Melanoma Flashcards
What are the anatomical subtypes of Melanoma?
1) Cutaneous Melanoma
- Superficial spreading
- Nodular Melanoma
- Melanoma Lentigo Maligna
2) Acral Melanoma
3) Mucosal Melanoma
What are the ABCDEs of detecting Melanoma?
A - Asymetry B - Border C - Colour D - Diameter E - Evolving
What are the predictors of Relapse and Survival?
1) Breslow Thickness
2) Regional LN status
3) Ulceration
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
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
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
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
What are the layers of skin
E.P.R.S
Epidermis
Papillary dermis
Reticular dermis
Subcutaneous fat
What is the average 5y OS for Stage III?
IIIA - 80%
IIIB - 60%
IIIC - 40%
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
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
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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
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
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
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%
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)
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
Which type of melanoma has BRAF, NRAS Mutations?
Non-chronic sun-damaged skin
80% of hem had mutations in BRAF and NRAS
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
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
What are the toxicities of Vemurafenib?
Keratoacanthomas (8%) Cutaneous SCC 12% Arthralgia 20% Rash 20% Fatigue 13%
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%
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
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
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%
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Long et al NEJM
PFS 9.3m vs 8.8m
Vemurafenib + Cobimetinib > Vemurafenib.
What is the evidence?
Larkin et al NEJM
PFS 9.9m (Combi) vs 6.2m (Vemurafib)
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)
