METASTATIC BREAST CANCER HER2 +VE (1).pptx

METASTATIC HR POSITVE BREAST CANCER

1. MANAGEMENT OF METASTATIC HER2+ BREAST CANCER DR.SARAVANA KUMAR Mch POST GRADUATE

2. metastatic BREAST CANCER HER2-positive breast cancer represents 15%-20% of breast malignancies and is characterized by an aggressive behavior and high recurrence rates. Anti-HER2-directed agents represent the mainstay of treatment of patients with HER2-positive metastatic breast cancer (MBC).. Combination of trastuzumab, pertuzumab and a taxane (THP) remains the preferred first-line

3. HER2 + HUMAN EPIDERMAL GROWTH FACTOR 2, ErbB2 gene, Chromosome 17 25% of Breast cancers Diagnosed: HER2 overexpression (IHC),Gene amplification (FISH) Associated with adverse prognosis with higher risk of recurrence, Triple positive: Lack or lower levels of ER expression & relative resistance to endocrine therapy & CMF based chemotherapy.

4. Targets HER 2: TZ, Drugs preventing HER2 dimerization: Pertuzumab Antibody drug conjugate: T-DM1 Targets HER2 & Immune cells: Margetuximab Drugs targeting Tyrosine kinase moiety of HER 2: Lapatinib, Neratinib . Drugs targeting the down stream pathway of HER2 : PI3K/AKT/mTor: Afatinib, Dacotinib, ibrutinib,…

5. HER 2 TARGETED THERAPY TRASTUZUMAB PERTUZUMAB TDM-1 Fam TZ DERUXTECAN MARGETUXIMAB

6. Prof. S. Subbiah et al

7. Disease relapse 1 year after completing adjuvant treatment or ‘de novo MBC Combination of trastuzumab, pertuzumab , and a taxane (THP) CLEOPATRA study . Phase III trial, 808 patients with HER2-positive MBC were treated with trastuzumab and docetaxel and were randomly assigned Also received pertuzumab or placebo. 8 years of follow-up, Overall survival (OS) was improved by 16.3 months in the pertuzumab arm [median OS 57.1 versus 40.8 months,

8. Cleopatra trial PERTUZUMAB-HER3 and EGFR- prevent dimerization Clinical activity depends on co administration of trasutuzumab Docetaxal+trastuzumab vs Docetaxal+Trastuzumab+pertuzumab Increased OS+PFS Chemotherapy should be includes –good clinical response

9. TRASTUZUMAB Humanized IgG 1 targets domain IV of HER2/ErbB2 member of EGFR/Erb B family of tyrosine kinases. 1 st mAb approved by FDA for treatment of Solid tumors & as adjuvant therapy. Herceptin. Risk factors: borderline left ventricle ejection fraction, HTN, Age >65yrs. TRASTUZUMAB PERTUZUMAB TDM-1 Fam TZ DERUXTECAN MARGETUXIMAB

10. 8mg/kg iv D1 followed by 6mg/kg iv D1* every 21 days 4mg/kg iv D1 followed by 2mg/kg iv weekly Adverse effect: CARDIOMYOPATHY / Cardiac dysfunction. More with anthracycline based chemotherapy- Doxorubicin, Epirubicin. (2% vs 1%) CARDIOMYOPATHY: 1-4% EF decreases by 10% Monitored by: 2D ECHO, Radionuclide ventriculography.

11. PERTUZUMAB Perjeta Humanized IgG1 mAb – binds domain II of HER2 PZ+ TZ+ Docetaxel: approved 1 st line for HER2+ metastatic breast cancer HER2+ , locally advanced, inflammatory, high risk early breast cancer (>2cm node±) CLEOPATRA trial . 840 mg/kg iv D1 followed by 420mg/kg iv D1 * every 21 days A/E: Diarrhea, no increased risk of cardiomyopathy. TRASTUZUMAB PERTUZUMAB TDM-1 Fam TZ DERUXTECAN MARGETUXIMAB

12. EMILIA TRIAL Ado-trastuzumab emtansine (T-DM1) Standard 2 nd line Improved progression-free survival (PFS) and OS In comparison with lapatinib/capecitabine

13. TDM-1 Ado- trastuzumab emtansine (Kadcyla) – ADC- (Antibody drug conjugate) composed of TZ linked to DM1 (potent derivative of maytansine) EMILIA trial- increased PFS, OS in progressive disease after TZ based chemotherapy. Resulting conjugated antibody has been shown to have substantial activity in trastuzumab-refractory breast cancer 3.6mg/kg iv D1 * every 21 days TRASTUZUMAB PERTUZUMAB TDM-1 Fam TZ DERUXTECAN MARGETUXIMAB

14. DESTINYBreast-03 trial. Phase III trial in which 524 patients with HER2-positive MBC previously treated with a Taxane and trastuzumab (60% with prior exposure to per- tuzumab ) were randomly assigned to receive T-DM1 or famtrastuzumab deruxtecan-nxki (T- DXd ), an antibody-drug conjugate (ADC) composed of an anti-HER2 antibody and a cytotoxic topoisomerase I inhibitor. 16.2 months for T- DXd vs 15.3 months for T-DM1, Significant improvement inn PFS (HR 0.28, 95% CI 0.22-0.37, P ¼ 7.8 10 -22 ), 12-month PFS rate of 75.8% with T- DXd versus 34.1% with T-DM1, providing compelling evidence

15. Fam TZ DERUXTECAN Enhertu, fam-TZ- Deruxtecan-nxki ADC, composed of TZ+ Cytotoxic topoisomerase inhibitor DESTINY-Breast01 trial- approved for metastatic breast cancer In progressive disease after TZ, PZ, TDM-1 based chemotherapy. 5.4mg/kg iv D1 * every 21 days TRASTUZUMAB PERTUZUMAB TDM-1 Fam TZ DERUXTECAN MARGETUXIMAB

16. TRASTUZUMAB DERUXTECAN Antibody drug conjugate Trastuzumab antibody has been linked to chemotherapy payload+topoisomerase inhibitors Higher response rate,long time to progression and improved survival among patient previously treated A;opecia,fatigue,diarhhea,interstial lung disease Inc response ratetime to progression,OS in LOW AMPLIFICATION(1+/2+),

17. HER2CLIMB trial, Phase III , tucatinib, an oral tyrosine kinase inhibitor (TKI), was compared with placebo, Combination with trastuzumab and capecitabine, 612 patients previously treated with trastuzumab, pertuzumab , and T-DM1. Follow-up of 29.6 months, 5.5-month improvement in OS (HR 0.73, P ¼ 0.004) and with increased PFS (HR 0.57, P < 0.00001).

18. TUCATINIB Selective TKI targets HER2 Protein kinase RCT-Trastuzumab+capecitabine +/- tucatinib Previously treated Increases PFS and OS Diarrhea,HFS,fatigue

19. NALA trial Phase III, Neratinib, an irreversible pan-HER TKI, in combination with capecitabine compared with lapatinib plus capecitabine in patients with HER2-positive MBC with 2 previous HER2-directed regimens prior exposure to pertuzumab and T-DM1, respectively). Improvement in PFS (HR 0.76, 95% CI 0.63-0.93), NO significant OS benefit (HR 0.88, 95% CI 0.72-1.07).

20. SOPHIA trial, Progression after two or more prior anti-HER2 therapies >99% previously treated with T-DM1 and pertuzumab , respectively) PTC in combination with Margetuximab , an Fc-engineered anti-HER2 monoclonal antibody aiming at increasing activation of innate and adaptive responses

21. Margetuximab led to an improvement in PFS (HR 0.76, 95% CI 0.59-0.98, P ¼ 0.03) N0 significant impact in OS (HR 0.89, 95% CI 0.69-1.13, P ¼ 0.33).

22. MARGETUXIMAB Margenza Chimeric IgG1 mAb SOPHIA I trial Metastatic HER2+ breast cancer refractory to other HER2+ agents. 15mg/kg iv D1 * every 21 days TRASTUZUMAB PERTUZUMAB TDM-1 Fam TZ DERUXTECAN MARGETUXIMAB

23. DISEASE RELAPSE UP TO 12 MONTHS AFTER COMPLETING ADJUVANT TREATMENT Disease relapse during or within 6 months after completing adjuvant therapy, Preferred treatment option is T- DXd based DESTINYBreast-03 trial. MBC diagnosed between 6 and 12 months after completing adjuvant therapy, Regimen in adjuvant setting included pertuzumab , T- DXd would be the preferred treatment,-( DESTINYBreast-03 trial.)

24. RELAPSE WITH CENTRAL NERVOUS SYSTEM METASTASES Approximately one-third of patients with HER2-positive MBC develop CNS metastases. Survival after CNS involvement is higher in patients with HER2-positive MBC compared to other subtypes, Due to better systemic and cranial disease control provided by anti-HER2 agents.

25. Initial treatment of symptomatic brain metastases (BM) Local with neurosurgery/radiotherapy Number of metastases, performance status, and systemic disease control. Good local control Not effective to prevent future CNS events.

26. CLEOPATRA trial showed longer median time to development of CNS metastases as first site of disease progression Pertuzumab arm (15.0 versus 11.9 months, HR 0.58, 95% CI 0.39-0.85),meaning that despite the low blood brain barrier (BBB) permeability, Monoclonal antibodies still play a role in first-line MBC with BM. EMILIA (T-DM1) and DESTINY- Breast03 (T- DXd ), included patients with CNS metastases (19.8% and 23.8%, respectively).

27. Small molecules such as anti-HER2TK ability to penetrate the BBB, showing activity in the CNS Overall response rates from 47% to 66%. HER2CLIMB (tucatinib) included patients with active CNS metastases, Demonstrating survival benefit for the addition of tucatinib to trastuzumab/capecitabine in patients with patients with active BM

28. HR POSITVE AND HER2 POSITIVE TAnDEM STUDY (post menopausal)- Anastazole vs Anastrozole +Trastuzumab Increased PFS+Higher Toxicities eLEcTRA trial-same as TAnDEM study PERTAIN TRIAL ALTERNATIVE TRIAL Not statistically significant

29. REFACTORY HER2 POSITIVE MBC Continue beyond progression improves in time to progression Lapatinib-dual kinase inhibitor-HER2 +EGFR Tyrosine kinase inhibitor Capecitabine +lapatinib Longer period of tumor control and improvement in response rate but not survival

30. TAKE HOME POINTS Treatment HER2-positive MBC is rapidlyevolving increased efficacy in THP remains the standard 1st-line, Trastuzumab deruxtecan preferred in the second-line Tucatinib in combination with trastuzumab/capecitabine valid option in patients with BM.