cells and recombinant DNA technology. Interferons bind to receptors on the cell surface and produce a variety of responses, including suppression of cell proliferation, enhancement of macrophage activity, and enhancement of the cytotoxic lymphocyte activity. Interferon is not cell cycle-specific. IFN-alpha- 2b is used to treat a variety of cancers, including malignant carcinoid, mycosis fungoides, and melanoma. It is injected intravesically for the treatment of bladder cancer. Bacillus Calmette-Guerin (BCG) is a live, attenuated Mycobacterium bovis bacteria used in the treatment of bladder cancer. It stimulates a local granulomatous reaction and stimulates specific and non-specific immune responses that lead to death of tumour cells. For the treatment of bladder cancer, BCG in 50 ml normal saline is instilled into the bladder and left there for two hours, with the patient changing position every 15 minutes for the first hour. Thalidomide has a MOA that is not completely understood. It has immunomodulatory effects by affecting tumour necrosis factor-alpha, stimulating T-cell proliferation, and increasing production of interleukin-2 and interferon. Thalidomide also inhibits angiogenesis and has sedative/hypnotic effects. It is used in the treatment of multiple myeloma. As a known teratogen, thalidomide must be prescribed and dispensed by clinicians who are registered with the CELGENE RevAid controlled distribution program in Canada. Patients must also be enrolled in the 49 acpho.org

6 RevAid Program and meet all conditions to access thalidomide. Females of childbearing potential are required to submit current pregnancy test results before the drug is released each month. Lenolidomide is a structural and functional analog of thalidomide, with two indications: 1) treatment of anemia in myelodysplastic syndrome (MDS) with a 5q deletion cytogenetic abnormality, and 2) multiple myeloma after failure of at least one prior therapy. Like thalidomide, lenalidomide is a known teratogen; physicians and pharmacists must be registered with the REVAID Program to prescribe and dispense the medication in Canada. Targeted therapies Traditional cytotoxic agents lack selectivity for cancer cells, and are toxic to both tumour and normal cells. In contrast, drugs that exploit cancer-specific targets and pathways critical for survival and growth of malignant cells tend to have less adverse effects. A number of new targeted therapies have been marketed over the last decade. Side effect profiles of these new agents are, for the most part, much more tolerable than those of traditional cytotoxic agents. However, because of the specific mechanisms of the targeted therapies, side effects associated with these agents are unique. Consequently, oncology pharmacists must be familiar with the adverse effects associated with each agent. how targeted therapies work Targeted therapies are based on cell responses to signals from their environment. In normal cell response, a ligand binds to the extracellular component of a cell membrane receptor (the ligand could be a growth factor, hormone or antibody). This interaction activates the receptor and initiates a cascade of intracellular signals that are part of the signal transduction pathway. Cellular responses are then activated (e.g. growth, proliferation and differentiation of cells). In a normal cell, the signaling cascade is turned on and then off. If the signal is not turned off appropriately, cell growth and proliferation may proceed inappropriately (neoplasia). Targeted therapies generally involve the use of molecules that bind to the ligands, the receptors, or the intracellular molecules involved in signal transduction pathways. Many of these ligand/receptor/ transduction pathways are found in normal healthy cells, but are more active in cancer cells. 50 acpho.org

7 Monoclonal antibodies (mabs) and small-molecule agents Early monoclonal antibodies were created by hybridizing myeloma cells (malignant B cells that proliferate indefinitely in culture) with normal B cells in mice (murine). To make a specific monoclonal, mice are first injected with an antigen (i.e. the target molecules). B-cells of the immunized mouse then produce antibodies that recognize the antigen. These cells are then fused with myeloma cells to continually multiply. The hybrid cells which continue to produce the target antibody are then selected and cloned to derive a single clone, producing monoclonal antibodies. Monoclonal antibodies are given intravenously, and bind only with target ligands and other proteins. Due to the presence of mouse components in the early mabs, the immune systems of patients recognized the products as foreign, resulting in allergic reactions and the production of anti-mouse antibodies. Chimeric mabs containing human and mouse components, humanized mabs containing < 15% murine components, and fully human mabs containing no murine products have now been developed, improving the safety profile of these agents. The use of different suffixes indicates the source of the monoclonal antibodies: omab mouse ximab chimeric zumab - humanized umab human Small molecules that directly bind to intracellular components of receptors and second messenger proteins involved in the signal transduction pathway are also used therapeutically. These compounds are smaller than monoclonal antibodies and have shorter half-lives, which allow for oral, but more frequent dosing. Cell Surface Glycoprotein Monoclonal Antibodies Rituximab Rituximab was the first mab approved as an anticancer agent (marketed in 1999 in Canada). Rituximab is a chimeric mab that binds to the CD20 antigen found on the surface of normal and malignant B cells. The CD20 antigen appears to regulate activation, differentiation and growth of B cells. Binding of rituximab to this antigen initiates immune effector functions which mediate B-cell lysis. Rituximab was initially used to treat relapsed or refractory, CD20-positive B-cell non-hodgkin s lymphoma. Its use has been expanded to include first-line therapy of aggressive and indolent non- Hodgkin s lymphomas and other malignancies with CD20 antigen expression. 51 acpho.org

8 Infusion-related symptoms are common, especially during the first infusion, due to an infusionrelated complex affected by the amount of circulating B cells. To minimize symptoms, which include fever, chills, nausea, asthenia, and headache, patients should receive acetaminophen and diphenhydramine as premedications. Also, the rate of the initial infusion should start at 50 mg/h and increased in increments of 50 mg/h every 30 minutes as tolerated to a maximum of 400 mg/h. Tumour lysis syndrome (TLS) may occur within 12 to 24 hours of the initial infusion. TLS is an oncologic emergency precipitated by spontaneous or chemotherapy-induced lysis of malignant cells. The massive release of intracellular products result in electrolyte abnormalities and metabolic derangements, which can lead to multiple organ failure including renal failure, and cardiac arrhythmias. TLS can occur in patients with or without a high tumour burden and in patients with a high number of circulating malignant lymphocytes (> 25 x 10 9 /L). Agents That Target Growth Factor Receptor Pathways Human Epidermal Growth Factor Receptor (HER) Family The HER family contains four receptor subtypes that control key cellular proliferation pathways. HER-1 (commonly known as EGFR) and HER-2 are overexpressed on several tumours, including breast, lung and colon cancers. Activation of these receptors is associated with uncontrolled cellular growth and proliferation, tumour metastasis, and prevention of apoptosis. Each member of this growth receptor family contains a transmembrane glycoprotein extracellular ligand binding site, a transmembrane domain, and a cytosolic tyrosine kinase tail. Monoclonal antibodies have been developed to bind to the extracellular receptors, and small molecules have been developed to bind to the intracellular tyrosine kinase receptors. HER Agents Trastuzumab is a humanized monoclonal antibody that binds to the extracellular domain of HER-2. The HER-2 receptor, also referred to as HER-2/neu, is overexpressed in 25% to 30% of breast cancers, and is associated with more aggressive disease, higher risk of relapse and a poor prognosis. Trastuzumab inhibits cell-cycle progression by decreasing cells entering the S Phase of the cell cycle. This leads to down regulation of HER-2 receptors on tumour cells and decreased cell division. It also leads to antibody-dependent cellular cytotoxicity and directly induces apoptosis in cells overexpressing the HER-2 protein. Trastuzumab is used in the treatment of HER-2 positive, localized and metastatic breast cancer. In the adjuvant setting, trastuzumab is administered for a total of 52 weeks. Trastuzumab administration has been associated with decreased left ventricular ejection fraction (LVEF), congestive heart failure, arrhythmias, hypertension, cardiomyopathy, and cardiac death. 52 acpho.org

9 When patients receive trastuzumab and an anthracycline concurrently, the risk of decreased LVEF is especially pronounced. Cardiac toxicity associated with trastuzumab appears to be different from that associated with anthracycline use. Trastuzumab-associated cardiotoxicity is usually reversible with discontinuation of treatment and initiation of standard cardiac medications if necessary (beta blockers with or without angiotensin-converting enzyme inhibitors). A thorough cardiac assessment is necessary prior to and during trastuzumab therapy. Lapatinib is an oral small molecule tyrosine kinase inhibitor. It is a potent, reversible inhibitor of both EGFR and HER2 receptors, and induces growth arrest and apoptosis. It is indicated in the treatment of metastatic HER2-positive breast cancer in combination with capecitabine. Like trastuzumab, lapatinib is associated with cardiotoxicity and QT/QTc prolongation. Baseline and periodic cardiac assessments should be considered; concurrent use of other QT-prolonging drugs should also be avoided if possible. Lapatinib is metabolized mainly by CYP3A4 and CYP3A5 liver enzymes. Grapefruit and grapefruit juice should be avoided when taking lapatinib. Concurrent medications should be assessed for potential drug interactions. Dose-limiting adverse effects of lapatinib include diarrhea and rash. Cetuximab is a recombinant chimeric monoclonal antibody that binds to human EGFR, specifically in cancers with the non-mutant, wild type K RAS gene, a part of the EGFR signaling cascade. Mutated K-RAS genes render EGFR inhibitor therapy ineffective. Cetuximab is approved for use in head and neck cancers and metastatic colorectal cancer. Severe infusion reactions, including cardiopulmonary arrest, are reported in 2 to 5% of patients. Although rare, these reactions may lead to fatal outcomes (< 1 in1000). A one-hour or longer observation period is recommended following each infusion. Mild to moderate infusion reactions may be managed with a slower infusion rate and prophylactic antihistamines for subsequent dosing. Severe reactions require immediate and permanent discontinuation of cetuximab. Panitumumab is a recombinant human monoclonal antibody that binds to human EGFR. It is approved as monotherapy of non-mutant, wild type K-RAS metastatic or advanced colorectal cancer after failure of fluorouracil, irinotecan and oxaliplatin-containing chemotherapy protocols. As with cetuximab, severe infusion reactions have been reported, but with no fatalities. Interstitial pneumonitis and pulmonary fibrosis have been reported; if lung symptoms occur, the drug must be discontinued. 53 acpho.org

10 Erlotinib is an orally active, small molecule, EGFR tyrosine kinase inhibitor that blocks signal transduction cascades responsible for proliferation, survival and metastases of cancer cells. These small molecules inhibit EGFR activity by competing with adenosine triphosphate for its binding site on the EGFR tyrosine kinase cytosolic domain. Erlotinib is used in treatment of locally advanced or metastatic NSCLC as second- or third-line therapy, or maintenance therapy in patients with stable disease after first-line chemotherapy. Erlotinib is metabolized mainly by the CYP3A4 pathway, and should be used with caution with CYP3A4 inhibitors and inducers. Use of erlotinib and warfarin may result in elevations of the INR. Use of erlotinib and proton pump inhibitors should be avoided because the bioavailability of erlotinib may be reduced by drugs that affect upper gastrointestinal ph. Rash and diarrhea are the most common side effects from erlotinib therapy. The rash may be predictive of response to the drug, and correlates with clinical benefit. The most common rash is a papulopustular eruption which appears on the face, upper chest and back. It usually appears within the first two weeks of therapy and resolves within four to six weeks. Severe rashes may occur, requiring dose reductions and treatment with oral steroids and antibiotics. Vascular Endothelial Growth Factor (VEGF) Angiogenesis, the development of new blood vessels, is unregulated in many tumours, leading to tumour growth, invasion and metastasis. VEGF, a pro-angiogenic growth factor, is released in response to hypoxia and other stresses to the cell. Elevated levels of VEGF have been associated with a poor prognosis in a variety of cancers including breast cancer, ovarian cancer, NSCLC and colon cancer. VEGF binds to the extracellular domain of growth factor receptors. There are three types of VEGF receptors located on endothelial cells and some tumour cells. Activation of the receptors turns on signal transduction pathways which result in the generation of proteases that break down the extracellular matrix, resulting in the initiation of angiogenesis. Bevacizumab is a recombinant humanized mab that binds to VEGF. Binding to all circulating VEGF prevents activation of the VEGF receptors. Bevacizumab is used in the treatment of colorectal cancer and malignant gliomas. The three most common adverse effects are hypertension, bleeding and thrombotic events. Blood pressure should be monitored during treatment, but elevated blood pressure tends to respond well to oral antihypertensive medications. The most common bleeding events are nosebleeds, but fatal CNS, pulmonary and gastrointestinal hemorrhages have been reported with bevacizumab therapy. Because of its bleeding risk, bevacizumab is not recommended for use within 28 days 54 acpho.org

11 of major surgery. In addition, bevacizumab is associated with the risk of cerebral infarction, myocardial infarction and deep venous thrombosis. Proteinuria has also been reported. Multikinase Inhibitors Multikinase inhibitors are orally active small molecules that inhibit many different receptor kinase pathways, some of which are involved in tumour cell signaling, proliferation, angiogenesis and apoptosis. They also contribute to the metastatic progression of cancer. Sunitinib targets multiple cell surface tyrosine kinases, including: vascular endothelial growth factor receptors (VEGF-R) 1, 2 and 3, platelet-derived growth factor receptors (PDGF-R), stem-cell factor receptor (c-kit), FMS-like tyrosine kinase 3 (FLT-3), colony stimulating factor receptor type 1 (CSF-1R), and glial cell line-derived neurotrophic factor receptors (RET). Sunitinib is indicated in the treatment of renal cell carcinoma and gastrointestinal stromal tumours (GIST). Sunitinib is a substrate of CYP3A4 and its plasma levels may be affected by drugs that induce or inhibit this enzyme. Adverse effects may include: Cutaneous, hand foot skin reaction (HFSR) involves symptoms of classic hand foot syndrome (localized lesions on palm of hands and soles of feet) plus development of dose-dependent, painful hyperkeratosis Yellowish skin colouration intense, yellow discolouration of the urine has been reported Hypertension patients should have their blood pressure monitored during therapy and treated with standard antihypertensive therapy if needed Hypothyroidism reported in over one-third of patients; baseline and routine monitoring of thyroid stimulating hormone (TSH) (every two to three months during therapy) is required Bleeding may range from nosebleeds to severe hemorrhage Cardiotoxicity sunitinib has been associated with decreased LVEF and dose-dependent QTprolongation Sorafenib is used to treat renal cell carcinoma and hepatocellular carcinoma. It targets serine/ threonine and receptor tyrosine kinases in the tumour vasculature (c-raf, VEGF-Rs 2 and 3, and PDGF-R beta) and in the tumour cell (c-raf, b-raf, KIT, FLT-3). HFSR occurs more commonly with sorafenib than sunitinib. Yellowish skin discoloration can occur with sorafenib therapy, but is more commonly seen with sunitinib. Hypertension and hemorrhage are also reported with sorafenib. Information on sorafenib cardiac toxicity is sparse, but cardiac ischemia and infarction have been reported. Metabolism of sorafenib involves many cytochrome P450 enzymes and glucuronidation. 55 acpho.org

12 Miscellaneous Targeted Agents Imatinib mesylate was the first oral targeted therapy associated with clinically significant response rates and received its notice of compliance from Health Canada in It inhibits the BCR-ABL tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). It binds to the kinase binding site of the BCR-ABL gene and competitively blocks access to adenosine triphosphate, thereby preventing phosphorylation and activation of cellular proliferation. Imatinib also blocks the tyrosine kinase activity of c-kit (stem cell factor receptor) and PDGF-R. Imatinib is indicated for the treatment of Philadelphiachromosome positive CML and acute lymphoblastic leukemia. It is also used to treat gastrointestinal stromal tumour (GIST) due to its involvement with c-kit. Imatinib is a substrate of CYP3A4 and an inhibitor of CYP3A4, 2D6 and 2C9; therefore, potential drug interactions must be assessed prior to initiation of therapy. Adverse effects from imatinib are usually mild; they include edema (mainly periorbital), and generalized fluid retention (1% to 2% of patients), which can be life-threatening. Most rashes are maculopapular, but Stevens-Johnson syndrome has been reported. Liver enzymes should be monitored due to the possibility of hepatotoxicity. Hemorrhage, cardiotoxicity and gastrointestinal perforations have also been reported. Dasatinib shares the same binding site on the BCR-ABL tyrosine kinase adenosine triphosphatebinding domain as imatinib. However, dasatinib retains activity in Philadelphia chromosomepositive CML and acute lymphocytic leukemia (ALL) patients who have developed resistance against imatinib. Dasatinib also inhibits a group of tyrosine kinases called SRC kinases that are involved in cellular differentiation, proliferation and survival. Therefore, dasatinib is used in Philadelphia chromosome positive CML and ALL patients who are resistant to imatinib. The toxicity profile of dasatinib is similar to that of imatinib. Additional toxicities include hypocalcemia and pleural effusions. Dasatinib is metabolized by the CYP3A4 isoenzyme. Bortezomib is a competitive inhibitor of the 26S proteosome (the proteosome is an enzyme complex that degrades intracellular proteins involved in regulating the cell cycle). As a result of this inhibition, there is accumulation of IкB, an inhibitor of the major transcription factor, NFкB. The end result is the prevention of transcription of the genes that promote cancer growth. Bortezomib is used in the treatment of multiple myeloma. Most side effects are mild, including fatigue, nausea and diarrhea. 56 acpho.org