New Anticancer Targeted Therapy Adelaida Mrombo Pharm D

New Anticancer Targeted Therapy Adelaida Mrombo, Pharm. D Candidate 2019

Abemaciclib (Verzenio) FDA Indication -Breast cancer, in women with HR+ and HER 2 - advanced or metastatic disease progression following endocrine therapy. Target/ MOA -Abemaciclib is a potent cyclin-dependent kinase (CDK) inhibitor which is selective for CDK 4 and 6. -It blocks retinoblastoma tumor suppressor protein phosphorylation and prevents progression through the cell cycle, resulting in arrest at the G 1 phase. Administration -Initiate 200 mg (monotherapy) or 150 mg (in combination with Fulvestrant) tablets by mouth twice daily. May be taken with or without food. -Continue taking the drug until disease progression or intolerable toxicity. -Take medication at approximately the same time everyday. Swallow whole tablets and do not chew, crush or split tablets before swallowing. BWW/Precautions -Diarrhea, neutropenia, hepatotoxicity, VTE and embryo-fetal toxicity. -Avoid concomitant use of the strong CYP 3 A inhibitor ketoconazole. Unique ADRs -Abdominal pain, prolongation QT interval and infection. Miscellaneous -Before initiating therapy, perform a CBC and ALT, AST and serum bilirubin. -Use appropriate precautions for receiving, handling, administration, and disposal.

Apalutamide (Erleada) FDA Indication -Treatment of non-metastatic, castration-resistant prostate cancer (NM-CRPC). Target/ MOA -Apalutamide is a nonsteroidal androgen receptor inhibitor; binds directly to the androgen receptor ligand-binding domain to prevent androgen-receptor translocation, DNA binding and receptor-mediated transcription. -Androgen receptor inhibition results in decreased proliferation of tumor cells and increased apoptosis, leading to a decrease in tumor volume. Administration -Take 240 mg (four 60 mg tablets) by mouth daily. Swallow tablets whole. -Administer at the same time each day, either with or without food. -Patients should also receive a gonadotropin-releasing hormone (Gn. RH) analog concurrently or should have had a bilateral orchiectomy. BWW/Precautions -Falls and fractures have occurred hence evaluate patients fracture and fall risk and treat patients with bone targeted agents according to guidelines. -Seizure have occurred, permanently discontinue drug in patient who develop a seizure during treatment. Unique ADRs -Falls and fractures, hypothyroidism, hypertension. Miscellaneous -Use appropriate precautions for receiving, handling, administration, and disposal. -Store in the original package at a controlled room temperature between 20 and 25 degrees C (68 and 77 degrees F). - Protect from light and moisture

Bevacizumab-awwb (Mvasi)[Biosimilar of Avastin] FDA Indication & Off-label use -Colorectal cancer, metastatic; non-small cell lung cancer, nonsquamous; glioblastoma, progressive; Renal cell carcinoma, metastatic -Off-label use: Age-related macular degeneration ; breast cancer, metastatic; diabetic macular edema; and endometrial cancer, recurrent or persistent, malignant pleural mesothelioma Target/ MOA -Bevacizumab is a recombinant, humanized monoclonal antibody which binds to, and neutralizes VEGF, preventing its association with endothelial receptors, Flt-1 and KDR. -VEGF binding initiates angiogenesis. Administration -Do not administer bevacizumab products until at least 28 days after surgery and the wound is fully healed. -Initial dose is IV infusion over 90 min; second infusion my be administered over 60 min if the initial infusion is well tolerated and third and subsequent infusions may be administered over 30 minutes if the 60 -minute infusion is well tolerated. BWW/Precautions -GI perforations, hemorrhage , and surgery and wound healing complications. Unique ADRs - Hypertension, VTE, peripheral edema, epistaxis, ovarian failure, hyperglycemia and hypomagnesemia. Miscellaneous -Store intact vials at 2°C to 8°C (36°F to 46°F) in original carton and do not freeze. -Protect from light; do not shake. -Solutions diluted in NS are stable for up to 8 hours under refrigeration.

Dacomitinib (Vizimpro) FDA Indication -NSCLC, metastatic Target/ MOA -Dacomitinib is an irreversible EGFR tyrosine kinase inhibitor with activity against EGFR/HER 1, HER 2, and HER 4, as well as some EGFR-activating mutations (exon 19 deletion or exon 21 L 858 R substitution mutation). Administration - 45 mg orally once daily until disease progression or unacceptable toxicity. -Administer dose at the same time each day with or without food. -Avoid the concomitant use of PPIs with dacomitinib. BWW/Precautions -Dermatologic toxicity, GI toxicity (severe and fatal diarrhea has been reported) and pulmonary toxicity- interstitial lung disease (ILD). Unique ADRs -Skin rash, conjunctivitis, paronychia, hypoalbuminemia, hyperglycemia, hypocalcemia, hypokalemia, stomatitis and hepatotoxicity. Miscellaneous -Store at 20°C to 25°C (68°F to 77°F)

Durvalumab (Imfinzi) FDA Indication -NSCLC, unresectable. -Urothelial carcinoma, locally advanced or metastatic. Target/ MOA -Durvalumab is a human Ig G 1 kappa monoclonal antibody which blocks programmed cell death ligand 1 (PD-L 1) binding to PD-1 and CD 80 (B 7. 1); PD-L 1 blockade leads to increased T-cell activation, allowing T-cells to kill tumor cells. Administration - 10 mg/kg IV infusion over 60 min once every 2 weeks through an IV line containing a sterile, low-protein binding 0. 2 or 0. 22 micron in-line filter. - Continue dose until disease progression or unacceptable toxicity or a maximum of 12 months. BWW/Precautions -Immune-mediated pneumonitis, hepatitis, colitis, endocrinopathies (thyroid disorders, adrenal insufficiency, T 1 DM and hypophysitis/hypopituitarism), nephritis, and dermatologic reactions (SJS/TEN). Unique ADRs -Fatigue, infection (UTIs), hyperglycemia, hypocalcemia, hyponatremia, hyperkalemia, dermatitis, constipation, increased LFTs and cough. Miscellaneous -Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. -Solutions diluted for infusion should be used immediately after preparation. -Protect vials from light. -Do not shake.

Duvelisib (Copktra) FDA Indication -Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), relapsed or refractory. -Follicular lymphoma, relapsed or refractory. Target/ MOA -Duvelisib is an oral PI 3 K inhibitor with dual inhibitory activity primarily against PI 3 K-δ and PI 3 K-γ. -Inhibition of PI 3 K-δ reduced tumor cell proliferation while allowing survival of normal cells. Inhibition of PI 3 K-γ reduces differentiation and migration of tumor microenvironment support cells. -Also duvelisib inhibits B-cell receptor signaling pathways and CXCR 12 -mediated chemotaxis of malignant B-cells as well as CXCL 12 -induced T cell migration and M-CSF and IL-4 driven M 2 macrophage polarization. Administration -Take 25 mg capsule orally twice daily (BID) with or without food. -The capsules should be swallowed whole. -Advise patients not to open, break, or chew the capsules. BWW/Precautions -Fatal and serious toxicities: infections, diarrhea or colitis, cutaneous reactions and pneumonitis. Unique ADRs - Fatigue, skin rash, hypophosphatemia, colitis, diarrhea, increased LFTs, sepsis, edema and renal insufficiency. Miscellaneous -Store at 20°C to 25°C (68°F to 77°F). -Store in original package until dispensing. Dispense blister packs in original container. -Prophylaxis for Pneumocystis jirovecii (PJP) until CD 4+ cell count > 200 cells/μL and antivirals to prevent CMV infection during treatment with duvelisib.

Encorafenib (Braftovi) FDA Indication -Melanoma, unresectable or metastatic Target/ MOA -Encorafenib targets BRAF V 600 E, V 600 D, and V 600 K, and has a longer dissociation half-life than other BRAF inhibitors. Administration -Take 450 mg orally once daily in combination with binimetinib until disease progression or unacceptable toxicity. -Take with or without food. BWW/Precautions -New Primary Malignancies (cutaneous and non-cutaneous malignancies) hemorrhage, uveitis, QT prolongation and embryo-fetal toxicity. Unique ADRs -Fatigue, nausea, vomiting, abdominal pain, hyperkeratosis and arthralgia. Miscellaneous -Store at 20°C to 25°C (68°F to 77°F). -Dispense in original bottle; do not remove desiccant. -Protect from moisture.

Lorlatinib (Lorbrena) FDA Indication -NSCLC, metastatic Target/ MOA -Lorlatinib is a reversible potent third generation TKI that targets ALK and ROS 1. - It is highly selective, overcomes known ALK resistance mutations, and penetrates the blood brain barrier. -Drug has additional activity against TYK 1, FER, FPS, TRKA, TRKB, TRKC, FAK 2, and ACK. Administration -100 mg tablet orally once daily, with or without food. -Swallow tablets whole and do not chew, crush or split them. -Take at the same time each day. BWW/Precautions -Hepatotoxicity with concomitant use of strong CYP 3 A inducers; CNS effects (seizures, hallucinations and changes in cognitive function, mood and sleep); hyperlipidemia, AV block, pneumonitis and embryo-fetal toxicity. Unique ADRs - Psychiatric, peripheral neuropathy, HA, pneumonitis, edema, fatigue, weight gain, increased LFTs, arthralgia, vision disorder and diarrhea. Miscellaneous -Store at 20°C to 25°C (68°F to 77°F).

Talazoparib (Talzenna) FDA Indication -Breast cancer, locally advanced or metastatic (BRCA-mutated, HER 2 -negative). Target/ MOA -Dual mechanism PARP inhibition. -PARP enzyme inhibition: Leads to disruption of enzymatic activity of SSB repair in BRCA+ tumor cells resulting to detrimental DSBs leading to tumor cell death. -PARP trapping: on SSBs prevents dissociation from damaged DNA hence inhibiting DNA repair process. Administration -1 mg capsule orally with or without food. -Swallow capsules whole; do not open or dissolve capsule. BWW/Precautions -Myelosuppression, secondary malignancy (MDS/AML), and GI toxicity. Unique ADRs -Fatigue, increased serum glucose, increased LFTs, HA, nausea and dizziness. Miscellaneous -Store at 20°C to 25°C (68°F to 77°F).

References 1. Abemaciclib. In: Lexi-Drugs [database on the Internet]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc. ; 2018 [updated 2018 Nov 16, cited 2018 Nov 14]. 2. Apalutamide (Erleada) [Internet]. Silver Spring [MD]: US Food and Drug Administration; 2018 [cited 2018 Nov 14]. Available from: https: //www. accessdata. fda. gov/drugsatfda_docs/label/2018/210951 s 000 lbl. pdf 3. Bevacizumab-awwb. In: Lexi-Drugs [database on the Internet]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc. ; 2018 [updated 2018 Nov 16, cited 2018 Nov 14]. 4. Dacomitinib (Vizimpro) [Internet]. Silver Spring [MD]: US Food and Drug Administration; 2018 [cited 2018 Nov 14]. Available from: https: //www. accessdata. fda. gov/drugsatfda_docs/label/2018/211288 s 000 lbl. pdf 5. Encorafenib (Braftovi) [Internet]. Silver Spring [MD]: US Food and Drug Administration; 2018 [cited 2018 Nov 14]. Available from: https: //www. accessdata. fda. gov/drugsatfda_docs/label/2018/210496 lbl. pdf 6. Duvelisib. In: Lexi-Drugs [database on the Internet]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc. ; 2018 [updated 2018 Nov 15, cited 2018 Nov 14]. 7. Durvalumab. In: Lexi-Drugs [database on the Internet]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc. ; 2018 [updated 2018 Nov 15 , cited 2018 Nov 14]. 8. Lorlatinib. In: Lexi-Drugs [database on the Internet]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc. ; 2018 [updated 2018 Nov 14, cited 2018 Nov 14]. 9. Talzenna (Talazoparib) [Internet]. Silver Spring [MD]: US Food and Drug Administration; 2018 [cited 2018 Nov 15]. Available from: https: //www. accessdata. fda. gov/drugsatfda_docs/label/2018/211651 s 000 lbl. pdf