Melanoma

Question 1

Prognostic factors of melanoma

Answer 1

Tumour thickness #1 most important

Mitotic rate #2 most important

Ulceration

Primary tumour location

Older age, male

Lymph node

Question 2

Define stage 0, 1, 2, 3 melanoma

Answer 2

Stage 0: melanoma doesn’t invade the dermis

Stage 1: <2mm with no ulceration, <1mm with ulceration

Stage 2: >2mm with no ulceration, >1mm with ulceration

Stage 3: LN involvement

Question 3

How common are BRAF mutations in melanoma?

Answer 3

40%

Typically skin with little chronic skin-induced damage

Question 4

2 types of BRAF mutation in melanoma?

Answer 4

V600E (most) and V600K

Question 5

How does BRAF mutation cause melanoma?

Answer 5

BRAF mutation –> downstream uninhibited activation of MEK and ERK pathways –> cell proliferation, survival

Question 6

MOA of vemurafenib and dabrafenib

Answer 6

BRAF inhibitors

Used in unresectable melanoma with BRAF mutation

Question 7

Why can’t we use BRAF inhibitors alone in melanoma with BRAF mutation?

Answer 7

> 80% will develop resistance

Adding a MEK inhibitor will increase time to resistance and reduce toxicity of BRAF inhibitor (reduce paradoxical activation of the MAPK pathway)

Question 8

Treatment of unresectable melanoma with BRAF mutation

Answer 8

BRAF inhibitor (vemurafenib or dabrafenib)

PLUS

MEK inhibitor (trametinib)

Question 9

How do CTLA4 inhibitors work?

Answer 9

Normally B7 (APC) binds to CD28 (T cell) to provide costimulation signal to activate T cell so it can kill the tumour cell

With time, T cell expresses CTLA4 which preferentially binds to B7 on APC, which has an inhibitory signal and therefore inhibits the T cell

By inhibiting CTLA4, we allow B7 and CD28 to continue binding and for T cells to be activated so it can do its job.

Question 10

List a CTLA4 inhibitor we use in melanoma

Answer 10

Ipilimumab

Question 11

How do PD1 inhibitors work?

Answer 11

PDL1 (found on many cells) bind to PD1 (on T cells) to provide an inhibitor signal on the T cell. Important in prevent chronic inflammation and tissue damage and promoting peripheral tolerance.

Tumour cells over express PDL1 so it will inhibit T cells from attacking them.

By inhibiting PD1 on T cells, it is unable to bind to the excess PDL1 on tumour cells so T cells can continue to be activated.

Question 12

List 2 PD1 inhibitors we use in melanoma

Answer 12

Pembrolizumab

Nivolumab

Question 13

Are CTLA4 inhibitors or PD1 inhibitors superior in melanoma?

Answer 13

PD1 inhibitors

Both combination is most superior

Question 14

Treatment of unresectable BRAF negative and fit patient

Answer 14

PD1 inhibitor (pembrolizumab or nivolumab)

PLUS

CTLA4 inhibitor (ipilimumab)

*Very toxic combination but highest survival

Question 15

Treatment of unresectable BRAF negative and less fit patient

Answer 15

PD1 inhibitor (pembrolizumab or nivolumab)

Question 16

Treatment of CNS metastasis in melanoma

Answer 16

Surgery or targeted radiotherapy or whole brain radiotherapy

Question 17

What’s pseudoprogression?

Answer 17

Tumour can get bigger before getting smaller

Can happen in immunotherapy

If patient is well, continue treatment then repeat CT in 4-6/52 to assess progression

Question 18

Are PD1 inhibitors or CTLA4 inhibitors more likely to have immunotoxicity?

Answer 18

CTLA4 inhibitors

BUT combination is the worst! (1 in 2 will need to stop treatment)

Question 19

List tissues/organs commonly affected by immunotoxicity (from immunotherapy)

Answer 19

Skin
GIT
Liver
Endo: Adrenals, thyroid, pituitary
Lung

Question 20

Why does immunotoxicity occur with immunotherapy?

Answer 20

By inhibiting CTLA4 and PD1, you prevent the inhibition of T cells and you upset the balance of the immune system = results in unopposed immune activation, inflammation, tissue damage

Question 21

Management of mild immunotoxicity (from immunotherapy)

Answer 21

Treat symptomatically

Continue the drug

Question 22

Management of persistnet mild or moderate immunotoxicity (from immunotherapy)

Answer 22

Oral pred 1mg/kg

Omit/reduce next dose until symptoms resole or return to baseline

Question 23

Management of severe/life threatening immunotoxicity

Answer 23

High dose IV pred. If symptoms improve, do steroid taper over at least 4 weeks

If symptoms do not improve within 5-7 days, consider alternative immunosuppressant

Cease immunotherapy permanently

Question 24

Which type of immunotoxicity is most likely to be permanent?

Answer 24

Endocrinopathy - thyroid, adrenals

Will need hormone replacement lifelong

Question 25

Do we do adjuvant immunotherapy in melanoma?

Answer 25

Not standard of care at the moment but this is a growing space

Question 26

What’s actinic keratosis at risk of?

Answer 26

Becoming invasive SCC

Progress at an unpredictable rate to invasive disease