Malignant Melanoma

1. MELANOMA
Standard of Care and Future Perspectives
Sofie Wilgenhof
The Netherlands Cancer Institute

2. Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
Advisory role: Eisai, Bristol-Myers Squibb, Pfizer, Novartis and Pierre Fabre (paid to institution)
DECLARATION OF INTERESTS
Sofie Wilgenhof

3. • Incidence and epidemiology
• Diagnosis
• Staging/Prognosis
• Treatment stage I-III
• Treatment stage IV
• Future perspectives

4. Melanoma: incidence and death rate
in The Netherlands
Incidence: steady increase
Mortality: decrease in the past 10 years

5. Cutaneous melanoma: risk factors
• UV irradiation
• Family history
• Multiple moles
• Fair skin
• immunosuppression
Lo JA et al. Science. 2014.

6. • Incidence and epidemiology
• Diagnosis
• Staging/Prognosis
• Treatment stage I-III
• Treatment stage IV
• Future perspectives

7. ‘Ugly duckling’ sign and ABCD(E) rule
A
B
C
D
E evolution bleeding, itching, signs of
inflammation

8. Melanoma diagnosis: excision biopsy
• entire tumor to adipose layer
• shave biopsies are obsolete
• minimal margin 1mm
• punch biopsy only if too large to excise

9. • Incidence and epidemiology
• Diagnosis
• Staging/Prognosis
• Treatment stage I-III
• Treatment stage IV
• Future perspectives

10. AJCC TNM eighth edition staging system of
melanoma

11. AJCC TNM eighth edition staging system of
melanoma
www.aad.org
Gershenwald et al. CA Cancer J Clin. 2017

12. AJCC TNM eighth edition staging system of
melanoma
Keung EZ. JNCI. 2020

13. • Incidence and epidemiology
• Diagnosis
• Staging/Prognosis
• Treatment stage I-III
• Treatment stage IV
• Future perspectives

14. Melanoma treatment local/locoregional disease:
wide local excision
+ SN biopsy
if thickness > 0.8 mm and/or ulceration
Michielin O. et al. Ann Oncol. 2019

15. Melanoma treatment – sentinel node

16. Complete lymph node dissection (CLND) in
sentinel node-positive patients?

17. Multicenter Selective Lymphadenectomy trial
(MSLT-I)
Morton DL. et al. NEJM. 2014
MSLT-I validated the staging potential of
the sentinel node biopsy but did not show
a survival benefit for this procedure

18. Multicenter Selective Lymphadenectomy trial
(MSLT-II)
Faries M.B. et al. NEJM. 2017

19. DeCOG-SLT trial final analysis
Leiter U. et al. JCO 2019
NO impact on survival for early CLND
compared with nodal observation with
periodic US of the SN-positive basin

20. Adjuvant radiotherapy: improves local control,
but no RFS and no OS
RFS OS LN RFS
→ No longer routinely recommended in the adjuvant setting
Henderson MA. Lancet Oncol. 2015

21. Melanoma adjuvant treatment – checkpoint
inhibition and targeted therapy
EORTC 18071
ipilimumab
placebo
Ipilimumab 10 mg/kg vs placebo
Stage IIIA-C, RFS HR 0.75, OS HR 0.73
Eggermont AMM et al. EJC. 2019; Eggermont AMM et al. NEJM. 2022; Ascierto PA et al. Lancet Oncol. 2020; Dummer R. et al. NEJM. 2020
EORTC 1325 Pembrolizumab vs placebo
Stage IIIA-C, RFS HR 0.61, OS HR NA
Checkmate 238 Ipilimumab 10 mg/kg vs nivolumab
Stage IIIB-C + IV, RFS HR 0.71, OS HR NA
Combi-AD Dabrafenib + trametinib vs placebo
Stage IIIA-C, RFS HR 0.51, OS HR NA

22. Melanoma adjuvant treatment – checkpoint
inhibition: ipilimumab + nivolumab
Weber JS. JCO. 2023

23. Adjuvant treatment in stage IIB/IIC
Luke JJ. Lancet. 2022 Long G. Pigment Cell Melanoma Res 2022

24. Adjuvant treatment options 2023
Adjuvant treatment in resected stage IIB/IIC melanoma:
• PD-1 blockade (pembrolizumab or nivolumab)
Adjuvant treatment in resected stage III melanoma:
• BRAF WT patients: PD-1 blockade (nivolumab or pembrolizumab)
• BRAF-mutated melanoma: dabrafenib/trametinib or PD-1 blockade.
Individual treatment decisions should be made with the patient,
factoring in the toxicity profiles.

25. Survival benefit?
Biomarkers?
(tissue-based gene expression score?/ctDNA?)
Neoadjuvant?
Adjuvant treatment 2023

26. Neoadjuvant therapy
Versluis JM, Long GV, Blank CU. Nat Med. 2020

27. Neoadjuvant–Adjuvant or Adjuvant-Only
Pembrolizumab in Advanced Melanoma
Patel SP. NEJM. 2023

28. Patel SP. NEJM. 2023
Neoadjuvant–Adjuvant or Adjuvant-Only
Pembrolizumab in Advanced Melanoma

29. • Incidence and epidemiology
• Diagnosis
• Staging/Prognosis
• Treatment stage I-III
• Treatment stage IV
• Future perspectives

30. DTIC (dacarbazine) versus temozolomide
Middleton MR et al. JCO. 2000
Median overall survival 6 months
5-year survival rate 6%

31. Genetic changes observed in melanoma
1985:N-RAS mutation
2002: B-RAF mutation
2006: c-KIT mutation
2005: CDK4 mutation
2009: GNAQ mutation
2009: erbB4 mutation
1997: PTEN loss
1994: loss of CDKN2
Davies et al. Nature 2002

32. Melanoma genetic alterations- frequencies of
BRAF and NRAS mutations
Jakob JA et al. Cancer. 2012

33. Mutations and copy number changes in selected
published melanoma driver genes
N K Hayward et al. Nature 1–6 (2017)
• BRAF, CDKN2A, NRAS and TP53 in cutaneous
melanoma
• BRAF, NRAS, NF1 and KIT in acral melanoma
(with lower frequencies than in cutaneous
melanoma)
• SF3B1 in mucosal melanoma

34. Inhibition of Mutated, Activated BRAF in
Metastatic Melanoma
Flaherty et al. NEJM. 2010

35. Improved survival with vemurafenib in
melanoma with BRAFV600E mutation
Chapman et al NEJM. 2011

36. Resistance to BRAF-inhibitor in melanoma
baseline 23 weeks
15 weeks
Wagle et al. JCO 2012

37. Rational for Dual targeting of the MAPK-pathway
BRAF
V600
MEK
Vemurafenib
Dabrafenib
Encorafenib
Trametinib
Cobimetinib
Binimetinib
ERK
Sekulic et al. 2008

38. Robert C. et al. NEJM 2015.
COMBi-V: dabrafenib + trametinib versus vemurafenib
COMBi-D: dabrafenib + trametinib versus dabrafenib
Long GV. et al. Lancet Oncol. 2015.
Ascierta PA. et al. Lancet Oncol. 2016
coBRIM: vemurafenib + cobimetinib versus vemurafenib COLOMBUS: encorafenib + binimetinib
Dummer R. et al. Lancet Oncol. 2018
versus vemurafenib versus encorafenib
BRAF/MEK double inhibition is superior to single-agent BRAF in
terms of response rates, PFS and OS.
Single-agent BRAFi should be used only in case of a
contraindication for MEK inhibitors.

39. Adverse events BRAF + MEK inhibition:
46-60% severe adverse events
Reduction of skin-related adverse events
Cardiac and ocular side effects from
MEK-inhibition
Pyrexia and chills with dabrafenib
Photosensitivity reactions with
vemurafenib
Increased GI side effects
Heinzerling L. ESMO open. 2019

40. Immune checkpoint inhibitors in melanoma
Ribas. NEJM. 2012
Hodi, Haanen, et al. NEJM. 2010
CTLA-4

41. Pooled overall survival analysis from 4846
ipilimumab treated patients
Median OS (95% CI): 9.5
months (9.0–10.0)
3-year OS rate (95% CI): 21%
(20%–22%)
Proportion
Alive
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months
0 12 24 36 48 60 72 84 96 108 120
Ipilimumab
CENSORED
Schadendorf et al. ECCO/ESMO 2013
Schadendorf et al. JCO. 2015
10 years

42. Immune checkpoint inhibitors in melanoma
Ribas. NEJM. 2012
CTLA-4 PD-1

44. Combining CTLA-4 and PD-1 blockade:
Checkmate 067 trial

45. Response rate and (6.5y) overall survival
ORR 58%
ORR 19%
ORR 44%
Larkin et al. NEJM. 2015; Larkin et al. NEM 2019 Wolchok JD. et al. J Clin Oncol. 2022

46. Nivolumab (anti-PD-1) + relatlimab (anti-LAG-3)
Tawbi HA et al. NEJM. 2022

47. Nivolumab (anti-PD-1) + relatlimab (anti-LAG-3)
Tawbi HA et al. NEJM 2022
Tawbi HA, ASCO 2023
Confirmed ORR by BICR NIVO + RELA (n = 355) NIVO (n = 359)
ORR % (95 CI) 44 (38-49) 34 (29-39)

48. Immune-related adverse events
Postow et al. NEJM. 2018; Steebruggen et al. NTvG 2016

49. Grade 3/4 adverse events
• Anti-PD-1: 10-14%
• Anti-PD-1 + anti-CTLA-4: 48-58%
• Anti-PD-1 + Anti-LAG-3: 22%
Immune-related adverse events

50. Sequence in BRAF-mutated melanoma pts?
Atkins Mb et al. JCO. 2023

51. Sequence in BRAF-mutated melanoma pts?
Patients with tumours not progressing
very quickly and not immediately
threatening an important organ or
function, should be considered for
immunotherapy first, preserving targeted
therapies for the subsequent lines.
Michielin O. et al. Ann Oncol. 2019

52. Brain metastases
• Interdisciplinary care in specialised referral
centres
• Treatment options:
• Neurosurgery
• Stereotactic radiosurgery (SRS)
• BRAFi/MEKi
• Immunotherapies
• (Whole-brain radiotherapy): should be avoided –
lack of efficacy – long-term toxicities

53. Brain metastases: BRAF + MEK inhibition
COMBI-MB: phase II trial,
dabrafenib + trametinib
Intracranial ORR: 58%
Davies MA et al. Lancet Oncol. 2017

54. Brain metastases: immunotherapy
Checkmate 204: phase II trial,
ipilimumab + nivolumab
Tawbi HA et al. NEJM. 2018
asymptomatic brain metastases symptomatic brain metastases
Tawbi HA et al. JCO. 2019
intracranial ORR: 55%

55. • Incidence and epidemiology
• Diagnosis
• Staging/Prognosis
• Treatment stage I-III
• Treatment stage IV
• Future perspectives

56. Future perspectives
• Determining sequence of targeted and immune checkpoint therapy in
patients with BRAF-mutated, advanced melanoma
• Optimal duration of immunotherapy in adjuvant and metastatic setting?
Response-driven?
• New checkpoints: LAG-3, TIGIT, TIM-3, B7-H3, B7-H4, OX-40, GITR, …
• Neoadjuvant treatment
• Predictive biomarkers
• Adoptive T-cell therapy: tumor-infiltrating lymphocytes (TIL)
• Personalised mRNA vaccine
• …

57. • Adjuvant encorafenib and binimetinib versus placebo in high-risk stage II
melanoma with a BRAFV600 mutation (COLOMBUS-AD)
• Adjuvant nivolumab in high-risk stage II melanoma with biomarker-based
risk-stratification (Nivo-Mela)
• Circulating tumor DNA–guided therapy for stage IIB/C melanoma after
surgical resection.(DETECTION)
• Adjuvant nivolumab + relatlimab versus nivolumab in resected stage III-IV
melanoma (Relativity-098)
• Adjuvant cemiplimab (anti-PD-1 MAb) + fianlimab (anti-LAG-3 MAb) versus
pembrolizumab in resected stage IIC–IV melanoma (NCT05608291)
• Adjuvant pembrolizumab/visbostolimab (anti-TIGIT) versus
pembrolizumab in resected high-risk stage II-IV melanoma (KEYVIBE-010)
• Neoadjuvant ipilimumab + nivolumab versus the standard adjuvant CPI in
patients with resectable stage III disease (NADINA)
Phase 3 (Neo)adjuvant clinical trials
Neoadjuvant
LAG-3
TIGIT
BRAFi + MEKi
Tissue-based gene
expression score
Circulating tumor
DNA biomarker

58. Adoptive T-cell therapy: TIL (tumor-infiltrating
lymphocytes)
Haanen JBAG. ESMO 2022

59. Rohaan, Svane, Haanen. NEJM. 2022
Adoptive T-cell therapy: TIL (tumor-infiltrating
lymphocytes)

60. Thank you for your attention! Good luck with the exam!!