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Flashcards in Melanoma Deck (43)
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1

Incidence of melanoma

11% of all new cancers diagnosed 2019

majority early stage; can be cured by surgery

3rd most common cancer

91% surviving at least 5 years

but the years of productive life lost to melanoma exceed those of all other solid tumors.

2

Risk factors for melanoma

 

  • high intermittent unprotected sun exposure eg. Blistering sunburns as a child
  • Fairskin, light eye colour, light hair, tendency to burn
  • presence of >10 dysplastic naevi
  • presence of over 100 common acquired naevi
  • fair skin, red hair  
  • Immunosuppression
  • Family History

3

Factors that determine prognostication of melanoma

 

  • Tumour Thickness
    • Higher rate of recurrence and death
    • Higher likelihood of microscopic involvement of regional lymphnodes
  • Mitotic Rate
    • Independent predictor of prognosis
    • Second most important predictor after thickness of tumour
  • Ulceration
  • Primary Tumour Location
  • Older Age and Male Sex
  • Lymph Nodes
    • One regional node -> 40-50% chance of systemic recurrence
    • More than one regional LN -> 75% changes of systemicrecurrence

4

Mx of melanoma based on staging

  • Stage 0 = surgical resection
  • Stage 1 = surgical resection, consider sentinel LN biopsy if >1mm or if >0.75mm + high risk features
  • Stage 2 = surgical resection, sentinal LN Bx, consider adjuvant RTx +/- systemic Tx
    • if sentinal LN bx positive -> becomes stage 3. Immediate completoin lymph node dissection a/w increased morbidity (lymphedema) without mortality benefits.
    • Strict monitoring (Q3/12 USS) and can perform node dissection if radiological or clinical progresiosn. 
  • Stage 3 = surgical resection, nodal dissection. consider adjuvant RTx +/- systemic Tx 
    • Surgery
      • Clinical/Radiological lymph Nodes ->  Lymphadenectomy
      • Sentinel Lymph Node Biopsy Positive (occult Lymph nodes) -> Observation with strict imaging protocol
  • Stage 3A – observation
  • Stage 3B/3C/3D/Resected Stage 4 (oligometastatic disease): Adjuvant Therapies
    • Dabrafenib & Trametinib for BRAF mutant (BRAF and MEL inhibition) for 12 months
      • Oral more convenient
      • OS benefit
    • Anti‐PD1 for all patients (regardless of PD1 or BRAF status)
      • Nivolumab q4w or Pembrolizumab q3w or q6W for 12 months
      • 54% Grade 3 or 4 adverse events
      • 10% improvement in overall survival HR 0.72
      • Long term immune related adverse events
      • nivolumab + pembrolizumab results pending for stage 3
  • Stage 4: metastatic melanoma
    • common sites: skin, lungs, liver, brain and bone
    • late relapses do occur >5 years
    • Only curative option is surgical resection of (oligo)metastasis if feasible
    • test for BRAF & cKIT mutations
    • cKIT mutation: mx with imatinib
    • Stable disease/slowly advancing disease
      1. Targeted therapy if mutation positive
      2. Anti-PD1: Pembroluzimab or Nivolumab
      3. Ipilumumab
    • Rapidly advancing disease
      1. Targeted therapy if mutation positive or Ipilumumab + Nivolumab (CNS disease. superior longterm survival, treatment free, no loss of QOL) 
      2. mutation wildtype: Pembroluzimab or Nivolumab if LDH Normal OR Ipilumumab + Nivolumab if LDH High
      3. Ipilumumab
      4. DTIC
      5. Fotemustine ( 1st line if cerebral mets present)
      6. Conservative (poor performance status).

5

Describe staging of melanoma

Stage 0 = melanoma in situ. within teh cells of the top layer of the skin, not invading the dermis

Stage 1 = <2mm + no ulceration. <1mm + ulceration

Stage 2 = >1mm + ulceration. >2mm + no ulceration

Stage 3 = LN involvement 

6

Mx of advanced melanoma

 

Historically:

  • median survival time 6.2 months. 
  • alive at 1 year 25.5%
  • median PFS 1.7 months 
  • Very pooroutcome
  • No significant impact from any treatment opitions including
    • Chemotherapy
    • IL-2
    • Inteferon Alpha

 

Now targeting molecular mutations e.g. BRAF & MEK inhibitor combination as first line in BRAF mutated melanoma 

7

Describe mutations in melanoma

 

can be defined both by pathology AND molecular changes

  • Subsets of Melanoma (and all cancers) can be defined at the molecular level by recurrent driver mutations that can occur within oncogenes -> constitutional activation of mutant signaling pathways -> induced and sustain tumorigenesis
  • Mutations within BRAF, GNA11, GNAQ, KIT, MEK, NRAS, CTNNB1 canbe found in approximately 70% of melanoma, the distribution of each varies depending on the site of the primary
    • BRAF: a/w intermittent sun exposure
    • cKIT: a/w acral & mucosal subtypes. good response to imatinib 

 

The most clinically relevant mutation is BRAF in melanoma. 

8

The most clinically relevant mutation in melanoma

BRAF

9

Describe BRAF mutation in melanoma

- which specific mutation 

- percentage of melanoma harbouring BRAF mutation

- ?more common in which age

- ?more common in chronic sun damage

 

V600E and V600K

40% of Melanoma harbour a BRAF Mutation

  • More common in melanomas arising in skin with little chronic sun-induced damage
  • Less frequent in chronic sun damage
  • More common in younger patients
  • More than 60 mutations have been mapped
    • 80%:V600E
    • 5-30%:V600K

Activation of the MEK & ERK pathway 

 

10

Describe BRAF inhibitors in melanoma

 

  • e.g. Vemurafenib
    • Selective V600E mutations
    • No activity CNS
  • e.g. Dabrafenib
    • Inhibits all V600 mutations
    • Activity CNS
  • e.g. Encorafenib
    • Inhibits all V600 mutations
    • Activity CNS
  • BRAF inhibitors attach to the mutant BRAF V600 which is constitutionally active in melanoma cells harbouring a BRAF mutation -> inhibits downstream activation of MEK/ERK -> ceased uncontrolled activation of cell proliferation, survival & migration
  • Specific to cells that have the mutant BRAF
  • Rapid response (70%) to drug within days, Immediate Metabolic Shutdownn, High levels of response 
  • superior progression free survival and overall survival compared to standard chemotherapy 
  • SE:
    • arthralgia, rash, photosensitivity, fatigue
    • skin toxicity, squamous cell carcinoma (23% - but eliminated when used with MEK inhibitor), Keratoacanthoma like -> needs excision
    • pyrexia (40-41 degrees) +/- flu like symptoms -> stop drug then improves within 48h
  • however >80% develop resistance most commonly via the MAPK reactivation through MEK -> MEK & BRAF inhibition  prevents the development of acquired resistance in preclinical models 
    • e.g. dabrafenib + trametinib
    • vemurafenib + cobimetinib

11

Describe BRAF & MEK inhibitor combination

  • to reduce resistance to BRAF inhibitors (bold below)
  • e.g. 
    • Dabrafenib  + Trametinib (inhibits all V600 mutations, activity in CNS)
    • encorafenib + binimetinib (less pyrexia, all V600 mutations, activity in CNS)
    • Vemurafenib + Cobimetinib (inhibits V600E mutation only, no activity in CNS)

 

  • MEK inhibitor to overcome resistance to BRAF Inhibitor which occurs in almost all patients
  • MEK inhibition works downstream in the MAPK pathway -> lengthen the period of time between onset of treatment response and onset of resistance -> prolongs the PFS and OS
  • SE: 
    • Fever: frequent, drenching sweats, tachycardia (much higher with Dabrafenib)
    • Photosensitivity: Much higher with Vemurafenib and Cobimetinib. Treatment needs to be tailored to patient (fevers v. photosensitivity) 
    • Rash, Pruritus
  • has a better safety profile than BRAF inhibitor alone due to a decrease in the paradoxical activation of the MAPK pathway
  • CURRENTLY FIRST LINE TREATMENT IN AUSTRALIA FOR BRAF MUTATED MELANOMA 

12

Describe immunotherapy/immune checkpoint inhibitors

- types

- mechanism of action

- SE

1. Anti-PD1: e.g. Pembrolizumab, Nivolumab

  • PD: programmed death 
  • In contrast to CTLA‐4 ligands (CD80 and CD 86), PD‐L1 is selectively expressed on many tumors and on cells within the tumor microenvironment in response to inflammatory stimuli.
  • PD‐L1: primary PD‐1 ligand that is up‐regulated in solid tumors -> downregulation of Tcell effector functions that destroy tumor tissue -> tumour cells survive
  • Blockade of the interaction between PD‐1 and PD‐L1 -> prevents T cell downregulation -> kills tumour cells 

 

2. Anti-CTLA4: e.g. Ipilimumab

  • CTLA‐4, a T cell receptor, is a naturally occurring negative regulator of the immune system. expressed on activated helper T cells and CTLs. inhibits T cell activation and proliferation. 
  • Binding of B7 (higher affinity than CD-28) to CTLA-4 instead of CD-28 prevents co-stimulatory signalling -> induces an inhibitory effect on T-cell activation and proliferation -> unable to kill cancer cell
  • use of CTLA-4 inhibitor -> boosts T cell function -> immune system kills cancer cells 

 

SE: immune-related adverse events (IRAEs), which are inflammatory in nature and may represent a breaking of tolerance to self-antigens

  • e.g. Rash, Colitis, arthritis, Hepatitis, Hypo/hyperthyroidism, pneumonistis
  • a/w tumour regression in pts with RCC and metastatic melanoma & with prolonged time to relapse in those with resected high risk melanoma.
  • variable timing of onset 
  • can be prolonged for weeks after cessation of ipilimumab.
  • Grade III/IV IRAEs generally reversible & most treated with standard anti‐inflammatory therapies i.e. Corticosteroids +/- mycophenalate, TNF blockade 
  • slow weaning of steroids due to high risk of rebound

13

Describe roles of T cells in cancer

 

  • Individual human tumours harbour a multitude of somatic mutations and epigenetically dysregulated genes -> potentially recognisable as foreign antigens on surface of cancer cells by APC & presented to the T cells for destruction 
  • immune system and “growing” cancers develop tolerance, so that paradoxically foreign molecules expressed by tumour cells are viewed as self & not destroyed. 

14

Describe immune response to tumours

1. Elimination 

  • Immune cells able to destroy all cancer cells.

2. Equilibrium

  • Immune cells become unable to eliminate all cancer cells, but may be able to prevent expansion and metastasis: i.e. static phase called equilibrium. Selection occurs for cancer cells with higher ability to metastasise 

3. Escape

  • over time, dynamic interaction between tumour and immune system -> selection for tumour cells which can escape the immune system -> clinically detectable tumours 

15

Describe tumour evasion of the immune system

 

  • Evading Immune Elimination
  • Loss of antigenicity
    • Acquisition of defects in antigen processing and presentation
    • Loss of immunogenic tumour antigens -> loss of proteins of cell surface to create peptide-MHC complex
  • Gain of immunosuppressive properties
    • Increased expression of PD-LA
    • Secretion of suppressive cytokines (ie. IL-10, TGFB)
  • Creating an immunosuppressive environment
    •  Recruiting immunosuppressive leukocytes 

16

Describe anti-CTLA4 inhibitors in melanoma

- physiology of CTLA-4 in T cells 

- mechanism of action of anti-CTLA4 inhibitors

- clinical significance

- SE

Usual physiology: 

  • Tumour Cells have foreign antigen/peptide on their surface -> presented by antigen presenting cells (APC) as MHC/antigen complex -> binds to T cell receptor (TCR)
  • Signals from the TCR are then amplified by co-stimulatory molecules (CD28/B7) -> T cell proliferations and differentiation -> destroys & lysis tumour cells 
  • Following activation of the T cell; Cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4) is up regulated in the T cell, with a much higher affinity for B7 (cf CD28) -> within 48 hours, CTLA4 binds to B7 molecule on the APC surface -> inhibitory signals to the T cells to decrease activity against tumour cells -> tumour cells live 

anti-CTLA4 inhibitor (ipilimumab):

  • a monoclonal antibody (given IV x 4 doses, 3 weeks apart, 3mg/kg)
  • binds to CTLA-4 when it is expressed on the surface of the T cell -> CTLA-4 now unable to bind with B7 -> B7 binds with CD28 for ongoing co-stimulation of the T cell (rather than downregulation) -> T cells continues to lysis tumour cells & have further immune activation 

Anti CTLA4 provides superior overall survival benefit compared to Chemotherapy. Lower rates of overall survival and response rate compared with Anti-PD1 agents and combination therapy 

SE: Grade 3-4 Immune Related Adverse Events *(CHECKMATE 067): 19.6% (11% GI related) 

17

Describe effects of ipilimumab in melanoma

  • Improvement in Overall Survival by <4 months
  • Improvement in long term (2 year) survival of 10%
  • Gp 100 vaccine- appeared to have no benefit 
  • Adding Ipilimumab to Dacarbazine (chemotherapy) improved the response rate, even at 2 years
  • has the potential for LONG TERM RESPONSE (?CURE); 10 year follow up data shows ongoing survivors from metastatic melanoma at 20%

18

Describe PD-1 inhibitors in melanoma

- usual physiology of PD-1 & PD-L1

- mechanism of action of PD-1 inhibitors

- examples

- clinical significance 

e.g. Pembrolizumab, Nivolumab

Usual physiology: 

  • PD-1 is a surface co-inhibitory receptor expressed on T cells, B cells, and NK following activation
  • has two ligands: PD-L1 and PD-L2, binding to these ligands -> inhibits T cell receptor signaling and downregulates immune response
  • Promotes tolerance and prevents tissue damage in the setting of chronic inflammation, promote peripheral tolerance and balance
  • Many solid tumours express or over express PD ligand 1 (PD-L1)

Anti-PD1 therapy: 

  • Cancer cells can upregulate the amount of PD-L1 expressed on the surface of the cell -> downregulation of the T cell activity using the negative feedback of PD1-PDL1 binding
  • Anti-PD1 Antibodies attach to PD-1 on T cells -> PD-1 now unable to bind with PD-L1 -> no downregulation of T cells & stimulates ongoing immune response -> kills tumour cells 
  • Given regularly on an ongoing basis
  • ( different compounds given on different dosing schedules, either mg/kg or flat dosing)
  • Length of treatment not established, possibly 2 years

High rates of response to Anti- PD1 therapy, > 50% (much higher than Ipilimumab, and chemotherapy). >30% overall survival at 1 year c.f. dacarbazine chemo. good longterm response. Rapid decrease in tumour bulk 

  • Nivolumab has shown improvement in recurrence free survival with less toxicity compared Ipilimumab. No overall survival benefit reported as yet 
    • Grade 3 or 4 SE: <10% (c.f. >50% in ipilimumab)
    • favours nivolumab regardless of PD-L1 status and BRAF status
    • high tumour mutation burden and tumour IFN-gamma expression levelscorrelate with improved recurrence free survival with both nivolumab and ipilimumab

19

Describe PD-1 inhibitors in cancers in general

Efficacy in (among others) melanoma, Lung (PBS listed for 2nd line treatment in metastatic NSCLC from August 1st), Renal (PBS listed), Bladder (PBS listed), Skin Cancer: Merkel, Squamous, H +N,  Hodgkins’ Lymphoma, Mismatch Repair Gene Defects in multiple cancer types 

 

Examples include, Pembrolizumab, Nivolumab, Atezolizumab, Durvalumab, Avelumab, Celipimab

20

Describe Anti-PD1 and Anti-CTLA4 Combination therapy in melanoma

- rationale

- regime

- clinical significance

- SE

e.g. Ipilimumab + Nivolumab

  • Dual blockade of Checkpoints Inhibitors
  • CTLA4 and PD-1 inhibit antitumour immunity through complementary and non-redundant mechanisms to downregulate the immune response.
  • synergistic improvement in antitumor responses.
  • Dual Blockade for 3 months, followed by up to 2years of Anti-PD1t herapy
  • Rapid Response to Treatment, Significant decrease in tumour bulk 

  • Anti CTLA4 + Anti PD1 provides superior overall survival benefit compared to Ipilimumab, and likely also to Nivolumab Anti-PD1

  • SE: Grade 3-4 Immune Related Adverse Events *(CHECKMATE 067): 44% 

21

Describe immunotoxicity/ specific immune related adverse effects

- mechanism

- areas involved

- timeline of sx 

Mechanism

  • Normal role of the the checkpoints PD-1 and CTLA-4 is to retain balance between activity and quiescence in the immune system.
  • By blocking these checkpoints with Anti-PD1 and Anti-CTLA4 -> unopposed immune activation and T-cell dysregulation ->  inflammation and tissue damage
  • Can occur to ANY tissue in the body, indiscriminate in nature 
  • Can involve Skin, GI tract, Liver, Endocrine (Thyroid, Adrenal Pituitary), Lung 

  • Onset of Symptoms varies, peak time in first 3 months

  • Depends on immunotherapy used, underlying immune related disease, underlying cancer diagnosis 

Unless there is a good alternative diagnosis for inflammation, symptoms should be considered autoimmune in nature and treated as such. Most irAE are reversible provided vigilant monitoring and early treatment *excludes most endocrinopathies which are rarely reversible BMS + Trial Investigators developed protocol-specific treatment guidelines for management of irAE 

22

Which immunotherapies cause the greatest rates of immune toxicity, and which areas are most affected?

Ipi/Nivo > Ipi >Nivo

  • Combination Therapy: 59% Grade 3 + 4 toxicity. Higher rates of: hepatic ++, lung, multiple concurrent tox
  • Ipilimumab: 28% Grade 3 + 4 toxicity Higher rates of: GI involvement
  • Nivolumab: 21% Grade 3 + 4Toxicity Higher rate of: endocrine

23

Mx of immunotoxicity 

- general principles

 

  • Mild: treat symptomatically
  • Persistent mild/moderate: oral corticosteroids (pred 1mg/kg daily or equivalent). omit next dose ipilimumab until symptmos resolve to return to baseline
  • Worsening symptoms/severe/ life threatening: treat with high dose IV corticosteroids (methylpred 2mg/kg daily or equivalent). gradual taper over >4 weeks. If symptoms do not respond within 5-7 days, consider alternative immunosuppressive therapies. permanently discontinue ipilimumab

+ Increase monitoring

+ Rule out non-immune related causes

+ Look at individual management guidelines for specific toxicities

+ Involve specialist teams

+ often very slow wean of steroids over 2-3months

24

Medications for mx of immunotoxicity

First line:

Steroids: oral, IV

 

Second and additional lines of treatment (with expert advice)

Infliximab

• Mycophenolate

• Azathioprine

• Budesonide

• IVIG

• Plasmaphoresis

• Anti-Thymocyte Globulin 

25

Monitoring immunotherapy treatment

Pseudoprogression: tumour volume looks larger, but pt clinically well. monitor with subsequent scans Q4-6 weeks. continue treatment. 10-30% 

hyperprogression can also occur

 

26

Describe cutaneous immune related adverse event

- px

- mx

 

Most common toxicity from Immunotherapy

Presentation

  • Most common:  macular papular rash over the trunk and chest
  • Less common:
    • Stephen Johnson
    • Sweet Syndrome
    • Bullous Pemphigoid
  • Can worsen
    • Psorasis
    • Lupus

Management

  • Mild
    • Symptomatic
    • Localised steroid cream
  • Moderate:  Systemic sral steroids
  • Severe:  Supportive care, admission, IV immunosuppression 

27

Describe rheumatological irAE

- px

- mx 

 

Also Flare of Previous Disease (can occur de novo also)

  • Polymyalgia Rheumatica
  • Myositis
  • Rhematoid Arthritis
  • Psoriatic Arthritis
  • Sjorgens Syndrome
  • Inflammatory Arthropathies
  • Vasculitis/Artiritis
  • Dermatomyositis
  • SLE

Management

  • Mild
    • Symptomatic
    • Simple Analgesia
  • Moderate
    • Low dose oral steroids +/-pulse
    • Steroid sparingagents
    • Try to continue on drugs
  • Severe: If multi-organ involvement may need high dose immunosuppression 

28

Describe GI irAE

- px

- mx

 

Presentation

  • Colitis
    • Diarrhoea (>4 above baseline)
    • PR blood loss/mucus
    • Cramping abominal pain
  • Oesophagitis/ /Gastritis/ Enterocolitis

Management

  • Exclude infectious cause,C.diff
  • Mild:  IV fluids, stool chart, hospital admission
  • Moderate-Severe: 
    • IV methylprednisolone 2mg/kg for 3/7
    • Infliximab
    • Slow wean of steroids
    • Stop drugs 

29

Describe endocrinopathies iRAE

- px

- mx

 

Thyroiditis, Hypophysitis, Adrenalitis

Presentation

  • Thyroiditis:  Hypo or Hyperthyroidism
  • Hypophysitis
    • Acute, visual change, headache
    • Lethargy, fluid/electrolyte imbalance
    • Decrease Libido 
  • Adrenalitis
    • Lethargy, weight loss, anorexia, nausea fatigue
    • Hypotension

Management during treatment

  • Regular review of Sx
  • Blood tests: thyroid levels, random cortisol

Management

  • Determine cause
  • Replace hormone
  • Will not recover function of endocrine glands with immunosuppression
  • Continue immunotherapy 

30

Describe pneumonitis irAE

- px

- mx

Presentation

  • Imaging Changes
  • Dry cough, Shortness of breath, Tachypnoea

Management

  • Exclude radiation change, infection
  • Mild: Monitor, reimage and review frequently
  • Moderate-Severe: 
    • Admit
    • Support O2 supplementation and ventilation
    • Commence methylprednisilone