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ACOS Surgical Oncology In-Depth Review 2014

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.

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ACOS Surgical Oncology In-Depth Review 2014

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  1. ACOS Surgical Oncology In-Depth Review 2014 Melanoma Surgical management and beyond Douglas M. Iddings D.O., FACS FACOS Surgical Oncologist

  2. No disclosures

  3. 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

  4. 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?

  5. 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

  6. Melanoma of the skin • Recommended Margins…..unchanged.

  7. 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

  8. 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

  9. 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

  10. 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.

  11. 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

  12. 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.

  13. New era in Metastatic Melanoma • Old era OS Barth J Am Coll Surg 1995; 181:193. • 1971 - 1978 N = 462 Median Survival = 8.1 months • 1979 - 1986 N = 748 Median Survival = 7.3 months • 1987 - 1993 N = 311 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”.

  14. 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. 20

  15. 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.

  16. 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. 100% Treatment Tumor size (%) 50% PR 0% 0 20 30 40 50 60 10 Post-treatment in weeks Weber Oncologist 2008;13(supp4);16 CR 20

  17. New era of Melanoma Therapy • Anti CTLA4 antibody • Takes the brakes off the immune response.

  18. 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

  19. CTLA4 Blockade for Melanoma“No brakes….look out!”

  20. 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.

  21. 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

  22. 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

  23. 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 ???

  24. 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.

  25. MH n=1

  26. 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 • CT otherwise negative • BRAF V600E mutated • Consider neo-adjuvant therapy • BRAF inhibitor with MEK Sondack SSO March 13, 2014

  27. 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

  28. 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.

  29. 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

  30. Advanced Melanoma TreatmentLooking 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.

  31. 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.

  32. Not the end….Thank you

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