ACOS
Surgical Oncology
In-Depth Review 2014
Melanoma
Surgical management and beyond
Douglas M. Iddings D.O., FACS FACOS
Surgical Oncologist
No disclosures
Objectives
• Discuss the old and new era in melanoma
therapy.
• Review the new and emerging treatments.
– Discuss the mechanism of action.
• Discuss a possible standard approach
• Discuss implications for surgeons
– Case examples
Melanoma Questions
• What year marked the new era in systemic
treatment of stage IV metastatic melanoma?
• What are the new emerging systemic treatment
agents?
• Is there any evidence or hope for neo-adjuvant
treatment in melanoma?
• What is the NCCN preferred treatment?
Melanoma of the skin
• All cancers
– 2013 total new cancers 1,660,290
• Melanoma of the Skin
– 2013 estimated new cases = 76,690
• 45,060 men (5%) and 31,630 (6%) female
– 2013 estimated deaths = 9,480
• 6,280 men and 3,200 female
Melanoma of the skin
• Recommended Margins…..unchanged.
Tumor thickness
Recommended Margins
In situ
0.5 – 1.0 mm
≤ 1.0 mm
1.0 mm (category 1)
1.01 – 2 mm
1 – 2 mm (category 1)
2.01 – 4 mm
2.0 mm (category 1)
> 4 mm
2.0 mm (category 1)
New and emerging treatments in
Metastatic Melanoma
• Old era as of February 2011
– Dacarbazine (DTIC), 1970’s
• Response rates <10% with no proven impact on survival.
– High-dose IFN, 1995
• The only approved adjuvant therapy
• Consistent benefit on relapse-free survival but controversial
survival benefit
– High-dose IL-2, 1998
• Response rate 16% in highly selected patients
• Rarely used outside of high volume centers
New era in Metastatic Melanoma
• Drugs approved for Melanoma by FDA in 2011
– Pegylated interferon alfa-2b
• Improved RFS in adjuvant therapy of stage III melanoma
• No proven impact on survival (5 year treatment regimen)
– Ipilimumab (anti-CTLA4 monoclonal antibody)
• Immunotherapy for stage IV melanoma
• Improved overall survival in 2 phase III trials
– Vemurafenib (V600 mutant BRAF inhibitor)
• For BRAF mutant melanoma (45% incidence)
• Rapid response rates, rarely durable
• Improved survival in a phase III trail compared to DTIC
NOT a new era in
adjuvant therapy for Melanoma
• Interferon meta-analysis (2013)
–
–
–
–
Mocellin et al Cochrane database of systemic reviews
17% improvement in relapse free survival
9% improvement in relative survival
Example: Patient with a single positive lymph node
• If a patient has a 70% estimated survival after surgery
• 9% relative survival would mean a 3% increase in OS
– From 70% up to 73% survival.
– Considering most patients would undergo treatment for a 1%
improvement. This is a reasonable treatment.
– How many patients would you need to treat to save a life
» 40 deaths / 100 pts with observation
» 37 deaths / 100 pts with interferon alpha
NOT a new era in
adjuvant therapy for Melanoma
• Interferon meta-analysis (2013)
– Conclusion
• Until better selection methods or more effective
therapies are available, the findings lend support to
the use of interferon alpha in the routine clinical
setting.
• Moreover, we must remember that other well
established adjuvant treatments used in CRC, breast
cancer and ovarian cancer are associated with
similar risk reductions.
NOT a new era in
adjuvant therapy for Melanoma
• Pegylated interferon alpha 2B x 5 years
–
–
–
–
Not a quantum leap
Improved relapse free survival
No significant improvement in overall survival
EORTC 18991
• Is there a subset of patients Stage III N1 and ulcerated that may
have a significant benefit.
• Instead a 9% difference there was a ~40% relative improvement
• Median survival difference of 3.7 years vs. >9 years
– In a subset of a subset / Hypothesis generating data
NOT a new era in
adjuvant therapy for Melanoma
• What do we need?
– Better prognostic markers to identify patients at risk of
relapse.
• SLN negative patient in particular
– Need predictors of efficacy and resistance as more therapies
become available.
• Determine what drug to start and when to move on to a new
agent.
New era in Metastatic Melanoma
• Old era OS Barth J Am Coll Surg 1995; 181:193.
– 1971 - 1978 N = 462
– 1979 - 1986 N = 748
– 1987 - 1993 N = 311
Median Survival = 8.1 months
Median Survival = 7.3 months
Median Survival = 7.0 months
– There has been no significant improvement in OS for
the past 30 years in stage IV melanoma.
• ~25% of patients with stage IV melanoma alive at 12 months
• This defines “The old melanoma era”.
New era in Metastatic Melanoma
• New era ~2011: The BRAF inhibitor
– BRAF mutations are common and can be targeted.
– This dials up the activity of the protein and this directs
cell proliferation and survival (among other things).
– ~90% of mutations are in one spot: V600E
• A substitution of one AA for another renders it deaf to the
molecules that normally turn down its volume.
New era in Melanoma Therapy
• About ½ of all melanomas have an activating
mutation in BRAF.
– Fuels growth by constituently activating the kinases
MEK and ERK.
– To overcome resistance to selective BRAF inhibitors,
MEK inhibitors are added.
– Other targets in the MEK pathway and in the PI3K
pathway are being investigated.
New era in Metastatic Melanoma
• New era ~2011: The anti-CTLA antibody
– Immunologic checkpoints that are suppressing the
anti-tumor immune response have been identified.
• Anti-CTLA4 antibody does not effect tumor cells, it only
effects a single molecule on T-cells.
Tumor size (%)
100%
Treatment
50%
PR
0%
0
10
20
30
Post-treatment in weeks
40
50
60
CR
Weber Oncologist 2008;13(supp4);16
New era of Melanoma Therapy
• Anti CTLA4 antibody
– Takes the brakes off the immune response.
CTLA4 Blockade for Melanoma
• Hodi et al, N Eng J Med 2010;363:711
–
–
–
–
At 4 months the survival curves start to separate.
~40% alive at 1 year (old era 25% alive at 1 year)
~25% alive at 2 years
Response rates were low and the response was slow.
• Robert et al, N Eng J Med 2011:364:2517
–
–
–
–
–
Number of deaths: 196 vs. 218 HR 0.72 p<0.001
1 year survival 47.3% vs 36.3%
2 year survival 28.5% vs. 17.9%
3 year survival 20.8 vs 12.2%
More durable response than targeted therapy
•
This is not a targeted therapy
CTLA4 Blockade for Melanoma
“No brakes….look out!”
Ipilimumab
immune related events
• T-cells can lose tolerance to self-antigens
– Common immune adverse events
•
•
•
•
Dermatitis
Hepatitis
Endocrinopathies/pituitary dysfunction
Enterocolitis
– Diarrhea often the first manifestation
– Toxicity dose not equal to response, but there is an
association.
PD-1 Blockade trials
• Re-activates an exhausted T-cell
– Topalian et al, N Eng J Med 2012; 366:2455
• 1 year survival 60-80%
• Some pts did not respond
– Wolchock et al, N Eng J Med 2013
• Combining Ipi with PD-1
• More rapid response and many are durable
• Most people responded
A “standard” approach to treatment for
Stage IV Melanoma in the New Era.
• If possible resect all disease and consider an adjuvant
therapy clinical trial.
• For unresectable or recurrent disease consider TILS +/high-dose IL-2 first for patients with excellent performance
status, few/no comorbidities and limited tumor burden.
• For failures, Ipilimumab if BRAF - or if BRAF +
(with V600 mutation) with limited disease burden.
• Vemurafenib for pts with BRAF mutant melanoma and
high disease burden, symptomatic disease or after
ipilimumab failure. Possibility with MEK inhibitor.
– When you want the quick response
MH Case example #1
• MH 33 year-old male with a 14cm solid mass in
the head of the pancreas; no jaundice. ECOG 0.
– No distant disease; CA 19-9 normal
– FNA adenocarcinoma ???
– Neo-adjuvant treatment for borderline resectable?
• Surgery: Extended Whipple procedure with midgut
• Final pathology: R0; undifferentiated carcinoma
– 1/24 lymph nodes involved with metastatic disease.
• CANCER TYPE ID Biotherangostics Inc.:
– Melanoma with 95% confidence; BRAF wildtype
MH case
• R0 after Ext. Whipple with no measurable disease
– No primary cutaneous or other melanoma identified
• No BRAF mutation
• Treated with Ipilimamab (anti-CTLA4 antibody)
– He was a non-responder, progressed on treatment developing
massive bulky symptomatic (focal) lymphadenopathy compressing
left kidney.
– Treated with radical extended en-bloc L nephrectomy for an R0
• Not a TILS candidate at NIH
• Clinical trial PD-1
– One year out from second surgery with no evidence of disease.
MH n=1
FM Case example #2
• 40 year-old male with bulky lymphadenopathy.
– Massive fixed left axillary nodal disease extending into neck.
• History of pigmented lesion on upper back.
–
–
–
–
2 ½ years ago had “benign” lesion removed.
Excisional biopsy of LN = Melanoma
Neo-adjuvant options
CT otherwise negative
Interferon
BRAF V600E mutated
DTIC
• Consider neo-adjuvant therapy
– BRAF inhibitor with MEK
Biochemotherapy
Ipilimumab
Anti PD-1
Sondack SSO March 13, 2014
FM Case example
• BRAF with MEK neo-adjuvant treatment reasonable
– Rapid response
• Lets review the supporting data: Limited neo-adjuvant data
– Moschos et al, J Clin Oncol 2006;24:3164
• High dose Interferon 1 month prior to surgery
• 11 patients responded (55%) 3 with a cCR
– Shah et al. Ann Oncol 2010;21:1718
• Chemotherapy 19 pts; 16% responded, 12 pts progressed while on treatment.
• More pts got worse while on treatment
– Lewis et al. J Clin Oncol 2006;24:3157
• Biochemotherapy 26% response rate with fewer patients progressing.
• High toxicity
FM Case example
• BRAF neo-adjuvant treatment reasonable +/- MEK inh
– 45% of melanomas have BRAF mutation
– Combination is now FDA approved
• More active and less toxic
– Combination can result in PET negative tumors by 2 weeks.
– Many respond and then may make surgery more effective.
• PD-1 would be reasonable if BRAF wildtype
• Possible combination Ipi and PD-1 as there seem to be
more rapid response and many can be durable.
FM Case example
• Surgical options
– Combined axillary and neck dissection
OR
– Staged LN resection with axillary dissection and monitor the neck
• 4/21 axillary LN involved s/p 6 months of treatment and was PET –
• Additional options after surgery
–
–
–
–
Consider radiation
Resume BRAF and MEK inhibitor until progression
No further therapy and follow with US
No clear standard
• If NED no additional therapy is common
Advanced Melanoma Treatment
Looking into the Future.
• Neo-adjuvant therapy using BRAF + MEK inhibitor for
BRAF mutant patients with unresectable or borderline
resectable tumors may become routine.
– Even for resectable larger tumors
• Neo-adjuvant therapy using PD-1+/- Ipi for BRAF
wildtype pts with similar unresectable or borderline
resectable tumors could be the other option.
• Surgical (selective resection) for pts with multiple
unresectable metastases treated with targeted therapy and
immunotherapy in whom there is a mixed response.
– GIST experience with pts treated with imatinib shows benefit for resection of
resistant tumors.
Summary
• 2011 marked the new era of melanoma treatment
with FDA approval of many new drugs.
– Ipilimumab (anti CTLA4 antibody) & BRAF inhibitor
– MEK inhibitor more recent and PD-1 likely coming
• Like pancreatic cancer, neo-adjuvant therapy for
melanoma could be an effective way to manage patients
and will likely not require a randomized trail.
• The NCCN feels the best treatment option for patients is to
consider a clinical trail.
Not the end….Thank you