Tratamentul Melanomului Metastatic-de la ghiduri la experienta clinica

O prezentare la a VII-a editie a conferintei nationale Melanom Romania, 2023

MELANOM MALIGN de la ghiduri la experienta clinica Dr. Gafton Elena medic primar oncologie medicala IRO IASI

Introduction to Skin Cancer

Classification of Melanoma Melanoma may be classified by the site affected into cutaneous (skin), ocular (eye, including uveal and conjunctival), mucosal (mucosal membrane lining the respiratory, gastrointestinal, or urogenital tracts), or unknown primaries. Cutaneous melanoma accounts for more than 90% of all melanoma cases.1,2 Cutaneous melanoma can be further divided into 4 major subtypes based on histologic features. Note that these histologic subtypes do not directly correlate with clinical behavior, but genotype-phenotype correlation studies have shown higher prevalence of certain mutations within a histologic subtype.2 Major histologic subtypes of cutaneous melanoma*2,3 Superficial spreading melanoma

Nodular melanoma

Acral-lentiginous melanoma

Lentigo maligna melanoma

Darkly pigmented, flat-tonodular lesion, highly irregular border

Often appears as flat, brown lesion arising in a lentigo maligna

Appearance†

Asymmetric, irregular border, Symmetric, rapidly enlarging, various shades, often arising elevated, or polypoid lesion; in a precursor nevi various shades or amelanotic Incidence‡

70%; more common in younger adults

15%

5%–10%

4%–10%; more common in elderly

Common sites of manifestation

Any; mostly trunk and extremities and sites with intermittent sun exposure

Any anatomic site

Palms, soles, or subungual (under the nail bed)

Sites with chronic sun exposure, eg, the head and neck and distal extremities

BRAF, NRAS

BRAF, NRAS

KIT

KIT

Common mutation(s)

*Minor histologic subtypes include amelanotic melanoma, spitzoid melanoma, and desmoplastic melanoma.4 †Representative images are shown. Appearances of individual lesions may vary. ‡Based on US incidence.

1.

Chang AE et al. Cancer. 1998;83(8):1664.

2.

Mitchell TC et al. Abeloff's Clinical Oncology; 2020:1034.

3.

Bastian BC. Annu Rev Pathol. 2014;9:239.

4.

Wells GL. Merck Manual Professional Version-Melanoma (Malignant Melanoma). March 2019.

Pathogenesis

Driver Mutations in Melanoma Several genetic alterations drive the development of melanoma (Table). The most frequently mutated oncogenic pathway in melanoma is the mitogen-activated protein kinase (MAPK) pathway that comprises RAS, BRAF, MEK, and ERK signaling. The MAPK pathway regulates cell growth, survival, and invasion, and is aberrantly activated in many melanomas.1,2 The phosphatidylinositol 3 kinase (PI3K) pathway is another commonly affected pathway that is primarily associated with the loss of the tumor suppressor phosphatase and tensin homolog (PTEN), leading to its constitutive activation.1 Common somatic mutations in melanoma1,3 Oncogene

Description

BRAF*

• Encodes a serine/threonine kinase in the MAPK pathway • The most common driver mutation occurring in 50%‒70% of melanoma • More than 60 mutations have been identified, with the most frequently observed mutation being the valine-to-glutamic acid change at codon 600 (V600E mutation; >80%), followed by V600K (20%) and the less common V600D, V600R, K601 and L597

NRAS*

• Encodes a RAS family protein upstream of BRAF in the MAPK pathway • The second most common driver mutation occurring in 15%‒20% of melanoma

NF1

• Encodes neurofibromin 1 that negatively regulates the MAPK/RAS pathway • NF1 mutation rarely occurs concurrently with BRAF or NRAS mutations

KIT

• Encodes a receptor tyrosine kinase (RTK) critical in melanocyte development • Occurs in 10% of mucosal, acral, and lentigo maligna melanoma • Mutations activate downstream targets, including the MAPK and PI3K pathways

GNAQ and GNA11

• Encode subunits of G proteins that act as coupling proteins between transmembrane receptors and intracellular signaling pathways, such as the MAPK pathway • Associated with 80% of uveal melanoma

*Mutations of BRAF and NRAS are mutually exclusive.

1.

2.

Mitchell TC et al. Abeloff's Clinical Oncology; 2020:1034.

Craig S et al. J Pathol. 2018;244(5):578

3.

Bello DM et al. Cancer Control. 2013;20(4):261.

Staging

Staging of Melanoma Melanoma is staged using the American Joint Committee on Cancer (AJCC) TNM staging system:1 • T category is based on the thickness of the melanoma and presence of ulceration.

• N category is based on the number of involved regional lymph nodes and presence of microsatellite, satellite, or in‐transit metastases, as confirmed by SLNB and pathologic assessment.

• M category is based on the presence and location of distant metastases, and LDH level.

Select the buttons for more information on each category.

T category N category M category

1.

Gershenwald JE et al. AJCC Cancer Staging Manual. 8th ed.; 2017:563.

T category for staging cutaneous melanoma1 T category

Thickness (mm)

Ulceration status

Tis (melanoma in situ)

Not applicable

Not applicable

T1 • T1a • T1b

≤1.0 a. <0.8 b. <0.8 0.8–1.0 mm

Unknown or unspecified a. Without ulceration b. With ulceration With or without ulceration

T2 • T2a • T2b

>1.0–2.0 a. >1.0–2.0 b. >1.0–2.0

Unknown or unspecified a. Without ulceration b. With ulceration

T3 • T3a • T3b

>2.0–4.0 a. >2.0–4.0 b. >2.0–4.0

Unknown or unspecified a. Without ulceration b. With ulceration

T4 • T4a • T4b

>4.0 a. >4.0 b. >4.0

Unknown or unspecified a. Without ulceration b. With ulceration

Staging

Staging of Melanoma Melanoma is staged using the American Joint Committee on Cancer (AJCC) TNM staging system:1 • T category is based on the thickness of the melanoma and presence of ulceration.

• N category is based on the number of involved regional lymph nodes and presence of microsatellite, satellite, or in‐transit metastases, as confirmed by SLNB and pathologic assessment.

• M category is based on the presence and location of distant metastases, and LDH level.

Select the buttons for more information on each category.

N category for staging cutaneous melanoma1 N category

Number of tumor‐involved regional lymph node

N0 N1

No regional metastases detected 1 tumor-involved node or in‐transit, satellite, and/or microsatellite metastases with no tumor-involved nodes a. 1 clinically occult* b. 1 clinically detected c. No regional lymph node disease 2 or 3 tumor-involved nodes or in‐transit, satellite, and/or microsatellite metastases with one tumor-involved node a. 2 or 3 clinically occult* b. 2 or 3, at least one of which was clinically detected c. 1 clinically occult* or clinically detected ≥4 tumor-involved nodes or in‐transit, satellite, and/or microsatellite metastases with ≥2 tumor-involved nodes, or any number of matted nodes without or with in‐transit, satellite, and/or microsatellite metastases a. ≥4 clinically occult* b. ≥4, at least one of which was clinically detected, or presence of any number of matted nodes c. ≥2 clinically occult* or clinically detected and/or presence of any number of matted nodes

T category N category M category

• N1a • N1b • N1c N2 • N2a • N2b • N2c N3

1.

Gershenwald JE et al. AJCC Cancer Staging Manual. 8th ed.; 2017:563.

• •

N3a N3b

•

N3c

*Detected by SLNB

Presence of in‐transit, satellite, and/or microsatellite metastases No

a. b. c.

No No Yes

a. b. c.

No No Yes

a. b.

No No

c.

Yes

Staging

Staging of Melanoma Melanoma is staged using the American Joint Committee on Cancer (AJCC) TNM staging system:1 • T category is based on the thickness of the melanoma and presence of ulceration.

• N category is based on the number of involved regional lymph nodes and presence of microsatellite, satellite, or in‐transit metastases, as confirmed by SLNB and pathologic assessment.

• M category is based on the presence and location of distant metastases, and LDH level.

Select the buttons for more information on each category.

T category N category M category

M category for staging cutaneous melanoma1 M category

Anatomic site

LDH level

M0

No evidence of distant metastasis

Not applicable

a.

Distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph node Distant metastasis to lung with or without M1a sites of disease

a.

c.

Distant metastasis to non-CNS visceral sites with or without M1a or M1b sites of disease

c.

d.

Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease

d.

M1 • M1a – M1a(0) – M1a(1) • M1b – M1b(0) – M1b(1) • M1c – M1c(0) – M1c(1) • M1d – M1d(0) – M1d(1)

b.

b.

Not recorded or unspecified – Not elevated – Elevated Not recorded or unspecified – Not elevated – Elevated Not recorded or unspecified – Not elevated – Elevated Not recorded or unspecified – Normal – Elevated

CNS, central nervous system; LDH, lactate dehydrogenase.

Suffixes for M category: (0) LDH not elevated, (1) LDH elevated. No suffix is used if LDH is not recorded or is unspecified.

1.

Gershenwald JE et al. AJCC Cancer Staging Manual. 8th ed.; 2017:563.

Staging

Stage Grouping Melanoma is grouped into stages based on clinical and pathologic staging.1 • Clinical staging is typically used after biopsy of the primary tumor, with clinical assessment for regional and distant metastases.

• Pathologic staging includes additional information from surgical specimen after wide-excision and regional lymph nodes after SLNB or lymphadenectomy. Pathologic staging is used to determine the substage of stage III melanomas.

Clinical and pathologic staging for cutaneous melanoma1 Stage

Stage

Clinical 0 IA IB IIA IIB IIC III

T Tis T1a

N N0 N0

M M0 M0

T1b T2a T2b T3a T3b T4a T4b Any T, Tis

N0 N0 N0 N0 N0 N0 N0 ≥N1

M0 M0 M0 M0 M0 M0 M0 M0

Pathologic 0 IA IB IIA IIB IIC IIIA IIIB

IIIC

IV 1.

Gershenwald JE et al. AJCC Cancer Staging Manual. 8th ed.; 2017:563.

Any T

Any N

M1

IIID IV

T Tis T1a T1b T2a

N N0 N0 N0 N0

M M0 M0 M0 M0

T2b T3a T3b T4a T4b T1a/b–T2a T0 T1a/b–T2a T2b/T3a T1a–T3a T3b/T4a T4b T4b Any T, Tis

N0 N0 N0 N0 N0 N1a or N2a N1b, N1c N1b/c or N2b N1a–N2b N2c or N3a/b/c Any N ≥N1 N1a–N2c N3a/b/c Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Prognosis

Prognosis of Melanoma Survival Rates

According to the 8th Edition International Melanoma Database (IMD):1 • For Stages I and II melanomas, where no regional lymph nodes are involved, the 5-year melanoma-specific survival (MSS) is 82%–99%. Note that more than 80% of patients with melanoma are diagnosed at the localized stage.2 • For Stage III melanomas, the 5-year MSS varies from 32% to 93% depending on subgroups with different T and N subcategories. Stage III melanoma patients are at high risk of relapse (35%–90% based on AJCC 7th edition available data).3 • For Stage IV melanomas, a 5-year MSS has not been proposed because the availability of contemporary data is limited and because survival differences among patients with stage IV melanoma historically were small (before the recent revolution in treatment options for advanced melanoma).1 However, based on the available US Surveillance, Epidemiology, and End Results (SEER) data, the 5-year relative survival rate for stage IV melanoma between 2009 and 2015 was 24.8%.2

MSS probability

Landmark MSS rates in patients with stage I to III melanoma from the 8th Edition IMD1

Time since diagnosis (years)

Kaplan-Meier MSS curves for patients with stages I to III melanoma from the 8th Edition IMD1 1.

2.

Gershenwald JE et al. CA Cancer J Clin. 2017;67(6):472.

NCI SEER. Cancer Stat Facts: Melanoma of the Skin. 2019.

3.

Eggermont AMM et al. N Engl J Med. 2018;378(19) Protocol.

Stage IA IB IIA IIB IIC IIIA IIIB IIIC IIID

5-year survival rate (%) 99 97 94 87 82 93 83 69 32

10-year survival rate (%) 98 94 88 82 75 88 77 60 24

ESMO Guidelines

Treatment Guidelines

ESMO Guidelines: Treatment Algorithm for Stage I - III Melanoma The treatment recommendations in the ESMO guidelines for Stage I-III cutaneous melanoma are summarized below: pT1b-T4b, cN0, cM0 SLN-negative

SLN-positive

No adjuvant criteriaa Standard follow-upb Relapse CLNDc [III, C]

Ultrasound-based follow-upb [I, A] Relapse CLNDc

Adjuvant treatment [I, A]

Adjuvant treatment [I, A]

Adjuvant criteriaa Adjuvant treatment [I, A]

Treatment algorithm for unresectable Stage I‒III melanomas Abbreviations: CLND, complete lymph node dissection; ESMO, European Society for Medical Oncology, SLN, sentinel lymph node. aCriteria for adjuvant therapy are Stage IIIA (SLN >1 mm), Stage IIIB/C for BRAF-mutated melanoma. Some of the current approvals include all Stage III, regardless of SLN deposit. Decision of treatment for Stage IIIA with SLN <1 mm should be made

on an individual basis, taking into consideration the exact prognosis of the patient. bThere is currently no consensus on the frequency of follow-up or methods used for patients with resected melanoma. Consultation of the relevant national guidelines is recommended. Intervals between clinic visits and imaging exams may be

tailored according to individual risk and personal needs of the patient. cFor SLN-positive patients, avoiding CLND is justified based on the results of the MSLT-II and DeCOG-SLT trials.

Michielin O et al. Ann Oncol. 2019;30(12):1884-1901.

10

Treatment Guidelines

ESMO Guidelines: Treatment Algorithm for Unresectable Stage III/IV Melanoma The treatment recommendations in the ESMO guidelines for advanced cutaneous melanoma are summarized below: Unresectable Stage III/IV disease

BRAF wild-typea

• • •

• •

If unfit for first-line immunotherapy

Anti‒PD-1 + anti‒CTLA-4 combination [I, A] Anti‒PD-1 monotherapy [I, A] T-VEC [I, B]

Clinical trial Rechallenge with immunotherapy

BRAF mutation‒positive

BRAF + MEK inhibitors [I, A]

• • •

Anti‒PD-1 + anti‒CTLA-4 combination [I, A] Anti‒PD-1 monotherapy [I, A] T-VEC [I, B]

• •

Clinical trial Rechallenge with targeted therapy

• • •

If fit for first-line immunotherapy Anti‒PD-1 + anti‒CTLA-4 combination [I, A] Anti‒PD-1 monotherapy [I, A] T-VEC [I, B] BRAF + MEK inhibitors [I, A]

• •

Clinical trial Rechallenge with immunotherapy

Treatment algorithm for unresectable Stage III/IV melanoma Abbreviations: CTLA-4, cytotoxic t-lymphocyte associated protein 4; ESMO, European Society for Medical Oncology, MEK, Mitogen-activated protein kinase kinase; PD-1, programmed cell death protein-1, T-VEC, Talimogene laherparepvec.. aFor NRAS mutation‒positive melanoma, first-line treatment is the same as for BRAF wild type. Progression will be treated with MEK inhibitors before clinical trial or rechallenge with immunotherapy.

Michielin O et al. Ann Oncol. 2019;30(12):1884-1901.

11

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Melanoma: Cutaneous V2.2023

Treatment of Stage II Melanoma – NCCN Guidelines NCCN Guidelines Treatment Algorithm for Stage IB (T2a) or II (T2b or higher)

As per the 2023 NCCN Guidelines ®: •

•

• •

Stage IB (T2a) or stage II (T2b or higher)a

Wide excision is the primary treatment for patients with stage II melanoma (category 1 – based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate) Melanoma

In situ

≤1.0 mm thick

>1.0–2 mm thick

>2.0 mm thick

Surgical margin

0.5–1 cm

1 cm

1–2 cm

2 cm

• History & physical examination • Baseline imaging/lab tests not recommended unless needed for surgical planning • Imagingb to evaluate specific signs or symptomsc

Sentinel lymph node biopsy is: – Not recommended for stage 0 to IA (T1a) (<0.8 mm thick, no ulceration) – Offered to patients with higher-risk stage IB or stage II melanoma Complete lymph node dissection is offered to patients with stage III disease based on a positive SLNB Adjuvant therapy for stage II disease is recommended in the context of a clinical trial; pembrolizumab for pathologically staged IIB/IIC disease is a recommended option

Discuss and offer SLNBa,d-f

Wide excisiong,h (category 1) with SLNBi,j

SLNB-positive

SLNB-negative

All recommendations are category 2A unless otherwise indicated. aMicrosatellitosis, when present in the initial biopsy or wide excision specimen, defines at least N1c and at least stage IIIB disease. Althoug h less well studied than other stage III patient populations, SLN status does have prognostic significance in patients with microsatellitosis, with a positive SLN upstaging a patient to at least N2c, stage IIIC. SLNB should be considered in patients with microsatellitosis, especially if it will alter management decisions. bSee Principles of Imaging-Workup (ME-D). cNodal basin US is not a substitute for SLNB. Consider nodal basin US prior to SLNB for patients with melanoma with an equivocal regional lymph node physical exam. Abnormal or suspicious findings on nodal basin US should be confirmed histologically, whenever possible. Negative nodal basin US is not a substitute for biopsy of clinically suspicious lymph nodes. dIn patients with pure desmoplastic melanoma (>90% of invasive melanoma associated with prominent stromal fibrosis), SLNB positivity is less common compared to mixed desmoplastic/ nondesmoplastic and conventional melanoma subtypes. Variability across studies in the rate of SLNB positivity in desmoplastic melanoma may be due to lack of standardized criteria for defining pure desmoplastic melanoma, histopathologic reproducibility, and/or reporting. In the setting of these conflicting reports, the role of SLNB in patients with pure desmoplastic melanoma remains controversial. eSLNB is an important staging tool. While SLNB itself has not been shown to improve DSS, it is associated with improved regional nodal disease control (Crystal JS, et al. JAMA Surg 2022;157:835-842). A positive SLNB would upstage a patient to stage III. Adjuvant therapy has been shown to mainly improve RFS (over OS) in selected patients with high-risk stage III disease. fDecision not to perform SLNB may be based on significant patient comorbidities, k,m patient preference, or other factors (such as advanced age and/or poor functional status). gSee Principles of Surgical Margins for Wide Excision of Primary Melanoma (ME -E). hFor patients with microsatellitosis in the wide excision specimen, see ME-4 for further workup and treatment. iSLNs should be evaluated with serial sectioning and IHC. jSee Principles of Sentinel Lymph Node Biopsy (SLNB) (ME-F). kAdjuvant pembrolizumab is active in reducing relapse events for resected stage IIB and IIC melanoma. However longer follow -up is needed to evaluate the impact of adjuvant pembrolizumab on OS. Clinicians considering adjuvant pembrolizumab therapy for stages IIB or IIC disease should have a detailed discussion with the patient, to weigh the pros and cons of treatment benefit vs toxicity. Factors to be considered, in addition to stage, include patient’s age, performance sta tus, personal/family history of autoimmune disease, and tolerance for risk. lConsider RT to site of resected primary tumor in selected high-risk patients based on desmoplastic histology and/or neurotropism. See Pr inciples of Radiation (ME-H). mPathologic staging (with SLNB) is strongly recommended for stage IIB and IIC melanoma prior to consideration of adjuvant pembrolizumab —to enhance risk/benefit patient discussions and optimize local/regional disease control.

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for Melanoma: Cutaneous V2.2023. © 2023 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guideline s® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete v ersion of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Stage III workup and primary treatment

Wide excisiong,h (category 1)

Clinical trial for stage II, or observation, or Pembrolizumab for pathologically staged IIB or IIC (category 1) , or locoregional radiation therapy (category 2B)l

Treatment of Stage III Melanoma – NCCN Guidelines NCCN Guidelines Treatment Algorithm for Stage III Melanoma Stage IIIA (SLNB-positive)

▪ Consider imaging for baseline staging ▪ Imaging to evaluate specific signs or symptoms ▪ Consider BRAF mutation testing

Stage IIIB/C/D (SLNB-positive)

▪ Imaging for baseline staging and to evaluate specific signs or symptoms ▪ BRAF mutation testing

Observation without additional nodal surgery, and with mandatory radiographic nodal surveillance (preferred) or CLND

Systemic therapy

Stage III (clinically positive nodes)

▪ Core biopsy preferred or FNA if feasible. If needle biopsy is not possible, excisional biopsy is acceptable ▪ Imaging for baseline staging and to evaluate specific signs or symptoms ▪ BRAF mutation testing

Resectable

Unresectable/borderline resectable

Wide excision of primary tumor (category 1) and therapeutic lymph node dissection or neoadjuvant therapy, preferably in the context of a clinical trial

Observation Systemic therapy and/or locoregional therapy

Observation

Systemic therapy (preferred), and/or Palliative RT, and/or Intralesional T-VEC, and/or Best supportive care

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for Melanoma: Cutaneous V2.2023. © 2023 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

Cutaneous Melanoma, Selected Recommendations for Primary Disease: NCCN Guidelines Primary treatment

Subsequent treatment

Adjuvant treatment optionsl

Clinical trial for stage II, or Observation, or Pembrolizumab for pathologically staged IIB or IIC (category 1), or Locoregional radiation therapy (category 2B)q Optionsl • Systemic therapy, preferred regimens Stage IB (T1b) Wide excision (category 1) • Nivolumabm,n Discuss and consider SLN– (<0.8 mm thick with ulceration or • Pembrolizumabm,n sentinel node biopsy Wide excision (category 1) + SLNB 0.8–1.0 mm thick ± ulceration)a SLN+ • Dabrafenib/trametinib for patients with BRAF V600–activating mutationm–o • Observationl,m Wide excision (category 1) Stage IB (T2a) or II Discuss and offer SLN– (T2b or higher)b sentinel node biopsyb • Systemic therapy options,l preferred regimens Wide excision (category 1) + SLNB SLN+ • Nivolumab (category 1) • Pembrolizumab (category 1) Stage IIIA (SLN+) Observation without additional nodal surgery, and with mandatory • Dabrafenib/trametinibo for patients with BRAF V600–activating mutation (category 1) radiographic nodal surveillance (preferred), or CLND Stage IIIB/C/D (SLN+) and/or Wide excision of primary tumor (category 1) + TLNDc, or • Locoregional therapy option Stage III (clinically positive node[s]) neoadjuvant therapy, preferably in the context of a clinical triald • Consider RT to nodal basin in selected high-risk patients based on location, size, and See Initial Treatment for number of involved nodes, gross and/or histologic extracapsular extensionp (category 2B) Less than complete resection Limited resectable disease: Unresectable Disease or • Complete excision to clear marginse • Observationl NED • Intralesional T-VEC Optionsl • Systemic therapyf–h Stage III (clinical satellite/ • Systemic therapy,i preferred regimens in-transit) • Nivolumab (category 1) Unresectable disease: • Pembrolizumab • Systemic therapyf–i (preferred) Clinical • Local therapy options: • Dabrafenib/trametinib for patients with BRAF Residual/progressive unresectable disease assessment • Intralesional injection options: (T-VEC)j (category 1) or IL-2k (category 2B) V600–activating mutationo ± imaging to k Residual resectable disease • Topical imiquimod for superficial dermal lesions (category 2B) • Observation determine • Consider RT (category 2B) treatment See Initial Treatment for Limited Resectable Disease NED after local or regional therapy • Palliation of symptomatic disease: Limited excision (category 2A) or Local ablation response or therapy (category 2B) Consider adjuvant systemic therapy options listed above progression NED after systemic therapy • Regional therapy options: All recommendations are category 2A unless (category 2B), or • ILI/ILP with melphalan otherwise indicated Observation NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Observation or continue same class of systemic therapy Stage 0 in situ Stage IA (<0.8 mm thick, no ulceration)a

Wide excision (category 1 for stage IA)

NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

a If a patient’s risk of a positive SLN is <5%, NCCN does not recommend SLNB. This would include clinical stage IA, T1a melanoma ( Breslow depth of <0.8 mm nonulcerated) without other adverse features, unless there is significant uncertainty about the adequa cy of microstaging (due to positive deep margins or limited sampling of a larger lesion). If a patient’s risk of a positive SLNB is 5% –10%, NCCN

recommends discussing and considering SLNB. This would include clinical stage IB, T1b melanoma (Breslow depth <0.8 mm with ul ceration or 0.8–1 mm with or without ulceration), or T1a lesions with Breslow depth ≥0.5 mm and other adverse features (age ≤42 yea rs, head/neck location, lymphovascular invasion, and/or mitotic index ≥2/mm2), with additive increased risk when multiple adverse features are present. bMicrosatellitosis, when present in the initial biopsy or wide excision specimen, defines at least N1c and at least stage IIIB disease. Althoug h less well studied than other stage III patient populations, SLN status does have prognostic significance in patients with microsatellitosis, with a positive SLN upstaging a patient to at least N2c, stage IIIC. SLNB should be considered in patients with microsatellitosis, especially if it will alter management decisions. cIn patients with extensive resectable nodal disease at very high risk of recurrence after complete resection, or if resectability of nodal disease is uncertain, recommend multidisciplinary tumor board review to consider neoadjuvant systemic therapy prefer ably in the context of a clinical trial. For patients with unresectable nodal disease, consider treatment with systemic therapy followed by resection, or treat as stage IV. Prospective trials supporting the systemic thera py options for metastatic or unresectable disease included only a small subset of patients with stage IIII disease (unresectable ). dClinical trials have also been designed to study pathologic response after neoadjuvant treatment and its effect on RFS. At pr esent, there is no consensus regarding the recommended agents to use, duration of neoadjuvant therapy, extent of subsequent surgery, or how pathologic res ponse to neoadjuvant therapy might impact the choice of adjuvant therapy outside the context of a prospective study. eConsider sentinel node biopsy for resectable clinical satellite/in-transit disease if it will change treatment options (category 2B). fSee full guideline for recommended systemic therapy options. gFor low-volume in-transit disease, the high risk of toxicities associated with certain combination regimens may outweigh the benefi t. hProspective trials supporting systemic therapy options for metastatic or unresectable disease included only a small subset of patients wi th stage III disease. iFor patients who have previously received systemic therapy for cutaneous melanoma (either as active treatment or adjuvant therapy), selection of systemic therapy regimen should be informed by respon se to prior systemic therapies. For patients who experienced progression of melanoma during or shortly after a prior therapy, co nsider agents of a different class. For patients who experience disease control (CR, PR, or SD) on a prior systemic therapy, and have no residual toxicity, but subsequently experienced disease progression/relapse >3 months after treatment discontinuation, adjuvant treatment with t he same agent or same class of agents may be considered. jThese options have been preference stratified as "Preferred Regimens.” k These options have been preference stratified as "Useful In Certain Circumstances." lThe choice of adjuvant systemic treatment versus observation should take into consideration the patient’s risk of melanoma recurrence and the risk of treatment toxicity. mIn patients with very-low-risk stage IIIA disease (non-ulcerated primary ≤2 mm thickness, SLN metastasis <1 mm), the toxicity of a djuvant therapy may outweigh the benefit. nAdjuvant dabrafenib/trametinib and pembrolizumab are category 1 options for patients with AJCC 7th Edition stage IIIA with SLN metastasis >1 mm or stage IIIB/C disease. Adjuvant nivolumab is a category 1 option for patients with AJCC 7th Edition stage IIIB/C disease. oIn the event of unacceptable toxicities to dabrafenib/trametinib, other BRAF/MEK inhibitor combinations can be considered. pAdjuvant nodal basin RT is associated with reduced lymph node field recurrence but has shown no improvement in RFS or OS. Its benefits must be weighed against potential toxicities such as lymphedema (limb) or oropharyngeal complications. The impact of these po tential toxicities should be considered in the context of available systemic adjuvant treatment options. qFor stage IIB/IIC patients being considered for adjuvant therapy, pretreatment imaging is appropriate.

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for Melanoma: Cutaneous V2.2023. © 2023 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guideline s® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significa nt data becomes available.

Cutaneous Melanoma, Selected Recommendations for Recurrent Disease: NCCN Guidelines (1 of 2) Clinical stage

True scar recurrence (persistent disease)a

Workup

Treatment of recurrence

Adjuvant treatment

Re-excise tumor site to appropriate marginsd • Consider lymphatic mapping/SLNB according to histopathology of the scar recurrence

• Biopsy to confirmc • Workup appropriate to primary tumor characteristics

Recommendations should be based on pathologic stage of recurrencel

NED Limited resectable disease: • Complete excision to clear marginse • T-VEC/Intralesional therapy • Systemic therapyf–h

Biopsy to confirmc

Local satellite/intransit recurrenceb

• • Imaging to assess extent of disease and to evaluate specific signs or symptoms • BRAF mutation testing if not previously performedc

Less than complete resection

Unresectable disease • Systemic therapyf–i (preferred) • Local therapy options: • Intralesional injection options: • T-VECj (category 1) • IL-2k (category 2B) • Topical imiquimod for superficial dermal lesions (category 2B)k • Consider RT (category 2B) • Palliation of symptomatic disease • Limited excision • Local ablation therapy (category 2B) • Regional therapy options: • ILI/ILP with melphalan

All recommendations are category 2A unless otherwise indicated.

See Initial Treatment for Unresectable Disease

Residual/progressive unresectable disease

Clinical assessment ± imaging to determine treatment response or progression

Optionsm • Systemic therapy optionsi • Preferred regimens • Nivolumab • Pembrolizumab • Dabrafenib/trametinibn for patients with BRAF V600–activating mutation • Useful in certain circumstances • Ipilimumab if prior exposure to anti–PD-1 therapy • Observation

Residual resectable disease

See Initial Treatment for Limited Resectable Disease

NED after local or regional therapy

Consider adjuvant systemic therapy options listed above (category 2B) or Observation

NED after systemic therapy

Observation or continue same class of systemic therapy

NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

a True scar recurrence (persistent disease) at the primary tumor wide excision site is defined by the presence of in situ and/o r radial growth phase abutting the surgical scar. b Local satellite/in-transit recurrence without in situ or radial growth phase, with intralymphatic deep dermal or subcutaneous fa t recurrence within the melanoma scar or satellite

metastasis adjacent to the melanoma scar. Satellite and in-transit metastases are biologically and prognostically similar. cInitial presentation with stage IV disease or clinical recurrence should be confirmed pathologically whenever possible or if clinically indicated. Biopsy techniques may include core (preferred), FNA, incisional/partial, or excisional.

Tissue is always preferred over cytology for mutational analysis. Obtain tissue to ascertain alterations in BRAF, and in the appropriate clinical setting, KIT from either biopsy of the metastasis (preferred) or archival material if the patient is being considered for targeted therapy. Consider broader genomic profiling if the test results might guide future treatment decisions or eligibility for participation in a clinical trial. dSee full guideline for margin recommendations. eConsider sentinel node biopsy for resectable clinical satellite/in-transit disease if it will change treatment options (category 2B). fSee full guideline for list of recommended systemic therapy options. gFor low-volume in-transit disease, the high risk of toxicities associated with certain combination regimens may outweigh the benefit. hProspective trials supporting systemic therapy options for metastatic or unresectable disease included only a small subset of patients with stage III disease. iFor patients who have previously received systemic therapy for cutaneous melanoma (either as active treatment or adjuvant therapy), selection of systemic therapy regimen should be informed by response to prior systemic therapies. For patients who experienced progression of melanoma during or shortly after a prior therapy, consider agents of a d ifferent class. For patients who experience disease control (CR, PR, or SD) on a prior systemic therapy, and have no residual toxicity, but subsequently experienced disease progression/relapse >3 months after treatment di scontinuation, systemic therapy with the same agent or same class of agents may be considered. jThese options have been preference stratified as "Preferred Regimens.” kThese options have been preference stratified as "Useful In Certain Circumstances.” lSee full guideline for recommendations based on pathologic stage. mThe choice of adjuvant systemic treatment versus observation should take into consideration the patient’s risk of melanoma re currence and the risk of treatment toxicity. nIn the event of unacceptable toxicities to dabrafenib/trametinib, other BRAF/MEK inhibitor combinations could be considered.

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for Melanoma: Cutaneous V2.2023. © 2023 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guideline s® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To vie w the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available.

Cutaneous Melanoma, Selected Recommendations for Recurrent Disease: NCCN Guidelines (2 of 2) Recurrence

Workup

Treatment of recurrence

Disease limited to nodal recurrence

Nodal recurrence

• Biopsy to confirma • Imaging to assess extent of disease and to evaluate specific signs or symptoms • BRAF mutation testing if not previously performeda

Resectable

Excise recurrence and perform TLND, or neoadjuvant therapy, preferably in the context of a clinical trialc

Unresectableb

Systemic therapyd (preferred) and/or Palliative RT and/or Intralesional T-VECe and/or Best supportive care

Resectable

Excise recurrence and, if previously incomplete, perform TLND, or neoadjuvant therapy, preferably in the context of a clinical trialc

Unresectableb

Systemic therapyd (preferred) and/or Palliative RT and/or Intralesional T-VECe and/or Best supportive care

No previous LND

Previous LND

Systemic disease

Treat as distant metastatic disease

All recommendations are category 2A unless otherwise indicated.

NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Adjuvant treatment Systemic therapy optionsf,g: • Preferred regimens • Nivolumab (category 1) • Pembrolizumab (category 1) • Dabrafenib/trametinibh for patients with BRAF V600–activating mutation (category 1) • Useful in certain circumstances • Ipilimumab if prior exposure to anti–PD-1 therapy and/or Locoregional therapy option: • Consider RT to nodal basin in selected high-risk patients based on location, size, and number of involved nodes, gross and/or histologic extracapsular extensioni (category 2B) or • Observationf Systemic therapy optionsf,g: • Preferred regimens • Nivolumab (category 1) • Pembrolizumab (category 1) • Dabrafenib/trametinibh for patients with BRAF V600–activating mutation (category 1) • Useful in certain circumstances • Ipilimumab if prior exposure to anti–PD-1 therapy • Clinical trial, if applicable and/or Locoregional therapy option: • Consider RT to nodal basin in selected high-risk patients based on location, size, and number of involved nodes, gross and/or histologic extracapsular extensioni (category 2B) or • Observationf

a Initial presentation with stage IV disease or clinical recurrence should be confirmed pathologically whenever possible or if clinically indicated. Biopsy techniques may include core (preferred), FNA, incisional/partial, or excisional. Tissue is always p referred over cytology for mutational analysis. Obtain tissue to ascertain alterations in BRAF, and in the

appropriate clinical setting, KIT from either biopsy of the metastasis (preferred) or archival material if the patient is being considered for targeted therapy. Consider broader genomic profiling if the test results might guide future treatment decisions or eligibility for participatio n in a clinical trial. bDisease is defined as technically unresectable (ie, involvement of a major neurovascular structure) or clinically unresectable (ie, remote nodal disease), where surgery alone wo uld have minimal clinical benefit. cClinical trials have also been designed to study pathologic response after neoadjuvant treatment and its effect on relapse -free survival. At present, there is no consensus regarding the recommended agents to use, duration of neoadjuvant therapy, extent of subsequent surgery, or how pathologic response to neoad juvant therapy might impact the choice of adjuvant therapy outside the context of a prospective study. dSee full guideline for list of recommended systemic therapy options. eThese options have been preference stratified as "Useful in Certain Circumstances.” fThe choice of adjuvant systemic treatment versus observation should take into consideration the patient’s risk of melanoma re currence and the risk of treatment toxicity. gFor patients who have previously received systemic therapy for cutaneous melanoma (either as active treatment or adjuvant the rapy), selection of adjuvant treatment regimen should be informed by response to prior systemic therapies. For patients who experienced progressi on of melanoma during or shortly after a prior therapy, consider adjuvant agents of a different class. For patients who experien ce disease control (CR, PR, or SD) on a prior systemic therapy, and have no residual toxicity, but subsequently experienced disease progression/relapse >3 months after treatment discontinuation, adjuvant treatment with the s ame agent or same class of agents may be considered. hOther BRAF/MEK inhibitor combinations can be considered in the event of unacceptable toxicities to dabrafenib/trametinib or b ased on side effect profiles. iAdjuvant nodal basin RT is associated with reduced lymph node field recurrence but has shown no improvement in RFS or OS. Its benefits must be weighed against potential toxicities such as lymphedema (limb) or oropharyngeal complications. The impact of these pote ntial toxicities should be considered in the context of available systemic adjuvant treatment options.

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for Melanoma: Cutaneous V2.2023. © 2023 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guideline s® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To vie w the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available.

Cutaneous Melanoma: Principle of Surgical Margins for Wide Excision Principles of Surgical Margins for Wide Excision of Primary Melanoma Tumor Thickness

Recommended Peripheral Surgical Marginsb

In situa

0.5–1 cm

≤1.0 mm

1 cm (category 1)

>1.0–2.0 mm

1–2 cm (category 1)

>2.0–4.0 mm

2 cm (category 1)

>4.0 mm

2 cm (category 1)

• There are no randomized trials to inform peripheral surgical margins or depth of wide excision for MIS. Depth of excision into the subcutaneous fat may be adequate and considered in anatomic locations where excision to fascia would cause significant morbidity • For invasive melanoma, wide excision involves removal of all tissue to the level of the fascia, which is typically preserved unless involved by tumor. Peripheral resection margins may be modified to accommodate individual anatomic or functional considerations. However, the safety and efficacy of narrower surgical margins have not been prospectively studied in a randomized controlled manner. Narrower than recommended margins may increase the risk for margin positivity and/or local recurrence • The gold standard for histologic assessment of excised melanoma is use of permanent sections. If MMS is performed, permanent section analysis of the central debulking specimen is strongly recommended to provide complete staging information. Consider delay of complex reconstruction or wound closure until histologic margin assessment is complete • MMS is not recommended for primary treatment of invasive cutaneous melanoma when standard clinical margins can be obtained. It may be considered selectively for minimally invasive (T1a) melanomas in anatomically constrained areas (ie, face, ears, acral sites), along with other surgical methods that provide comprehensive histologic assessment, such as staged excision with permanent sections for dermatopathology reviewa • With respect to disease-related outcomes, there have been no prospective comparisons of different excision methods, including conventional wide excision, MMS, and staged excision with permanent sections. All randomized controlled trials of resection margins for invasive cutaneous melanoma were performed using standard wide excision technique. Of note, few included head/neck melanomas and none included acral melanomas • In the setting of an adequate biopsy, digit-sparing surgery may be an option for subungual MIS and select thin tumors (<0.8 mm), although further investigation is needed All recommendations are category 2A unless otherwise indicated. aFor large and/or poorly defined MIS, LM or acral lentiginous subtypes, or LM melanoma with a minimally invasive (T1a) component (also referred to as high -cumulative sun damage [CSD] melanoma), surgical margins >0.5 cm may be necessary, and techniques for comprehensive histologic

assessment of margins (ie, complete circumferential peripheral and deep margin assessment) should be considered. If MMS is pe rformed, use of frozen section melanocytic IHC stains may assist in accurate interpretation of histologic margins and has been a ssociated with lower local recurrence rates. For selected patients with positive margins after surgery, in whom further resection is not feasible or des irable, consider topical imiquimod (for patients with MIS/LM type) or RT. bExcision recommendations are based on measured clinical margins taken at the time of surgery and not gross or histologic margins, as measured by the pathologist (category 1). However, narrower peripheral histologic mar gins have been associated with higher rates of local recurrence for invasive melanoma, though not worse melanoma -specific survival. Narrow pathologic margins, particularly of the invasive component, may warrant further surgical resection. Adapted with permission from the NCCN Clinica l Practice Guidelines in Oncology (NCCN Guidelines ®) for Melanoma: Cutaneous V2.2023. © 2023 National Comprehensive Cancer Network, Inc. All rights reserved.

The NCCN Guidelines ® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in pro gress that may be refined as often as new significant data becomes available.

Cutaneous Melanoma, Recommendations for Distant Metastatic Disease: NCCN Guidelines Treatment

Workup

Distant metastatic disease (stage IV)

▪ Biopsy to confirma ▪ LDH ▪ Imaging for baseline staging and to evaluate specific signs and symptoms ▪ BRAF mutation testing if not previously performed on a metastatic lesiona

Multidisciplinary consultation

Oligometastatic

Widely disseminated

Metastasis-directed therapy ▪ Resection ▪ Stereotactic ablative therapy ▪ T-VEC/Intralesional therapy (for accessible lesions) Systemic therapy (See options on next slide)

Imaging to assess response or progression

NED

Residual disease

Treat as distant metastatic disease (See below) NED

Negative for other disease

Resect Residual disease

Positive for other disease

Treat as widely disseminated pathway (See below)

Without brain metastases With brain metastases

Multidisciplinary consultation

Adjuvant treatment optionsb ▪ Systemic therapy optionsc • Preferred regimens Nivolumab (category 1) Pembrolizumabd(category 1) Nivolumab/ipilimumab • Other recommended regimens – For patients with BRAF V600-activating mutation • Dabrafenib/trametinib (category 2B) • Vemurafenib/cobimetinib (category 2B) • Encorafenib/binimetinib (category 2B) • Useful in certain circumstances – Ipilimumab if prior exposure to anti–PD-1 agentse ▪ Observation Options include: ▪ Systemic therapy (preferred) (See options on next slide) ▪ For extracranial lesions: intralesional T-VECf,g ▪ Consider palliative resection and/or RT for symptomatic extracranial disease ▪ Best supportive/palliative care

All recommendations are category 2A unless otherwise indicated.

NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. a Initial presentation with stage IV disease or clinical recurrence should be confirmed pathologically whenever possible or if clinically indicated. Biopsy techniques may include core (preferred), FNA, incisional/partial, or excisional. Tissue is always p referred over cytology for mutational analysis. Obtain tissue to ascertain

alterations in BRAF, and in the appropriate clinical setting, KIT from either biopsy of the metastasis (preferred) or archival material if the patient is being considered for targeted therapy. Consider broader genomic profiling if the test results might guide future treatment decisions or eligibility for participation in a clinical trial. bThe choice of adjuvant systemic treatment versus observation should take into consideration the patient’s risk of melanoma re currence and the risk of treatment toxicity. See Systemic Therapy Considerations. cFor patients who have previously received systemic therapy for cutaneous melanoma (either as active treatment or adjuvant therapy), selection of adjuvant treatment regimen should be informed by response to prior systemic ther apies. For patients who experienced progression of melanoma during or shortly after a prior therapy, consider adjuvant agents of a different class. For patients who experience disease control (CR, PR, or SD) on a prior systemic therapy, and have no residual toxicity, but subsequently experienced disease progression/ relapse >3 months after treatment discontinuation, adjuvant treatment with the same agent or same class of agents may be conside red. dAlthough patients with resected stage IV disease were not included in the phase III prospective randomized trial testing adjuvant pembrolizumab, it is included as an option here b ecause all available evidence suggests that pembrolizumab and nivolumab have highly similar efficacy and safety in patients with melanoma. eIpilimumab is included as an adjuvant treatment option for patients with resected stage IV disease who have prior exposure to anti–PD-1 agents based on extrapolation of data demonstrating its efficacy as adjuvant treatment for resected stage III disease and demonstrated efficacy for unresectable stag e IV disease. fThese options have been preference stratified as "Useful In Certain Circumstances." gT-VEC has shown a response rate (lasting ≥6 months) of 16% in highly selected patients with AJCC 7th Edition stage IV –M1a disease (skin, subcutaneous, and/or remote nodes).

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for Melanoma: Cutaneous V3.2022. © 2022 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines ® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To vie w the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available.

Cutaneous Melanoma, Recommendations for Distant Metastatic Disease: NCCN Guidelines (continued) Systemic Therapy Options for Metastatic or Unresectable Disease First-line Systemic Therapya

Second-line or Subsequent Therapyb

Preferred regimens ➢ Combination checkpoint blockade (preffered) ◊ Nivolumab/ipilimumab (category 1)e,f,g,h ◊ Nivolumab and relatlimab-rmbw ➢ Anti PD-1 monotherapy ◊ Pembrolizumab (category 1) ◊ Nivolumab (category 1) Other recommended regimens ➢ Combination targeted therapy if BRAF V600-activating mutationj,k,l,m,n ◊ Dabrafenib/trametinib (category 1) ◊ Vemurafenib/cobimetinib (category 1) ◊ Encorafenib/binimetinib (category 1) ➢ Pembrolizumab/low-dose ipilimumab (category 2B)

Preferred regimens ▪ Anti–PD-1 monotherapyc,d • Pembrolizumab Disease • Nivolumab progression, ▪ Nivolumab/ipilimumabc,d,e intolerance, ▪ Nivolumab and relatlimab-rmbwq and/or ▪ Pembrolizumab/low-dose ipilimumab for tumors that have progressed after prior anti–PD-1 therapyc,d projected risk ▪ Combination targeted therapy if BRAF V600–activating mutationg,h,i of progression • Dabrafenib/trametinib with • Vemurafenib/cobimetinib BRAF-targeted • Encorafenib/binimetinib therapy Other regimens ▪ Ipilimumabc ▪ High-dose IL-2l Useful in certain circumstances* ◊ For activating mutations of KIT- KIT inhibitor therapy (eg, imatinib, dasatinib, nilotinib, ripretinib) ◊ For ROS1 fusions- Crizotinib, entrectinib ◊ For NTRK fusions– Larotrectinib, entrectinib All recommendations are category 2A unless otherwise indicated. ◊ For BRAF fusions and non-V600 mutationss0– Trametinib NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims ◊ For NRAS-mutated tumors (for progression following immune checkpoint inhibitor therapy)– Binimetinibt (category 2B) any responsibility for their application or use in any way. ◊ Combination therapy– Pembrolizumab/Lenvatinib, Ipilimumabe/intralesional T-VEC (category 2B) NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. ◊ Combination BRAF/MEK + PD(L)-1 checkpoint inhibitors (eg, dabrafenib/trametinib + pembrolizumab or vemurafenib/cobimetinib + atezolizumab) ◊ Cytotoxic agentsv The choice of a treatment is based on evaluation of the individual patient. For patients who experience progression of melanoma during or shortly after first-line therapy, consider second-line agents if not used first line and if from a different class. For patients who progressed on single -agent anti–PD-1 checkpoint immunotherapy, anti–PD-1/ipilimumab combination therapy or ipilimumab Consider best supportive care for poor performance monotherapy is a reasonable treatment option. For patients who experience disease control (CR, PR, or SD) and have no residua l toxicity, but subsequently experience disease progression/relapse >3 months after treatment discontinuation, re -induction with the same agent or same status class of agents may be considered. See NCCN Guidelines for Management of Immunotherapy-Related Toxicities for a

b

c

proactive monitoring and management of toxicities in patients undergoing treatment with immune checkpoint inhibitors. dTesting for tumor PD-L1 should not guide clinical decision-making. The utility of this biomarker requires further investigation. eNivolumab/ipilimumab combination therapy is associated with improved overall response rate (ORR), progression -free survival (PFS), and OS compared with single-agent ipilimumab, at the expense of significantly increased toxicity. Compared to nivolumab, the impact of nivolumab /ipilimumab combination therapy on OS is not known. The phase III trial of nivolumab/ipilimumab or nivolumab monotherapy vers us ipilimumab monotherapy was conducted in previously untreated patients with unresectable stage III or IV melanoma. Relative in dications for combination nivolumab/ipilimumab in comparison to PD-1 monotherapy include: patient willingness to take on high risk of treatment-related toxicities (immune-related adverse events [irAEs]); absence of comorbidities or autoimmune processes that would elevat e the risk of irAEs; and patient social support and anticipated compliance with medical team to handle toxicities. fPositive VE1 IHC results are sufficient for starting targeted therapy in patients who are symptomatic or have rapidly progressing disease. Confirmatory BRAF molecular testing is encouraged. gSee Management of Toxicities Associated with Targeted Therapy. hIn previously untreated patients with unresectable AJCC 7th Edition stage IIIC or stage IV disease, BRAF/MEK inhibitor combin ation therapy was associated with improved response rate, PFS, and OS compared to BRAF inhibitor monotherapy. iIf BRAF/MEK inhibitor combination therapy is contraindicated, BRAF inhibitor monotherapy is an option, especially in patients who are not appropriate candidates for checkpoint immunotherapy. jDosing used in KN-029: Pembrolizumab 2 mg/kg IV plus ipilimumab 1 mg/kg IV every 3 weeks (Q3W) for four doses, followed by pembrolizumab 2 mg/kg Q3W for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investiga tor decision. kIn a randomized, double-blind, placebo-controlled, phase 3 trial, the addition of atezolizumab to vemurafenib and cobimetinib wa s associated with longer median PFS and longer duration of response; however, the triplet induced more toxicity than the vemurafenib/cobimetinib doublet. Until mature OS data are published, it is not clear that the triplet regimen is preferred ov er sequential BRAF/MEK inhibitor therapy followed by PD-L1 or PD-1 inhibition. lHigh-dose IL-2 should not be used for patients with inadequate organ reserve, poor performance status, or untreated or active br ain metastases. For patients with small brain metastases and without significant peritumoral edema, IL-2 therapy may be considered (category 2B). Therapy should be restricted to an institution with medical staff experienced in the administration and management of these regimens. mIn patients who were previously untreated or had prior failure of immunotherapy, binimetinib was associated with a response r ate of 15%, and demonstrated a modest improvement in PFS with no improvement in OS compared with single-agent dacarbazine. nFor cytotoxic therapy recommendations, see Other Systemic Therapies. oFor patients with confirmed progression or unresectable or metastatic melanoma after treatment with an anti –PD-1–/PD-L1–based therapy, including in combination with anti–CTLA-4 for ≥2 doses.

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for Melanoma: Cutaneous V2..2023. © 2022 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines ® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guid elines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data b ecomes available. **Some of the drug listed are not yet EMA approved. Data presented here are for purpose of scientific exchange.MSD does not recommend the use of its medication outside of their licensed indications listed, please refer to SmPC for full pres cribing information.

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ANAMNEZA ▪ Pacient V.M., sex M, 47 ani ▪ AHC nesemnificative ▪ APP nesemnificative

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ISTORIC • Debut: – Septembrie 2020:

adenopatie axilara stanga 2,5/3 cm.

▪ Octombrie 2020 – Consult chirurgical

• biopsie ADP axilara stanga.

-- ADP laterocervicale, supraclaviculare si axilare stangi.

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Diagnostic HP • HP: Metastaza ganglionara de melanom malign.

Mutatia BRAF V600E prezenta

23

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Evaluare imagistica • Noiembrie 2020: – PET-CT: Blocuri ADP hipermetabolice, unele partial necrozate, cu urmatoarele localizari: • Nivel III cervical profund stang 72/24mm; • Nivel IV cervical profund stang 32/50mm; • Subclavicular stang 15/12mm; • Interpectoral stang 27/26mm; • Axilar stang 50/68/99mm;

24

PET CT

Poze arhiva personala

PET CT

Poze arhiva personala

26

PET CT

Poze arhiva personala

27

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Evaluare preterapeutica HLG – anemie grad I; TGO – 25U/L, TGP – 40U/L; Glicemie = 88 mg/dl.

Creatinina = 0.79 mg/dl; Uree = 31mg/dl.

Ionograma serica: in limite normale.

LDH= 330 UI/l Consult cardiologic, urologic, dermatologic, ORL- N

28

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Diagnostic final

• •

Metastaze ganglionare multiple de melanom malign (Tx) Mutatia BRAF V600E prezenta

•

DECIZIE TERAPEUTICA TAFINLAR (Dabrafenib) 300 mg/zi + MEKINIST (Trametinib) 2 mg/zi

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Evolutia leziunilor tumorale sub tratament CT torace, abdomen, pelvis •

15.11.2020 Leziuni tinta:

Bloc ADP axilar stang 50/68/99mm

27.02.2021

29.05.2022

→ multiple ADP 30/33/54mm →

Bloc ADP lcv III 72/24mm; IV 32/50mm → 41/16mm, 9/26mm→

ADP 18/21mm

16/8mm,9/12mm

• Leziuni non-tinta: NU • Leziuni noi: NU • Evaluarile imagistice ulterioare- aspect stationar.

12

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Evolutia leziunilor tumorale sub Dabrafenib+Trametinib PET-CT nov. 2020

Poze arhiva personala

CT feb. 2021

CT mai 2022

13

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30 luni de tratament cu TAFINLAR + MEKINIST pana in prezent • Noiembrie 2020: Debut Dabrafenib+Trametinib toxicitate hepatica-valori transaminaze x 2LSN- remisa prin administrare de hepatoprotectoare, fara reducerea dozei

frison - in cursul primei luni de tratament, nu a necesitat intreruperea tratamentului sau reducerea dozei -

RASPUNS PARTIAL LA TRATAMENT

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Caz clinic ▪ Pacienta P.A in varsta de 67 ani, mediul rural ▪ AHC nesemnificative

▪ APP: HTA gr III, DZ tip 2, Leucemie limfatica cronica ▪ FEB 2021: dureri abdominale, tranzit intestinal incetinit.

Biologic – anemie gr III

Examen clinic

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Evaluare imagistica ▪ APR 2021 Evaluare imagistica: CT torace, abdomen, pelvis- noduli pulmonari bilaterali, cei mai mari de 15/17

mm, suspecti de determinari secundare, ADP mediastinale. La nivel hepatic 3 noduli hippoecogeni, cel mai mare in segm VII 28 mm. Ingrosare parietala circumferentiala ansa ileala, cu localizare in hipogastru, supravezical, dilatarea ansei masoara 11mm si prezinta nivel hidro-aeric

▪ MAI 2021 S-a intervenit chirurgical si s-a practicat enterectomie segmentara cu entero-enteroanastomoza laterolaterala

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▪ Leziuni non-tinta: stationar ▪ Leziuni noi - fara leziuni noi aparute -

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19 luni de IMUNOTERAPIE cu Nivolumab+Ipilimumab→Nivolumab linia 1

▪ IULIE 2021 Debut Nivolumab + Ipilimumab -Data reactii adverse raportate – fara reactii adverse

→ BENEFICIU CLINIC – ECOG 1 - 20 OCT 2021 CT → scaderea in dimensiuni a leziunilor tinta

→ RASPUNS PARTIAL - MARTIE 2022- METASTAZA CEREBRALA – s-a efectuat radioterapie stereotactica Si avand invedere raspunsul partial mentinut – DECIZIE : CONTINUARE NIVOLUMAB

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VA MULTUMESC! O prezentare la a VII-a editie a conferintei nationale Melanom Romania, 2023