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ODACon™ Supportive Care Summit: Managing Toxicities of Novel Breast Cancer Therapies - HER2 Tyrosine Kinase Inhibitors

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ODACon™ Supportive Care Summit: Managing Toxicities of Novel Breast Cancer Therapies - HER2 Tyrosine Kinase Inhibitors

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i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.

These slides, presented by, Abbey Kaler, MS, APRN, FNP-C, Advanced Practice Registered Nurse in the Advanced Breast Cancer Program at the University of Texas MD Anderson Cancer Center, will review data on HER2 tyrosine kinase inhibitors, including tucatinib and neratinib, and will compare their activity and safety profiles in combination with other medications for breast cancer. She will also highlight the differing considerations for management of patients taking these drugs.

i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.

These slides, presented by, Abbey Kaler, MS, APRN, FNP-C, Advanced Practice Registered Nurse in the Advanced Breast Cancer Program at the University of Texas MD Anderson Cancer Center, will review data on HER2 tyrosine kinase inhibitors, including tucatinib and neratinib, and will compare their activity and safety profiles in combination with other medications for breast cancer. She will also highlight the differing considerations for management of patients taking these drugs.

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ODACon™ Supportive Care Summit: Managing Toxicities of Novel Breast Cancer Therapies - HER2 Tyrosine Kinase Inhibitors

  1. 1. ODACon™ Supportive Care Summit: Managing Toxicities of Novel Breast Cancer Therapies k HER2 Tyrosine Kinase Inhibitors Abbey Kaler, MS, APRN, FNP-C Advanced Practice Registered Nurse University of Texas MD Anderson Cancer Center
  2. 2. Disclosures Advisory board/panel: AstraZeneca Speaker’s bureau: Novartis, Sanofi Genzyme i3 Health has mitigated all relevant financial relationships
  3. 3. Learning Objectives HER2 = human epidermal growth factor receptor 2. Assess the indications and safety and efficacy profiles of HER2 tyrosine kinase inhibitors for breast cancer Evaluate clinical tools for assessing and grading adverse events associated with novel HER2 tyrosine kinase inhibitors Apply strategies to optimize safety and tolerability of novel HER2 tyrosine kinase inhibitors Develop educational strategies to help patients understand the benefits and risks of their breast cancer treatment plan
  4. 4. HER2-Positive Diagnosis CEP17 = centromeric region of chromosome 17. Marchiò et al, 2021; BreastCancer.org, 2022. HER2 Expression by Immunohistochemistry (IHC) Score 0 Score 1+ HER2-Negative HER2-Positive HER2-Borderline HER2-Positive HER2-Negative HER2 Expression by Fluorescence in Situ Hybridization (FISH) Red: HER2 Green: CEP17 Score 2+ Score 3+ IHC score 1+ or IHC score 2+ plus negative FISH HER2-Low
  5. 5. HER2 Tyrosine Kinase: Definition ACS, 2022b; Iancu et al, 2022; MyCancerGenome®, 2016. Human epidermal growth factor receptor 2 (HER2 or also called ERBB2) is a type of protein known as a kinase Tyrosine kinases phosphorylate specific amino acids on substrate enzymes Kinases send signals to the cell to grow and divide They alter signal transduction, leading to downstream changes to modify cell growth, migration, differentiation, apoptosis, and death
  6. 6. HER2 Tyrosine Kinase: Definition (cont.) TKI = tyrosine kinase inhibitor. ACS, 2022b; Iancu et al, 2022; MyCancerGenome®, 2016. Drugs that block kinases are called kinase inhibitors Blocking these initial signals via TKIs can prevent the aberrant action of the mutated or dysfunctional TKs 2 classes of drugs that block HER2 signaling Monoclonal antibodies: extracellular Small molecules: intracellular
  7. 7. HER2 TKIs: Background TK = tyrosine kinase; EGFR = epidermal growth factor receptor. Image from PDB entry 1XKK courtesy of Fvasconcellos. Iancu et al, 2022; Pottier et al, 2020; ACS, 2022a. Over 50 TKIs FDA-approved for cancer Bladder Breast Gastrointestinal (GI) Leukemia Lung Lymphoma Melanoma Renal cell Thyroid Anti-EGFR TKIs used in breast cancer HER2 is a member of the EGFR family HER2 overexpression in ~20% of breast cancer Lapatinib EGFR/HER2/HER4 inhibitor
  8. 8. HER2 TKIs FDA-Approved for Breast Cancer ACS, 2022b; Dent et al, 2021; Pottier et al, 2020. Lapatinib: reversible inhibitor of HER1 and HER2, first approval in 2007 Neratinib: irreversible (covalent) pan-HER (HER1, HER2, and HER4) inhibitor, first approval in 2017 Tucatinib: reversible, selective HER2 inhibitor with low affinity for EGFR, first approval in 2020
  9. 9. HER2 TKIs Approved for Breast Cancer (cont.) ACS, 2022b. Lapatinib Pill taken daily Used to treat advanced breast cancer Typically given along with trastuzumab and the chemo drug capecitabine Neratinib Pill taken daily Used to treat early-stage breast cancer after treatment with trastuzumab for 1 year; usually given for 1 year Can also be given along with the chemo drug capecitabine to treat metastatic disease, typically after ≥2 other anti-HER2 targeted drugs Tucatinib Pill, typically taken twice a day Used to treat advanced breast cancer after ≥1 prior HER-targeted drug Usually given along with trastuzumab and the chemo drug capecitabine
  10. 10. HER2 TKIs: Safety and Efficacy in Clinical Trials
  11. 11. NALA: Neratinib for Metastatic Breast Cancer PFS = progression-free survival; CNS = central nervous system. Saura et al, 2020. Neratinib + capecitabine vs lapatinib + capecitabine Patients with HER2-positive metastatic breast cancer and ≥2 prior HER2 therapies for metastatic breast cancer Median PFS: 8.8 months with neratinib, 6.6 months with lapatinib Median OS: 24.0 months with neratinib, 22.2 months with lapatinib Included patients with asymptomatic or stable brain metastases Fewer patients in the neratinib + capecitabine group required interventions for CNS metastases vs lapatinib + capecitabine (22.8% vs 29.2%), suggesting prevention of or delayed time to development of CNS disease After ≥2 Previous HER2-Directed Therapies HR-negative HR-positive
  12. 12. ExteNET: Neratinib for Early Breast Cancer HR = hormone receptor; OS = overall survival. Chan et al, 2021. Phase 3 randomized controlled trial 2,840 patients with HER2-positive early breast cancer after neoadjuvant/adjuvant trastuzumab-based therapy Neratinib significantly improved invasive disease-free survival (iDFS) in the HER2- positive/HR-positive population who initiated treatment ≤1 year after trastuzumab (≤1 year). A similar trend was observed in patients who had residual disease after neoadjuvant treatment iDFS at 5 years was 5.1% in HR-positive/≤1-year patients and 1.3% in HR-positive/ >1-year patients Improvements in central nervous system events and OS were consistent with iDFS benefits, suggesting long-term benefit for neratinib in this population In HR-positive/≤1-year patients, neratinib had a numerical improvement in OS at 8 years HER2-Positive Early Breast Cancer
  13. 13. ExteNET: Neratinib (cont.) Intention-to-treat population HER2-positive/HR-positive early-stage breast cancer within 1 year of prior trastuzumab Patients with residual disease after neoadjuvant therapy 1,334 patients HER2-positive/HR-positive early-stage breast cancer within 1 year of prior trastuzumab 295 patients HER2-positive/HR-positive early-stage breast cancer within 1 year of prior trastuzumab with residual disease after neoadjuvant therapy Invasive disease- free survival 5-year follow-up Overall survival 8-years follow-up Absolute benefit 5.1% for neratinib vs placebo Absolute benefit 2.1% for neratinib vs placebo Absolute benefit 7.4% for neratinib vs placebo Absolute benefit 9.1% for neratinib vs placebo Chan et al, 2021. 2,840 patients HER2+ early-stage breast cancer after trastuzumab
  14. 14. ExteNET: Neratinib for Breast Cancer (cont.) Chan et al, 2021. Safety: HR-Positive/≤1 Year Population Neratinib (n=662) Placebo (n=657) Any treatment-emergent adverse event (TEAE) (TEAE) 649 (98%) 587 (86%) Grade 3/4 TEAE 327 (49%) 76 (12%) Fatal TEAE 1 (<1%) 0 TEAE leading to dose reduction 203 (31%) 13 (2%) TEAE leading to treatment discontinuation 178 (27%) 30 (5%) Grade 1-2 Grade 3 Grade 1-2 Grade 3 Diarrhea 365 (55%) 261 (39%) 219 (32%) 7 (1%) Nausea 280 (42%) 9 (1%) 135 (21%) 2 (<1%) Fatigue 177 (27%) 13 (2%) 129 (20%) 2 (<1%) Vomiting 150 (23%) 24 (4%) 41 (6%) 2 (<1%) Abdominal pain 145 (22%) 11 (2%) 58 (9%) 1 (<1%) Headache 119 (18%) 6 (<1%) 125 (19%) 1 (<1%) Upper abdominal pain 90 (14%) 6 (<1%) 35 (5%) 3 (<1%) Rash 90 (14%) 3 (<1%) 40 (6%) 0 Decreased appetite 79 (12%) 1 (<1%) 13 (2%) 0 Muscle spasms 81 (12%) 0 21 (3%) 1 (<1%)
  15. 15. HER2CLIMB: Tucatinib/Trastuzumab/Capecitabine Murthy et al, 2020; Curigliano et al, 2022. Phase 3 randomized controlled trial 612 patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases Progression-free survival at 1 year: 33.1% in the tucatinib combination group 12.3% in the placebo combination group Median duration of progression-free survival: 7.8 months in the tucatinib combination group 5.6 months in the placebo combination group Overall survival at 2 years: 44.9% in the tucatinib-combination group 26.6% in the placebo-combination group HER2-Positive Metastatic Breast Cancer
  16. 16. HER2CLIMB: Tucatinib/Trastuzumab/Capecitabine (cont.) Curigliano et al, 2022. Final Analysis: Progression-Free Survival
  17. 17. HER2CLIMB: Tucatinib/Trastuzumab/Capecitabine (cont.) Curigliano et al, 2022. Final Analysis: Overall Survival Particularly notable survival outcomes, as nearly half of patients enrolled in HER2CLIMB had brain metastases, including patients who had active brain metastases at baseline
  18. 18. Murthy et al, 2020; Le Du et al, 2021. Progression-Free Survival for Patients With Brain Metastases HER2CLIMB: Tucatinib/Trastuzumab/Capecitabine (cont.) First large randomized trial to include patients with metastatic breast cancer and active brain metastases, and the first to demonstrate a significant impact on central nervous system (CNS) disease by adding a systemic therapy
  19. 19. AE = adverse event; PPE = palmar-plantar erythrodysesthesia. Murthy et al, 2020; Curigliano et al, 2022. Safety HER2CLIMB: Tucatinib/Trastuzumab/Capecitabine (cont.) Event Tucatinib-Combination Group (n=404) Placebo-Combination Group (n=197) Any grade Grade ≥3 Any grade Grade ≥3 Any AE 401 (99.3%) 245 (60.6%) 191 (97.0%) 101 (51.3%) Diarrhea 331 (81.9%) 53 (13.1%) 106 (53.8%) 17 (8.6%) PPE syndrome 264 (65.3%) 57 (14.1%) 105 (53.3%) 18 (9.1%) Nausea 243 (60.1%) 16 (4.0%) 88 (44.7%) 7 (3.6%) Fatigue 193 (47.8%) 22 (5.4%) 87 (44.2%) 8 (4.1%) Vomiting 152 (37.6%) 13 (3.2%) 51 (25.9%) 8 (4.1%) Stomatitis 105 (26.0%) 10 (2.5%) 28 (14.2%) 1 (0.5%) Decreased appetite 105 (26.0%) 3 (0.7%) 41 (20.8%) 0 Headache 96 (23.8%) 3 (0.7%) 40 (20.3%) 3 (1.5%) Aspartate aminotransferase increased increased 89 (22.0%) 19 (4.7%) 22 (11.2%) 1 (0.5%) Alanine aminotransferase increased 81 (20.0%) 23 (5.7%) 13 (6.6%) 1 (0.5%) Anemia 88 (21.8%) 17 (4.2%) 24 (12.2%) 5 (2.5%) Blood bilirubin increased 81 (20.0%) 4 (1.0%) 21 (10.7%) 5 (2.5%)
  20. 20. HER2 TKIs: Adverse Events
  21. 21. Side Effects of HER2 TKIs for Breast Cancer Tykerb® prescribing information, 2022; Nerlynx® prescribing information, 2022; Tukysa® prescribing information, 2022. Lapatinib Neratinib Tucatinib Boxed warning: hepatotoxicity Heart failure Interstitial lung disease Prolonged QT interval Embryotoxicity Diarrhea Hand-foot syndrome Nausea Vomiting Fatigue Diarrhea Hepatotoxicity Embryotoxicity Nausea Abdominal pain and distention Vomiting Rash Stomatitis Muscle spasms Skin and nail disorder Diarrhea Hepatotoxicity Embryotoxic Hand-foot syndrome Nausea Fatigue Stomatitis Abdominal pain Headache Anemia
  22. 22. Monitoring for HER2 TKIs in Breast Cancer Iancu et al, 2022; Dent et al, 2021; Nerlynx® prescribing information, 2022; Tykerb® prescribing information, 2022. Echocardiogram or multigated blood-pool imaging (MUGA) and electrolyte monitoring; left ventricular ejection fraction monitoring (lapatinib) Liver enzyme panels
  23. 23. Cardiac Toxicity: Lapatinib QTc = corrected QT interval. NCI, 2017. HER2 TKIs for Breast Cancer Cardiac event Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Heart failure Asymptomatic with laboratory (eg, brain natriuretic peptide) or or cardiac imaging abnormalities Symptoms with mild-to- moderate activity or exertion Severe with symptoms at at rest or with minimal activity/exertion, or intervention indicated Life-threatening consequences, or or urgent intervention indicated (eg, (eg, continuous intravenous therapy or mechanical hemodynamic support) Death QT prolongation prolongation QTc 450-480 ms QTc 481-500 ms Average QTc ≥501 ms or >60-ms change from baseline Torsades de Pointes, or polymorphic ventricular tachycardia, or signs of symptoms symptoms of serious arrhythmia —
  24. 24. QTc Prolongation: Lapatinib Giudicessi et al, 2019; Kim et al, 2021. Normal patient interval <440 ms Definition: QT interval prolongation >450 ms in males >460 ms in females Risk factors: Advanced age Renal and hepatic dysfunction Multi-comorbidities Polypharmacy Electrolyte imbalances from nausea, vomiting, diarrhea, decreased oral intake HER2 TKIs for Breast Cancer
  25. 25. Management of QTc Prolongation ECG = electrocardiogram. Tykerb® prescribing information, 2022; Kim et al, 2021; Chemocare.com, 2022. ECG should be assessed before initiating the treatment and should be monitored regularly depending on risk level Electrolyte abnormalities (especially potassium and magnesium) should be corrected before the start of treatment Ask patients to immediately report palpitations and shortness of breath HER2 TKIs for Breast Cancer
  26. 26. Assessing and Grading Adverse Events: Liver Toxicity ULN = upper limit of normal; GGT = gamma-glutamyl transferase; DILI = drug-induced liver injury; ADL = activities of daily living. NCI, 2017. Adverse event Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Alkaline phosphatase phosphatase increased >ULN–2.5x ULN if baseline was was normal, or 2-2.5x baseline if if baseline was abnormal >2.5–5x ULN if baseline was normal, or >2.5-5x baseline if baseline was abnormal >5-20x ULN if baseline was normal, or >5-20x baseline if baseline was abnormal >20x ULN if baseline was normal, or >20x baseline if baseline was abnormal - Alanine aminotransferase increased >ULN–3x ULN if baseline was normal, or 1.5-3x baseline if baseline was abnormal >3-5x ULN if baseline was normal, or >3-5x baseline if baseline was abnormal >5-20x ULN if baseline was normal, or >5-20x baseline if baseline was abnormal >20x ULN if baseline was normal, or >20x baseline if baseline was abnormal - Aspartate aminotransferase increased >ULN–3x ULN if baseline was normal, or 1.5-3x baseline if baseline was abnormal >3-5x ULN if baseline was normal, or >3-5x baseline if baseline was abnormal >5-20x ULN if baseline was normal, or >5-20x baseline if baseline was abnormal >20x ULN if baseline was normal, or >20x baseline if baseline was abnormal - Blood bilirubin increased >ULN–1.5x ULN if baseline was was normal, or >1-1.5x baseline baseline if baseline was abnormal >1.5-3x ULN if baseline was normal, or >1.5-3x baseline if baseline was abnormal >3-10x ULN if baseline was normal, or >3-10x baseline if baseline was abnormal >10x ULN if baseline was normal, or >10x baseline if baseline was abnormal - GGT increased >ULN–2.5x ULN if baseline was was normal, or 2-2.5x baseline if if baseline was abnormal >2.5-5x ULN if baseline was normal, or >2.5-5x baseline if baseline was abnormal >5-20x ULN if baseline was normal, or >5-20x baseline if baseline was abnormal >20x ULN if baseline was normal, or >20x baseline if baseline was abnormal - Hepatic failure - - Asterixis, or mild encephalopathy, or drug- induced liver injury (DILI), or limiting self-care ADL Life-threatening consequences, consequences, or moderate-to- to-severe encephalopathy, or coma Death Portal hypertension - Decreased portal vein flow Reversal/retrograde portal vein vein flow associated with varices and/or ascites Life-threatening consequences, consequences, or urgent intervention needed Death
  27. 27. Management of Liver Toxicity LFT = liver function test. Tykerb® prescribing information, 2022; Nerlynx® prescribing information, 2022; Tukysa® prescribing information, 2022; Le Du et al, 2021. LFT monitoring before start of treatment and regularly afterwards, and as indicated Lapatinib: every 4-6 weeks Neratinib: monthly for the first 3 months, then every 3 months Tucatinib: every 3 weeks Hepatotoxicity may occur days to months after starting treatment and may be asymptomatic, so monitoring is critical Management: hold dose until improvement and/or reduce dose; permanent discontinuation for severe liver impairment HER2 TKIs for Breast Cancer
  28. 28. Diarrhea NCI = National Cancer Institute; CTCAE = Common Terminology Criteria for Adverse Events. NCI, 2017. NCI CTCAE v5.0 Diarrhea Adverse event Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Diarrhea Increase of <4 stools per day over over baseline, or mild increase in ostomy output compared with baseline Increase of 4-6 stools per day over baseline, baseline, or moderate moderate increase in ostomy output compared with baseline, or limiting instrumental ADL Increase of ≥7 stools per per day over baseline, or or hospitalization indicated, or severe increase in ostomy output output compared with baseline, or limiting self- self-care ADL Life-threatening consequences, or urgent intervention indicated Death
  29. 29. Management of Diarrhea Tykerb® prescribing information, 2022; Nerlynx® prescribing information, 2022; Tukysa® prescribing information, 2022; Le Du et al, 2021. Management of diarrhea should be proactive Special guidance for neratinib: initiate loperamide with first dose of neratinib and continue loperamide for 2 cycles (56 days), then use loperamide as needed to maintain 1-2 bowel movements per day Or 2-week neratinib dose escalation with antidiarrheals added as indicated For all HER2 TKIs Grade 1, 2, and 3: start or adjust antidiarrheals, make dietary modifications, maintain fluid intake Grade 3 or grade 1 or 2 with complicating features: interrupt dosing, consider dose reduction upon restarting treatment when diarrhea resolves to grade ≤1 Grade 4: permanently discontinue HER2 TKIs for Breast Cancer
  30. 30. Hand-Foot Syndrome Kwakman et al, 2022; BreastCancer.org, 2022b. Occurs when drug leaks out of capillaries on palms of hands/soles of feet Lateral parts/distal fat pads of palms usually affected before soles of feet Symptoms Numbness Itching, tingling, or burning sensation Redness In patients with skin of color, may present as macular hyperpigmentation instead of redness Swelling Discomfort Tenderness Rash Flaking, cracked, or peeling skin Blisters, ulcers, or sores Intense pain Difficulty walking or using hands Palmar-Plantar Erythrodysesthesia Syndrome
  31. 31. Hand-Foot Syndrome (cont.) ADL = activities of daily living; WHO = World Health Organization; NCI = National Cancer Institute. Kwakman et al, 2022; NCI 2017. Grading Grade 1 Grade 2 Grade 3 Grade 4 WHO Dysesthesia/paresthesia, tingling in hands and feet Discomfort in walking and/or in in holding objects, painless swelling, redness Painful swelling and redness in palms and soles, and around fingernails and toes Scaling, ulceration, blistering, severe pain NCI Minimal skin changes or dermatitis (redness, swelling, hyperkeratosis) without pain Skin changes (peeling, blisters, blisters, bleeding, fissures, swelling, hyperkeratosis) with pain, limiting instrumental ADL ADL Severe skin changes (peeling, blisters, bleeding, bleeding, fissures, swelling, swelling, hyperkeratosis) with pain, limiting self-care care ADL - Grading for patients of color on capecitabine therapy Hyperpigmentation of palms and soles Thickening of skin and palms and soles, with pain and loss of of function Ulceration, dermatitis, or scaling -
  32. 32. Hand-Foot Syndrome (cont.) Kwakman et al, 2022; BreastCancer.org, 2022b. In week following treatment Avoid prolonged heat exposure on hands and feet Avoid hot water Keep pressure off hands and feet Avoid massages or rubbing hands and feet Don’t use tools like screwdrivers, hammers, gardening tools, and knives (chopping) Limit exercise involving running and jumping Patient Education About Prevention
  33. 33. Hand-Foot Syndrome (cont.) Kwakman et al, 2022; BreastCancer.org, 2022b. Apply ice packs wrapped in a towel Elevate hands and feet whenever sitting or lying down Pat skin dry; don’t rub dry Pat mild skin cream into skin to keep it moist Wear loose and ventilated shoes; don’t wear tight shoes or shoes that rub Stay away from harsh chemicals like laundry detergent or cleaning supplies Management
  34. 34. Oral Medications and Adherence OTC = over-the-counter. Iancu et al, 2022; Nerlynx® prescribing information, 2022. Unique dosing for each medication and patient Many factors can contribute to reduced potency and the development of acquired resistance Whether or not food intake affects bioavailability Mechanism of drug metabolism and elimination Liver and kidney function Presence of other medications that alter stomach pH Patient demographics Drug-to-drug interactions OTC medications (including antacids with neratinib) Herbal supplements Vitamins Foods including grapefruit (lapatinib and neratinib) HER2 TKIs for Breast Cancer
  35. 35. Patient Education s/s = signs/symptoms. Chemocare.com, 2022. Adherence to prescribed treatment regimen Management of side effects: Cardiac toxicity Communicate urgent s/s to clinical team Liver toxicity Diarrhea Drug-to-drug interactions HER2 TKIs for Breast Cancer
  36. 36. Case Study: Ms. TY DCIS = ductal carcinoma in situ; ER = estrogen receptor; PR = progesterone receptor; TPH = docetaxel/trastuzumab/pertuzumab; TP = trastuzumab/pertuzumab. 2014 Left breast 5-mm DCIS, grade 2, left segmental mastectomy, 1-mm margins Left axillary dissection, 15 negative lymph nodes Radiotherapy Declined adjuvant endocrine 2017 New metastatic disease to the bone and lymph nodes ER 60% positive, PR 60% positive, HER2-amplified by FISH (ratio 5.30) TPH x4 months (docetaxel dropped after 4 months due to toxicity) TP + tamoxifen + zoledronic acid
  37. 37. Case Study: Ms. TY MRI = magnetic resonance imaging. 2021 Headaches MRI brain: 4.1-cm right frontal metastasis, 0.9-cm left cerebellar lesion, 0.6-cm ring-enhancing focus Right frontal lobe craniotomy, ER 0%, PR 0%, HER2 3+ Gamma knife to cerebellar lesion Tucatinib, capecitabine, and trastuzumab
  38. 38. Case Study: Ms. TY (cont.) Why was Ms. TY started on tucatinib/capecitabine/trastuzumab and not trastuzumab emtansine as second-line therapy in the metastatic setting? a. Time since original diagnosis b. New brain metastasis c. Only completed 4 cycles of TPH d. Prior metastasis to bone and lymph
  39. 39. Case Study: Ms. TY (cont.) Why was Ms. TY started on tucatinib/capecitabine/trastuzumab and not trastuzumab emtansine as second-line therapy in the metastatic setting? a. Time since original diagnosis b. New brain metastasis c. Only completed 4 cycles of TPH d. Prior metastasis to bone and lymph
  40. 40. Key Takeaways HER2 is a protein kinase, overexpressed on the cell surface of ~20% of breast cancers, that sends signals to grow and divide TKIs target these cancer cells while causing less damage to normal cells HER2 TKIs have improved survival for HER2-positive breast cancer Particularly in patients with brain metastases Potentially serious s/s: Congestive heart failure QT interval prolongation LFT elevations Diarrhea Oral medication adherence is key!
  41. 41. Thank you! Abbey Kaler, MS, APRN, FNP-C acjeansonne@mdanderson.org @AbbeyKaler
  42. 42. References American Cancer Society (2022a). Breast cancer facts and figures 2022-2024. Available at: https://www.cancer.org/research/cancer-facts-statistics/breast-cancer-facts-figures.html American Cancer Society (2022b). Targeted drug therapy for breast cancer. Available: https://www.cancer.org/cancer/breast-cancer/treatment/targeted-therapy-for-breast-cancer.html BreastCancer.org (2022). What are anti-HER2 therapies? Available at: https://www.breastcancer.org/treatment/targeted-therapy/what-are-anti-her2-therapies Chan A, Moy B, Mansi J, Ejlertsen B, et al (2021). Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer, 21(1):80-91.e7. DOI:10.1016/j.clbc.2020.09.014 Chemocare.com (2022). Lapatinib. Available at: https://chemocare.com/chemotherapy/drug-info/lapitinib.aspx Curigliano G, Mueller V, Borges V et al (2022). Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol, 33(3):321-329. DOI:10.1016/j.annonc.2021.12.005 Dent SF, Morse A, Burnette S, et al (2021). Cardiovascular toxicity of novel HER2-targeted therapies in the treatment of breast cancer. Curr Oncol Rep, 23(11):128. DOI:10.1007/s11912-021- 01114-x Giudicessi JR, Noseworthy PA & Ackerman MJ (2019). The QT interval. Circulation, 139(24):2711-2713. DOI:10.1161/CIRCULATIONAHA.119.039598 Iancu G, Serban D, Badiu CD, et al (2022). Tyrosine kinase inhibitors in breast cancer (Review). Spandidos Pub, 23(2), 114. DOI:10.3892/etm.2021.11037 Kim PY, Irizarry-Caro JA, Ramesh T, et al (2021). How to diagnose and manage QT prolongation in cancer patients. JACC CardioOncol, 3(1):145-149. DOI:10.1016/j.jaccao.2021.01.002 Le Du F, Diéras V & Curigliano G (2021). The role of tyrosine kinase inhibitors in the treatment of HER2+ metastatic breast cancer. Euro J Cancer, 154:175-189. DOI:10.1016/j.ejca.2021.06.026 Marchiò C, Annaratone L, Marques A, et al (2021). Evolving concepts in HER2 evaluation in breast cancer: Heterogeneity, HER2-low carcinomas and beyond. Semin Cancer Biol, 72:123-135. DOI:10.1016/j.semcancer.2020.02.016 Murthy RK, Loi S, Okines A, et al (2020). Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med, 13;382(7):597-609. DOI:10.1056/NEJMoa1914609 MyCancerGenome® (2016). Receptor tyrosine kinase/growth factor signaling. Available at: https://www.mycancergenome.org/content/pathways/receptor-tyrosine-kinase-growth-factor-signaling/ National Cancer Institute (2017). Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf Nerlynx® (neratinib) prescribing information (2022). Puma Biotechnology. Available at: https://nerlynxhcp.com/pdf/full-prescribing-information.pdf
  43. 43. References (cont.) Pottier C, Fresnais M, Gilon M, et al (2020). Tyrosine kinase inhibitors in cancer: breakthrough and challenges of targeted therapy. Cancers (Basel), 12(3):731. DOI:10.3390/cancers12030731 National Cancer Institute (2017). Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf Saura C, Oliveira M, Feng YH, et al (2020). Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥2 HER2-directed regimens: phase III NALA trial. J Clin Oncol, 38(27):3138-3149. DOI:10.1200/JCO.20.00147 Tukysa® (tucatinib) prescribing information (2022). Seagen. Available at: https://www.tukysahcp.com/pdf/TUKYSA_Full_Ltr_Master.pdf Tykerb® (lapatinib) prescribing information (2022). GlaxoSmithKline. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022059s007lbl.pdf Yang X, Wu D, Yuan S (2020). Tyrosine kinase inhibitors in the combination therapy of HER2 positive breast cancer. Technol Cancer Res Treat, 19:1533033820962140. DOI:10.1177/1533033820962140

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