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

6. Systemic therapy in Malignant
Melanoma
Cytotoxics Immunotherapy BRAF inhibitors MEK inhibitors Miscellaneous
Dacarbazine
Temozolomide
Nab Paclitaxel
Fotemustine
Pacli + Carbo
Other
combinations
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

8. Single Agent Cytotoxics
• RR – 20%
• S/E – Myelosuppression, NauseaDacarbazine
• EORTC 18032 (TMZ v DTIC)
• OSHR – 1.0, PFSHR – 0.92, RR – 14.4% v 9.8%Temozolomide
• Nab Pacli v DTIC (No brain mets, LDH low)
• PFS – 4.8 v 2.5 mo HR -0.792
• OS- 12.8 v 10.7 mo HR- 0.831
Nab Paclitaxel

9. Combination Chemotherapy

10. Adjuvant Systemic Therapy
HD IFN alfa2b
Peg IFN alfa
Immunotherapy
CTLA 4 inh
PD 1 inh
BRAF inh

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

14. ()
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)

15. C
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17. EORTC 18071 - Results

20. Common side effects of checkpoint
inhibitors
Fatigue
Diarrhoea
Itching
Rash
Nausea
Vomiting
Fatigue
Lymphocytopenia
Hyponatremia
Shortness of breath
Musculoskeletal pain
Anorexia
Cough
Anemia, fatigue
Hyperglycemia
Hyponatremia
Hypoalbuminemia
Itching
Cough
Nausea

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

24. 3 Y RFS – 58% v 39%
3 Y OS – 86% v 77%

25. Negative Trials
•Vemurafenib v
placebo
•DFS – No Difference
BRIM 8
•Nivo + Ipi v Nivo
•RFS – No Difference
CHECKMATE
915

26. Metastatic Disease

27. Systemic Agents in Unresectable or Metastatic Melanoma

28. IMMUNOTHERAPY
High Dose
Interleukine-2
Vaccines
Checkpoint
inhibitors
• CTLA 4 inhibitors
• PD1 inhibitors
Adoptive cell
transfer
therapy
(ACT)

29. 1st 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)
2nd cycle
ORR – 16 %

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

31. Checkpoint Inhibitors
• IPILIMUMAB
• PEMBROLIZUMAB
• NIVOLUMAB

32. Hodi et al 2010

33. Robert et al, 2011

48. Targeted Therapy

50. BRAF & MEK inhibitors

51. Why using only BRAF inhibitor is
counterproductive?

52. Resistance to BRAF inhibitor

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

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

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

68. Thank You