Melanoma: Therapeutic Progress and the Improvements Continue David W. Ollila, MD Professor of Surgery Jesse and James Millis Professor of Melanoma Research May 20, 2016 Disclosures: NONE
Outline 2016 Therapeutic options: Stage IV patients» Systemic» Surgical Therapeutic options: Stage III patients» Systemic» Surgical Sentinel Node Update 5/19/2016 2
Stages IIIbc IV Metastatic Melanoma 5/19/2016 3
US FDA Approved Stage IV Systemic Therapy Options Dacarbazine (1970s)» Complete Response 3-5% Interleukin-2 (1998)» Complete Response 7-8% US FDA Approved Stage III Systemic Therapy Options Interferon alpha-2b (1995)» Disease-free but no overall survival advantage
Somatic Mutations in Melanoma COSMIC Database April 2012
A. B-RAF Oncogenic Addiction in Melanoma is Bad C. PTEN Loss B. B-RAF N-RAS Long J Clin Oncol 2011 Jacob Cancer 2012 Nathanson ASCO 2011
B-Raf Inhibitors (B-RAFi; e.g. vemurafenib, dabrafenib) Prolong Survival in B-RAF V600E/(K) Melanoma Chapman ASCO 2012 Hauschild ASCO 2012
MEK inhibitors (MEKi) Have Clinical Benefit in B-RAF V600E/K Melanoma that is Smaller Than That of B-RAFi Flaherty N Engl J Med 2012
Checkpoint Blockade -Inhibiting the Inhibitors Tumor? Pardoll Nat Rev Cancer 2012
Differences in Checkpoint inhibitors 5/19/2016 Ribas N Engl J Med 2012 10
Ipilimumab Prolongs Survival 10.1 vs. 6.4 months, HR 0.66 Hodi et al NEJM 2010
PD-1 Inhibitory Antibodies (BMS936558, MK3475) Topalian N Engl J Med 2012
Combination Checkpoint Inhibitors 5/19/2016 Larkin J N Engl J Med. 2015 Jul 2;373(1):23-34 13
US FDA Approved Stage IV Systemic Therapy Options Ipilimumab (2011)» 10.1 vs. 6.4 months, HR 0.66 Vemurafenib (2011)» 13.6 vs. 9.7 months, HR 0.70 Dabrafenib (2013)» PFS 5.1 vs 2.7 months HR 0.33 Trametinib (2014)» Combination for BRAF mutant
US FDA Approved Stage IV Systemic Therapy Options Pembrolizumab (2014)» Response Rate 26% Nivolumab (2014)» RR 40% vs 14% p<0.001» One yr survival 72% vs 42% Combinations..
US FDA Approved Stage IV Systemic Therapy Options Nivolumab + Ipilimumab (2015)» Untreated Stage IV melanoma» Nivo + Ipi vs Nivo vs Ipi» RR 57% vs 43% vs 19% p<0.001» Median survival not yet published» Side Effects: colitis, diarrhea, pyrexia, pneumonitis Larkin J N Engl J Med. 2015 Jul 2;373(1):23-34
M1a M1b M1c Surgical Options Complete metastasectomy» Surgical removal of all radiographic and clinical stage IV disease» Curative intent Incomplete metastasectomy» Partial removal of radiographic and clinical stage IV disease» Palliative intent
Stage IV AJCC Stage IV Melanoma* M1a: Skin, soft tissue or distant lymph nodes M1b: Pulmonary M1c: All other visceral sites Median Survival Range (mos) 5-Yr OS Range (%) M1a (n=728) 17-50 14-61 M1b (n=698) 14-28 14-50 M1c (n=395) 8-49 28-41 *Complete metastasectomy Non-randomized data
A phase 2 trial of complete resection for Stage IV melanoma: Results of SWOG S9430 77 patients were enrolled from 18 different centers. The primary analysis included 64 completely resected patients. Twenty patients (31%) had visceral disease. Median overall survival was 21 months (95% CI, 16-34 months). Overall survivals at 3 and 4 years were 36% and 31%, respectively 5/19/2016 Cancer pp 4740 4706, 15 October 2011 19
Metastasectomy for Distant Metastatic Melanoma: Analysis of Data from the First Multicenter Selective Lymphadenectomy Trial 291 patients with stage IV recurrence, 161 (55 %) underwent surgery with/without systemic therapy Median survival: 15.8 vs. 6.9 months 4-year survival: 20.8 vs. 7.0% (p < 0.0001; HR 0.406) M1a median > 60 vs. 12.4 months, p = 0.0001 M1b median 17.9 vs. 9.1 months, p = 0.11 M1c median 15.0 vs. 6.3 months p = 0.0001 5/19/2016 Ann Surg Oncol. 2012 Aug;19(8):2547-55. 20
Holy Grail for Stage IV Melanoma: Surgical Resection + Adjuvant Therapy Randomized, double-blind, placebo-controlled phase 3 trial Accrual Goal 600-700 Primary endpoint: Overall Survival Note: E1609 addresses NED M1a and M1b disease Surgical Resection Rendering Patient NED Stratification Factors Number of individual lesions: 1, 2-3, 4-5 Site of mets: M1a: softtissue & nodal mets M1b: visceral mets R A N D O M I Z E Novel Agent(s) Placebo? Ipi? BRAF inhibitor?
Holy Grail for Stage IV Melanoma: Neoadjuvant Therapy + Surgical Resection Randomized, double-blind, placebo-controlled phase 3 trial Accrual Goal: Small numbers 300-400 Primary endpoint: Pathologic Complete Response Note: Neoadjuvant trials address NED IIIc M1ab disease Stratification Factors Number of individual lesions: 1, 2-3, 4-5 Site of mets: M1a: softtissue & nodal mets M1b: visceral mets R A N D O M I Z E Novel Agent(s) Checkpoint inhibitors? Targeted inhibitors? Surgical Resection Rendering Patient NED
Outline 2015 Therapeutic options: Stage IV patients» Systemic» Surgical Therapeutic options: Stage III patients» Systemic» Surgical Sentinel Node Update 5/19/2016 23
Stage IIIc IV M1a Metastatic Melanoma 5/19/2016 24
Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. Eligible: Unresectable IIIb, IIIc, M1a, M1b, M1c R A N D O M I Z E TVEC GMC-SF Primary outcome: Durable response rate Secondary outcome: Overall survival Andtbacka RH, Kaufman HL, Collichio F, et al., J Clin Oncol. 2015 Sep 1;33(25):2780-8. 5/19/2016 26
Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. Andtbacka RH, Kaufman HL, Collichio F, et al., J Clin Oncol. 2015 Sep 1;33(25):2780-8. 5/19/2016 27
Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. Andtbacka RH, Kaufman HL, Collichio F, et al., J Clin Oncol. 2015 Sep 1;33(25):2780-8. 5/19/2016 28
After 3 Injections..
US FDA Approved Stage IIIb,c M1a,b,c Systemic Therapy Options Andtbacka RH, Kaufman HL, Collichio F, et al., J Clin Oncol. 2015 Sep 1;33(25):2780-8 5/19/2016 30
Outline 2015 Therapeutic options: Stage IV patients» Systemic» Surgical Therapeutic options: Stage III patients» Systemic» Surgical Sentinel Node Update 5/19/2016 31
(MSLT-I) Compares Immediate vs. Delayed CLND for Nodal Metastases Melanoma 1.2-3.5mm SN(-) WEX + SNB 60% Observation Randomized SN(+) Immediate CLND WEX + Watch & Wait Observ. 40% Nodal Recurrence Delayed CLND Melanoma-specific Survival p=ns Morton, NEJM 2006
(MSLT-I) Compares Immediate vs. Delayed CLND for Nodal Metastases Melanoma 1.2-3.5mm 5 year Melanoma Survival: SN(-) WEX + SNB 60% Observation Randomized SN(+) Immediate CLND WEX + Watch & Wait Observ. 40% Nodal Recurrence Delayed CLND Mean # Nodes 4.3 1.4 3.3 90.2% 72.3% 52.4% HR 2.48; p<0.001 HR 0.51; p<0.001 Morton, NEJM 2006
Morton, NEJM 2006 To come Patients with T2/T3 melanomas and nodal metastases derive a 20% absolute survival advantage with a SN procedure and CLND as compared to watchful waiting CAVEAT: DSMB advised release of data to physicians and public because multiple endpoints had been reached, but not overall survival
No survival advantage 1/2008 Standard of care for patients with T2 or T3 melanoma 24% False-positivity 1/2008
Demonstrating Biology Metastatic melanoma cells, regardless of the size of the cluster, have biologic relevance Ollila et al., JACS 2009 Society of Surgical Oncology Position Statement Annals of Surgical Oncology 2012
Recurrence and Death events for each tumor burden group (n=578) Tumor Burden Node negative N (% ) Recurrence n(%) Distance Recurrence n(%) Death n(%) 488 (84%) 56 (11%) 35 (7%) 52 (11%) <0.1mm 33 (6%) 8 (24%) 5 (15%) 5 (15%) 0.1-1.0mm 27 (5%) 10 (37%) 6 (22%) 6 (22%) >1.0mm 30 (5%) 21 (70%) 14 (47%) 12 (40%) Ollila et al., JACS 2009
(MSLT-I) Compares Immediate vs. Delayed CLND for Nodal Metastases Melanoma 1.2-3.5mm SN(-) WEX + SNB 60% Observation Randomized SN(+) Immediate CLND WEX + Watch & Wait Observ. 40% Nodal Recurrence Delayed CLND Melanoma-specific Survival p=ns Morton, NEJM 2014
(MSLT-I) Compares Immediate vs. Delayed CLND for Nodal Metastases Melanoma 1.2-3.5mm 10 year Melanoma Survival: SN(-) WEX + SNB 60% Observation Randomized SN(+) Immediate CLND WEX + Watch & Wait Observ. 40% Nodal Recurrence Delayed CLND Mean # Nodes 4.3 1.4 3.3 85.1% 62.1% 33.5% HR 3.09; p<0.001 HR 0.51; p<0.001 Morton, NEJM 2014
Recommendations for Stage III SN+ Patients Patients with any disease, including submicroscopic (<0.1mm) deposits of metastatic melanoma have biologically relevant, potentially life-threatening disease. CLND is recommended unless enrolled on a clinical trial Systemic adjuvant therapy options: observation, ipilimumab or clinical trial
Recommendations for Palpable Stage III Patients Staging with PET/CT CLND is recommended unless enrolled on a clinical trial Systemic adjuvant therapy options: observation, TVEC, ipilimumab or clinical trial
UNC Dermatology & Skin Cancer Center Thank you NC Cancer Hospital 42