Systemic therapy in malignant melanoma

SYSTEMIC TREATMENT OF MALIGNANT MELANOMA
IO, BRAF MEK NHIBITORS

1. Systemic therapy in Malignant Melanoma Dr. Rajib Bhattacharjee DNB SS PDT (Medical Oncology)

2. What is melanoma

3. Systemic therapy in Malignant Melanoma Cytotoxics Immunotherapy BRAF inhibitors MEK inhibitors Miscellaneous Dacarbazine Temozolomide Nab Paclitaxel Fotemustine Pacli + Carbo Other c ombination s Dartmouth, CVD, etc Interleukin 2 Aldesleukin Checkpoint inh Ipilimumab Nivolumab Pembrolizumab Dabrafenib Vemurafenib Encorafenib Trametinib Cobimetinib Binimetinib IFN alfa T –VEC TIL – ACT KIT inhibitors Imatinib Dasatiib Sunitinib

4. Single Agent Cytotoxics

5. Combination Chemotherapy

6. Outcomes of IFN alfa 2b ECOG Trials – E1684, E1690, E1694, E2696 METAANALYSIS of 15 trials – improvement in OS & RFS

7. () EORTC 18991 (n = 1256) Peg IFN v Observation 7 Y RFS – 39% V 35% (HR – 0.87) OS – No difference (p = 0.57) (stage III N1 ulcerated OS HR – 0.59 )

8. C h e c k p o I n t s

9. EORTC 18071 - Results

10. Common side effects of checkpoint inhibitors

11. Immune mediated side effects of Checkpoint Inhibitors Enterocolitis Hepatitis Dermatitis Neuropathy Endocrinoathy – Hypophysitis , Thyroiditis

12. 3 Y RFS – 58% v 39% 3 Y OS – 86% v 77%

13. Negative Trials

14. Metastatic Disease

15. Systemic Agents in Unresectable or Metastatic Melanoma

16. IMMUNOTHERAPY

17. 1 st cycle ALDESLEUKIN 6-7.2 L U/Kg 8 hrly (till toxicity/ 15 doses) Gap of 10 days repeat if response/STABLE (assessed after 2 months) 2 nd cycle ORR – 16 %

18. Vaccine Heteroclitic gp 100:209-217 (210M) melanoma peptide vaccine RR – 16% v 6 % OS – 18.0 v 11.1 mo

19. Checkpoint Inhibitors IPILIMUMAB PEMBROLIZUMAB NIVOLUMAB

20. Hodi et al 2010

21. Robert et al, 2011

22. Targeted Therapy

23. BRAF & MEK inhibitors

24. Why using only BRAF inhibitor is counterproductive?

25. Resistance to BRAF inhibitor

26. OS – 22.3 v 17.4 mo (HR – 0.7) Toxicities – 37% v 28%

27. Seems like both BRAF inhibitor and immunotherapy works well.. How about using them together?

28. C-KIT Inhibitors Imatinib Dasatinib Sunitinib Actionable KIT mutations L596 V559 K622E

29. Thank You