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Flashcards in Melanoma Deck (26):
1

What are the anatomical subtypes of Melanoma?

1) Cutaneous Melanoma
- Superficial spreading
- Nodular Melanoma
- Melanoma Lentigo Maligna
2) Acral Melanoma
3) Mucosal Melanoma

2

What are the ABCDEs of detecting Melanoma?

A - Asymetry
B - Border
C - Colour
D - Diameter
E - Evolving

3

What are the predictors of Relapse and Survival?

1) Breslow Thickness
2) Regional LN status
3) Ulceration

4

What is the Breslow's Thickness classification? And how does it correlate with the Clark Level?

Clark Level I -
Clark Level II - 0-0.75 mm
Clark Level III - 0.76mm - 1.50mm
Clark Level IV - 1.50mm - 3.99 mm
Clark Level V - 4mm or bigger

5

What is the routine staging for Melanoma?

1) Histology
- Margins
- Depth
- Breslow
- Clark Level

2) Radiological imaging
- CT/MRI
- or PET

3) Sentinel LN sampling

4) AJCC staging

6

What is the BRIM-3 trial ?

Chapman NEJM 2011

Vemurafenib 960 mg BD vs DTIC 1000 mg/m2 Q21d

ORR 50% vs 5%
Improved mOS 9m vs 7m

S/e for Vemurafenib:
- Rash, Fatigue, keratoacanthoma

7

What is MEIK inhibition

Flaherty NEJM 2012

Ph 3, V600E or V600k mutant BRAF

Trimetinib/Dacarbazine +/- Pacliatxel

PHS 5m vs 1.5m HR 0.45
OS: Trametinib vs Chemotherapy

8

What are the layers of skin

E.P.R.S

Epidermis
Papillary dermis
Reticular dermis
Subcutaneous fat

9

What is the average 5y OS for Stage III?

IIIA - 80%
IIIB - 60%
IIIC - 40%

10

Tell me about the MSLT-1 study

Morton et al. NEJM 2006

N=2000 patients with melanoma
S/p WE of local tumor

2 groups:
1) Nodal observation --> Lymphadenectomy for nodal relapse
2) SLNB --> Immediate lymphadenectomy for LN+

Subset analysis:
- immediate lymphadenectomy improves:
>> survival for those with nodal met detected on SLNB
>> DFS for all patients
>> distant DFS and melanoma-specific survival for those with nodal mets from intermediate thicknesses melanoma

11

What is the evidence for Alpha-interferon adjuvant therapy?

1) EST 1684 study by Kirkwood JCO 1996

S/p resected cutaneous melanoma
High-risk disease

2 arms:
1) Observation
2) Induction IFN alpha --> Maintenance Alpha-IN
- Induction = IV 5/7 per week X 4 weeks
- Maintenance = SC injection 3x/week for 48 weeks

RESULTS:
- improve RFS and OS by ~ 1year

=============
2) Mocellin et al Cochrane meta-analysis 2013
18 RCTs with 10500 patients
DFS HR0.83
OS benefit HR 0.91 --> 9% benefit in terms of OS

12

Any evidence for Ipilumumab?

Yes. EORTC 18071
Eggermont Lancet Oncol 2015

High-risk, stage III, completely resected melanoma
Almost 1000 patients

2 arms:
1) Induction Ipilumumab for 3 months --> maintenance Ipilumumab up to 3 years
2) Induction Placebo for 3 months --> Maintenance placebo up to 3 years

RESULTS:
3y RFS 45% vs 35%(Placebo); HR 0.75
2y median survival 26m vs 17m

13

What is the role of Adjuvant RT?

ANZMTG JCO 2013

LNF was reduced with Adjuvant RT, but no difference in OS.

This study evaluated the role of adjuvant RT following lymphadenectomy.
Pts with high risk of LNF relapse, received adjuvant RT (ART) 48Gy/20# vs observation

14

What is the evidence for DTIC > Dartmouth regimen?

Chapman et al JCO 1999

N=250
Metastatic melanoma

2 arms:
1) DTIC (=Dacarbazine)
2) Dartmouth regimen
- Dacarbazine (=DTIC)
- Temozolomide
- Carmustine
- CDDP

Results:
1) Median Survival time 7monhs.
- No difference in survival time
2) OR 18% with DTIC vs 10%

15

How about Temozolomide vs DTIC?

DTIC = Dacarabzine

Met melanoma, n=300

RESULTS:
OS: 7.5m vs 6.5m (DTIC) p=o.054
CR/PR rate: 13.5% vs 12%(DTIC)

16

How about evidence for IL-2?

Yes, Atkins et al JCO 1999

N=270 patients with metastatic melanoma.

S/p HD IL-2
- Q8H doses
- 14 doses over 5 days
- repeat after 6-9 days
- repeat after 6-12 weeks
- ORR 16%, of which 5% CR

17

Which type of melanoma has BRAF, NRAS Mutations?

Non-chronic sun-damaged skin
80% of hem had mutations in BRAF and NRAS

18

How often are somatic mutations in uveal melanoma?

30 - 50%

Frequent somatic mutations of GNAQ in uveal melanoma and blue Naevi noted

Mutations in GNA11 also noted

19

What is the evidence for Vemurafenib in melanoma?

NEJM 2011, Chapman

Phase 3 study, n=675
Melanoma with BRAF V600E mutation

2 arms:
1) Vemurafenib 960mg BD
2) DTIC 1000mg/m2 Q3w

RESULTS:
ORR 50% vs 5% (DTIC)
Med OS 8m s 9.5m

20

What are the toxicities of Vemurafenib?

Keratoacanthomas (8%)
Cutaneous SCC 12%
Arthralgia 20%
Rash 20%
Fatigue 13%

21

What is the Evidence for combined Nivolumab and Ipilimumab?

Larkin NEJM 2015

3 arms:
1) Nivo + Ipi
2) Nivo
3) Ipi

RESULTS:
Med PFS 11.5m (Combi) vs 7m (Nivo) vs 3m
OR 60% (Combi) vs 40% (Nivo) vs 20%
CR 11% (Combi) vs 8% (Nivo) vs 2%

22

What are the mechanisms of resistance in BRAF inhibition?

1) COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signaling
2) Acquired resistance to Vemurafenib by PDGR-B up regulation
3) Acquired resistance to Vemurafenib by NRAS mutations
4) MEK1 mutations
*2 and 3 are mutually exclusive

Rarely through BRAF secondary mutations

23

How about if only MEK is inhibited in a BRAF-Mutated melanoma?

Flaherty NEJM 2012
N=300
V600E or V600K mutations

Trametinib vs Dacarbazine vs Paclitaxel
PFS 5m (Trametinib) vs 1.5m (chemo)
OS HR 0.5

24

How about combination of MEK inhibition and RAF inhibition?

Flaherty NEJM 2012

N = 250

2 arms:
1) Dabrafenib + Trimetinib
2) Dabrafenib

RESULTS:
- Median PFS: 6m (Dabrafenib) vs 9.5m (Combination)
- ORR 55% vs 9.5m
- SCC 20% vs 7%

==========
Long et al NEJM
PFS 9.3m vs 8.8m

25

Vemurafenib + Cobimetinib > Vemurafenib.
What is the evidence?

Larkin et al NEJM

PFS 9.9m (Combi) vs 6.2m (Vemurafib)

26

What are the various RR?

Nivolumab (Anti-PD1) =
ORR 30%
Overall response 40%
CR 8%
Med PFS 7m

Ipilimumab: (anti-PD1)
Med PFS 3m alone, OS 10m -11m
Overall response 20%, CR 2%

Nivo+Ipi=
Median PFS 11.5m
OR 60% CR 10%

Pembrolizumab (Anti-PD1) =
ORR 25% (after Ipi and BRAF)