Melanomer!

Question 1

Raf pathway?

Answer 1

Activating BRAF mutations in up to 50%; mostly Val600Glu. Get constitutive activity. Discovery of BRAF inhibitors led to dramatic improvements.

Question 2

5 year survival for melanoma 2002-2006?

Answer 2

Stage IV; 10-25%; Stage III 50%; Stage 1 very good.

Question 3

Problem with BRAFi?

Answer 3

In wild type cells (as BRAF mutations are somatic), low inhibitor concentrations lifted negative feedback of MAPK/ERK pathway and gave paradoxical activation. Get bizarre toxicites e.g. hyperkeratosis, SCC, secondary melanomas. Also got resistance fairly quickly, often via upregulation of AKT pathway.

Question 4

Managing resistance to BRAFi?

Answer 4

Give inhibitors to PI3K, AKT and mTOR (in other pathway) to prevent circumvention. Also, as well as BRAF, gave inhibitors to MEK (downstream of RAF) to “double block” same pathway.

Question 5

BRAF/MEK inhibitors and toxicity?

Answer 5

Get different toxicities rather than hyperproliferation; pyrexia, nausea etc. but none of the bizarre cutaneous manifestations

Question 6

Why is melanoma susceptible to immunotherapy?

Answer 6

Has particularly high mutational burden; means more vulnerable to immunotherapy as more neoantigens etc.?

Question 7

Two mechanisms of immunotherapy in MM?

Answer 7

1. PD1/PDL1 (downregulates activity of EFFECTOR T cells)

2. CTLA4 (a dampener of T cell ACTIVATION)

Question 8

Anti CTLA4?

Answer 8

Ipilimumab. Vs dacarbazine alone, improved survival in 2010 study, with some patients gaining long term control

Question 9

Anti PD1?

Answer 9

Pembrolizumab. In 2017 trial vs ipilimumab, showed improved survival

Question 10

Problem with PDL1 expression as a biomarker?

Answer 10

Expression can vary with treatment so one off sample not valid reason to not treat. Although expression is correlated with efficacy, some patients with negative PDL1 may still response to pembro!

Question 11

Combination therapy with PD1 and anti CTLA4?

Answer 11

Hodi, 2018, showed improved survival over either alone (ipilumumab [CTLA4] vs nivolumab)

Question 12

Toxicities with these immune checkpoint inhibitors?

Answer 12

Autoimmune reactions; very dangerous and can happen at any time. Need good PS to be on these drugs. PArticularly ipilummab-related colitis, anti-PD1 related pneumonitis. Particularly dangerous if already have AI disease

Question 13

Immunotherapy and BRAF status?

Answer 13

Response to ipilimumab and nivolumab independent of BRAF status. Patients therefore have a choice of BRAF/MEK or anti-PD1/CTLA4

Question 14

Premise for combining the two treatment strategies?

Answer 14

BRAF targeted pathway giving swift, dramatic remissions and immune checkpoint pathway giving serious, durable results. Also, BRAF inhibitors change immune microenvironment

Question 15

The main BRAFi?

Answer 15

Dabrafenib

Question 16

The main MEK?

Answer 16

Trametinib

Question 17

The next horizon for these drugs?

Answer 17

All previously was stage IV i.e. incurable; now looking adjuvant setting for resected Stage III melanoma. Papers so far from Long (2017) have shown value of dafrafenib and trametinib vs placebo, and of nivolumab vs ipilumamab in this setting.