Malignant Melanoma Flashcards
What are the 3 main types of skin cancer?
Malignant melanoma
Non-melanoma skin cancers: BCC/Basal cell carcinoma. SCC/Squamous cell carcinoma.
Who does skin cancer mainly affect?
White-skinned people.
Where is melanoma most common?
Aus and NZ
What are the risk factors for melanoma?
Sun exposure.
Number of moles.
Skin type: fair skin.
Family history.
How is melanoma diagnosed?
Pts presents.
Dermascope examination.
Excisional biospy: removal of entire lesion.
Histopathology: examination of lesion and analysis.
Where does melanoma tend to spread?
Lymph nodes.
Liver
Brain
Lungs
How are stage 0-3 melanomas treated?
Stage 0-3 tumours: excision followed by wide local excision to remove good margin of healthy tumour.
> 50% of stage 3 tumours recur.
What percentage of stage 3 tumours will recur?
> 50%
How are stage 4 melanomas treated?
Stage 4: chemotherapy, biological therapies e.g. ipilimumab, pembrolizumab, vemurafenib, dabrafenib.
How can melanomas be identified?
ABCDEF Asymmetry Border Colour Diameter Evolution/elevation Funny looking
What does ABCD(EF) refer to?
Way to identify tumours: Asymmetry Border Colour Diameter Evolution/elevation Funny looking
For stage 4 melanoma, what is the 10 year survival?
<10%
Ipilimumab was the first agent to show what?
An increase in overall survival in advanced/unresectable MM.
What is ipilimumab? (structure)
Recomb human monoclonal antibody that binds to CTLA-4 (cytotoxic T-lymphocyte associated antigen 4).
How does Ipilimumab function as a chemotherapeutic agent?
Blocks interaction of CTLA-4 and its ligands, CD80 and CD86.
Normally, CTLA-4 serves as an immune checkpoint that down-regulates pathways of T-cell activation and prevents autoimmunity. By blocking this function, Ipilimumab potentiates the antitumour T-cell response, resulting in unrestricted T-cell proliferation.
Thus, the mechanism of action of ipilimumab in pts with melanoma is indirect, possibly through T-cell mediated antitumour immune responses.
What are the side effects associated with ipilimumab?
diarrhoea Rash Pruritus Fatigue Nausea & vomiting Decreased appetite Abdominal pain Colitis Hepatitis
Ipilimumab is licensed for the treatment of
Previously untreated advanced MM or after prior therapy.
What does Ipilimumb bind to?
CTLA-4 -> cytotoxic T-lymphocyte associated antigen 4.
How much does Ipilimumab cost?
£25,000 for 1 dose, given every 3 weeks for 4 weeks in total.
What class of drug is Vemurafenib?
BRAF inhibitor.
Oral tyrosine kinase inhibitor.
The ligands which Ipilimumab blocks CTLA-4 from interacting with.
CD80, CD86.
A recombinant monoclonal antibody that binds to CTLA-4.
Ipilimumab.
What route must Ipilimumab be given by?
IV
What route can Vemurafenib be given by?
Oral.
It is an orally active tyrosine kinase inhibitor.
What is BRAF?
A gene that is mutated in 60% of melanomas and becomes constitutively active causing cell proliferation and tumour growth.
What patients can be given Vemurafenib?
Only those with the BRAF V600 mutation.
Pos 600, glutamate becomes valine.
What percentage of pts have tumour regression quickly with vemurafenib?
~90%
What are the main side effects of vemurafenib?
Fatigue Joint pain (painkillers, heat/ice packs) Rash (emollient, antihistamine or painkillers) Sensitivity to sun (SPF 30-50 needed in all weathers, wear long sleeves, apply a UV resistant film to windows) Nausea Alopecia Pruritus Headache
What are the main distinguishing side effects of vemurafenib?
Sensitivity (SPF30-50) to sun, uv films on windows.
Can ironically cause cutaneous squamous cell carcinomas have been reported in 20% of patients (minor cancers), patients need to be aware to check for any new/changing skin lesions.
When should vemurafenib be taken and how?
With food twice a day, orally as it is in tablet form.
Major advantage over Ipilimumab.
Vemurafenib is a _______ inhibitor which is approved by NICE for patients with _________ __ who have the ____ _____ mutation.
CTLA-4 inhibitor.
Advanced MM.
BRAF V600.
Glutamine to valine mutation.
Why does Vemurafenib have many interactions with other drugs?
It is metabolised by cytochrome p450 enzymes and has many drug interactions.
What does Dabrafenib have in common with Vemurafenib?
Also a BRAF inhibitor.
NICE approved in same pts.
IT is used more often.
What are the side effects of dabrafenib? what type of drug is it?
Fever (pts report >38 - not infectious) Fatigue Joint pain Rash Headache Nausea Diarrhoea Cutaneous squamous cell carcinomas have been reported in 10% of patients. Uveitis in 1% of patients - pts report any eye redness.
Cutaneous squamous cell carcinoma have been reported in 10% of patients taking which advanced MM treatment?
Dabrafenib
What route can dabrefenib be given by?
Oral. Again many drug interactions as it is metabolised by CYP450
Pembrolizumab is one of the first of a new generation of immuno-oncology therapies called anti-___s
One of the first of a new generation of immuno-oncology therapies called anti-PD-1s (programmed death receptor-1)
What is Pembrolizumab, how is it given and how does it work?
Humanized monoclonal antibody given by IV infusion that blocks the interaction between PD-1 (programmed death receptor-1) found on T cells and its ligands, PD-L1 and PD-L2.
By blocking the interaction with the receptor ligands, pembrolizumab releases the PD-1 pathway mediated inhibition of the immune response, including the anti-tumour immune response (i.e. it “takes the brakes off the immune system”).
Which treatment for advanced MM can cause uveitis?
Dabrafenib
How does pembrolizumab take the breaks off the immune system?
It blocks the interaction between PD-1 (programmed death receptor 1) found on T cells and its ligands, PD-L1 and PD-L2. This releases the PD-1 pathway mediated inhibition of the immune response, including anti-tumour immune response.
Humanized monoclonal antibody given by IV infusion that blocks the interaction between PD-1 (programmed death receptor-1) found on T cells and its ligands, PD-L1 and PD-L2.
Pembrolizumab
What is the overall survival at 18 months post initiation of Pembrolizumab treatment and what is the overall response rate to treatment?
18 months = 62%
Overall response rate = 24%.
One of the first of a new generation of immuno-oncology therapies called anti-PD-1s (programmed death receptor-1)
Pembrolizumab
What is the inidication for Pembrolizumab use?
Indicated for previously untreated advanced MM or following ipilimumab/BRAF inhibitor
What are the important side effects of pembrolizumab?
Decreased appetite
Immune-mediated adverse reactions such as pneumonitis, colitis and hepatitis.
What are the first line treatment options for advanced/unresectable MM with no BRAF V600 mutation?
Either Ipilimumab (expensive) or Pembrolizumab.
Second line: whichever wasnt used first line.
What are the 1st line treatment options for BRAF V600 mutation MM?
Vemurafenib/dabrefenib.
What are the second line treatment options for BRAF V600 mutation MM?
Ipilimumab/pembrolizumab.
