MELANOMA Updated May 2018 by: Dr. Michael Herman (PGY-5 Medical Oncology Resident, University of Toronto) Reviewed by: Dr. Sudha Rajagopal (Medical Oncologist, Carlo Fidani Regional Cancer Centre, University of Toronto) DISCLAIMER: The following are study notes compiled by the above PGY-5 medical oncology resident and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College.

A) PUBLIC HEALTH

EPIDEMIOLOGY - Incidence: 7thmost common cancer in Canada; 19th in the world. Incidence is rising.

o The 15-49 age group is most affected, with melanoma being 4thmost common cancer in this group.

- Mortality:14thmost common cause of cancer death in Canada in men, and 15thin women. RISK FACTORS - Environmental/Characteristics:

o UV radiation (outdoors or tanning beds), blistering sunburn, fair complexion – light eyes and skin that burns easily, increased number of melanocytic nevi, dysplastic nevi, congenital melanocytic nevi, immunosuppression, family history of melanoma, personal history of melanoma or non-melanoma skin cancer, familial atypical multiple mole melanoma syndrome (FAMMM)

- Genetic: o High risk: p16 (INK4A) germline mutation, also known as CDKN2A;CDK4,

xeroderma pigmentosum genes, BAP1, TERT o Low to moderate risk: BRCA2, retinoblastoma gene (RB1), melanocortin-1 receptor

gene, MITF (E318K) variant

PREVENTION & SCREENING - All individuals should assess moles for ABCDE: Asymmetry, border irregularity, color variation,

diameter greater than 6 mm, evolving morphologically or symptomatically - Surveillance skin exams are indicated for patients at high risk (personal or family history of

melanoma, CDKN2A mutation carriers, FAMMM, immunosuppressed)

B) PRESENTATION & DIAGNOSIS

SYMPTOMS & SIGNS

- Common symptoms/signs: see ABCDE above. In transit lesions: separate lesions from primary <2cm away. Satellite lesions: >2cm from primary but within local lymph node drainage area.

- Common presentations: evolving mole. If acral lentiginous, often misdiagnosed as fungal infection. If metastatic, signs/symptoms related to involved sites.

INVESTIGATIONS - Laboratory: LDH optional for stage III, recommended for stage IV. - Diagnostic Imaging: variable practices, guidelines differ. - From Alberta Health Services:

- Stage IA, low risk: image only if specific signs/symptoms. - Stage IB, intermediate risk or II high risk: CXR indicated if >4mm thick, otherwise

optional - Higher stages: Consider baseline imaging CT chest/abdomen/pelvis, MRI/CT of head,

+/- PET. - In any stage image for specific signs/symptoms.

- From ESMO 2015: - Low-risk melanoma (pT1a): no other investigations necessary. - For pT1b-T3a: US for locoregional lymph node metastases - For >pT3a: CT or PET recommended.

- From NCCN 2018: - Stage IA-II: image only if specific signs/symptoms - Stage IIIA: consider imagine - Stage IIIB/C: baseline imagine recommended with CT chest/abdo/pelvis or PET scan, +/-

MRI brain - Diagnostic procedures:

- Biopsy: Excisional preferred. Punch or incisional biopsies may be adequate. Multiple areas may need to be sampled. Superficial shave biopsy strongly discouraged.

- Sentinel lymph node biopsy: See Treatment Section.

PATHOLOGY & MOLECULAR BIOLOGY - Common Histology: superficial spreading 65%, nodular 25%, acral-lentiginous 5%,

lentigo maligna 5%, mucosal <1%.Uveal melanoma can be classified into Class 1a and b (low metastatic potential) or class 2 (high metastatic potential) based on gene expression.

- Common Metastatic Sites: lung, liver, brain. - Relevant Molecular Biology:

1. MAPK pathway (mitogen activated protein kinase), is activated in the majority of melanomas. Includes the RAS family of G-proteins, which are important signal transducers. Activating NRAS mutation occurs in 10-15% melanomas, and is a driver of oncogenesis.

o Most important mediators downstream of activated RAS are BRAF and CRAF kinases. BRAF activating mutation in 40-50% of melanoma patients. BRAF V600E mutation is most common, followed by V600K. Small molecule inhibitors of BRAF: vemurafenib, dabrafenib, encorafenib.

o MEK is downstream from BRAF, and BRAF mutation correlates with response to MEK inhibitors (e.g.: trametinib, cobimetinib, binimetinib).

o CRAF pathway activation requires several steps and there are no descriptions of activating CRAF mutations.

2. C-KIT mutations: Present in 15-20% of acral or mucosal melanomas, and less (i.e. 2% in one study) in areas of chronic skin damage (Handolias, Pig Cell Mel 2010). Imatinib, nilotinib activity has been shown in phase II studies (Hodi, JCO 2013; Carvajal, Clin Can Res 2015).

3. GNAQ or GNA11: most common mutations in uveal melanoma. Lead to activation

of downstream signaling such as MAPK pathway.

STAGING

AJCC 8thedition Tis Thickness Ulceration status/ mitoses

(mm) T1 <=1.00 a. no ulceration and mitosis <1/mm2

b. with ulceration or mitosis >=1/mm2 T2 1.01-2.00 a. no ulceration

b. with ulceration T3 2.01-4.00 a. no ulceration

b. with ulceration T4 >4.00 a. no ulceration

b. with ulceration N # met nodes Nodal met burden N0 0 NA N1 0-1 a. clinically occult, no MSI

b. clinically detected, no MSI c: 0 nodes, MSI present

N2 1-3 a. 2-3 nodes clinically occult, no MSI

b. 2-3 nodes clinically detected, no MSI c: 1 node clinical or occult, MSI present

N3 >1 node a. >3 nodes clinically occult, no MSI

b. >3 nodes clinically detected, no MSI c: >1 node clinical or occult, MSI present

M Site M0 No distant mets M1a Distant skin, SC

or nodal mets M1b Lung mets M1c All other visceral

mets M1d Brain mets M(0) Normal LDH M(1) Elevated LDH

Stage 0 Tis N0 M0 Stage IA T1a N0 M0 Stage IB T1b or T2a N0 M0 Stage IIA T2b or T3a N0 M0 Stage IIB T3b or T4a N0 M0 Stage IIC T4b N0 M0 Stage IIIA T1-2a N1a, N2a M0 Stage IIIB T0-2a

T1-2a T2b-3a

N1b-c N2b N1a-2b

M0

Stage IIIc

T0 T1a-3a T3b-4a

N2b-c, N3b-c N2c-N3c Any N

M0

T4b N1a-2c Stage IIId T4b N3a-c M0

Stage IV Any Any M1 C) TREATMENT LOCALIZED / ADJUVANT

- Bottom Line General Approach: Surgical resection followed by adjuvant therapy if high risk Surgery:

- Wide local excision (WLE). If in-situ: 5 mm margins. If <=1mm depth of invasion: 1 cm margin. If 1.01-2mm depth: 1-2 cm margin. >=2.01mm: 2 cm margin.

- Sentinel lymph node biopsy (SLN bx): If depth of invasion >0.8mm. Consider for <0.8mm with high risk features such as ulceration, high mitotic rate, lymphovascular invasion (LVI) (not standardized criteria). SLN bx used for staging, does not affect OS.

- Lymph node dissection (LND) – should not be done prophylactically. Can be done if proven SLN positive or diagnosed with nodal relapse. (Balch, Ann Surg 224: 225, 1996)

- MSLT-II study shows no survival benefit to CLND therefore US nodal surveillance of SLN positive patients is now becoming the standard of care.

Radiation:

- Consider high dose radiation post-op for: microscopic extranodal extension, microscopic residual disease, extensive nodal disease where complete resection unlikely (one or more parotid nodes, two or more cervical or axillary nodes, three or more inguinal nodes); resected bulky nodal disease >3cm diameter. If regional nodes unresectable can consider palliative rads.

Systemic therapy:

- Interferon-alpha 2b (20x106U/m2/d IV 5 days/week x4 weeks, followed by 10x106U/m2 SC 3 times weekly for 48 weeks).

o Consider for the following high-risk patients: tumor thickness >=4.0 mm; tumour thickness 2.01-4.0 mm with ulceration; resected in-transit metastases; regional lymph node metastases clinically apparent or found on SLN/LND; regional lymph node recurrence; involved nodes excised but no known primary melanoma.

o CCO and ESMO guidelines indicate Pegylated IFN also acceptable alternative. Dose: 6 mcg/kg/wk SC x8 wks followed by 3 mcg/kg/wk SC x 5 yrs.

o Prognosis: 5yr OS for resected stage II-III cutaneous melanoma is 60%. Can be improved by 3% with adjuvant IFN. (Mocellin, Cochrane Database 2013).

o Common side effects are fatigue, fever, myalgia, anorexia, nausea, headache and chills (“flu-like” symptoms), depression, increased liver enzymes

- Newer agents: Preferred if funding available - Ipilimumab: 3mg/kg q 3 weeks x4 doses then q 3 months for up to 3 years. Studied in stage

3A-C with at least 1mm lymph node met - Nivolumab: 3mg/kg q 2 weeks for up to 1 year. Studies in stage 3B-C and resected stage 4 - Pembrolizumab: 200mg q 3 weeks for up to 18 doses. Studied in stage 3A-C with at least

1mm lymph node met - Dabrafenib/Trametinib: Dabrafenib 150mg twice daily + trametinib 2mg once daily for up to

12 months. Studied in stage 3A-C with at least 1mm lymph node met, BRAF V600K/V600E positive

- See Trial references below

MSLT 1- Final report of Sentinel-node biopsy vs nodal observation in melanoma (Morton,

NEJM, 2014, p 599-609

Regimen ● Wide local excision for all ● Arm 1: SLN bx + LND if positive SLN/nodal relapse ● Arm 2:Observation + LND if nodal relapse Primary Endpoint ● Melanoma-specific survival Inclusion/Exclusion ● Inclusion: Localized cutaneous melanoma Clark level III with Breslow Criteria thickness >=1.00mm, or Clark IV with any Breslow thickness. Size (N) ● 2001 patients Results ● 10-yr melanoma-specific survival:No sig difference. Mean (SE) 81.4+/-1.5% SLN vs 78.3+/-2.0% obs (HR 0.84 95%CI 0.64-1.09, p=0.18) ● 10-yr DFS:Intermediate thickness mean (±SE): 71.3±1.8% vs 64.7±2.3% obs (HR 0.76, p=0.01) Thick: 50.7±4.0% vs 40.5±4.7%, (HR 0.70, p=0.03) ● 10yr melanoma-specific survival rate with vs without nodal mets:intermediate thickness: 62.1±4.8% vs 85.1±1.5% (HR 3.09, p<0.001). Thick: 48.0±7.0% vs 64.6±4.9%, (HR 1.75, p=0.03). ● Quality of life: not reported. Toxicity ● Not reported. Conclusion SLN biopsy-based management improves DFS, but not melanoma-specific survival for all patients. It prolongs distant DFS and melanoma-specific survival for patients with nodal metastases from intermediate-thickness melanomas. Other Comments ● Analyzed by intermediate thickness melanoma 1.20-3.50mm vs thick melanoma >3.50mm:

MSLT II Regimen • Arm 1: Complete lymph node dissection

• Arm 2: Observation, with clinical and U/S surveillance every 4 months during the first 2 years, every 6 months during years 3 through 5, and then annually

Mechanism of Action of Experimental Drug N/A

Primary Endpoint • Melanoma specific survival Inclusion/Exclusion Criteria

• Inclusion: Age 18-75, clinically localized cutaneous melanoma, ECOG 0-1, non-melanoma specific life expectancy >10 years, tumor positive sentinel lymph node by pathology or RT-PCR

Size (N) • N=1939 Results • 3 year melanoma specific survival: 86% in both groups HR 1.08 95% CI

0.88-1.34 • 3 year DFS: 68% CLND vs 63% observation, driven by mostly lymph

node recurrences. No difference in distant metastasis free survival, HR 1.10 95% CI 0.92-1.31

Toxicity • Increased rates of lymphedema (24% vs 6%) in CLND group

Conclusion • In patients with positive SLNB, immediate completion lymph node dissection decreases lymph node recurrence vs observation but does not improve melanoma specific survival

Other Comments

Cochrane Meta-analysis (Mocellin, Cochrane Database, 2013) Regimen ● Adjuvant IFNalpha Primary Endpoint ● Disease-free survival, Overall survival Inclusion/Exclusion ● AJCC Stage II-III resected cutaneous melanoma Criteria Size (N) ● 18 RCTS, 10499 patients Results ● Survival:9% risk reduction (HR 0.91, 95% CI 3-15%). NNT 35 (95% CI 21-108). ● DFS:17% risk reduction (HR 0.83, 95% CI 13-22%). Conclusion ● Results support efficacy of adjuvant IFN alpha for high risk melanoma, in terms of DFS and OS. It is valid as a reference treatment for RCTS of new therapeutics in this setting. Other Comments ● Subgroup analysis did not answer questions re: dosage, duration, and node positive/negative. ● No significant between-study heterogeneity.

EORTC 18071 (NEJM 375;19 November 10, 2016. Eggermont et al.)

Regimen ● Arm 1: Ipilimumab 10 mg/kg q3 wks x4 doses, then maintenance q3 months for up to maximum of 3 years ● Arm 2: Placebo

Mechanism of ● Ipilimumab: fully human IgG1 to the cytotoxic Action of T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint molecule Experimental Drug Primary Endpoint ● Recurrence-free survival. Inclusion/Exclusion ● Inclusion: Stage IIA-C with no in-transit metastases. Must have Criteria completely excised primary with negative margins. Complete lymph

node dissection required within 12 weeks before randomized. ● Exclusion: ECOG >1, autoimmune disease, uncontrolled infection cardiovascular disease, major lab abnormalities in CBC, CR, liver enzymes or LDH. Use of systemic steroids or previous systemic therapy for melanoma

Size (N) ● 951 patients Results

● RFS: 40.8 % (36 – 45.6) vs 30.3% (26 -34.3) at 5 years. HR 0.76 ● OS: 65.4 (60.8–69.6) vs 65.4 (60.8–69.6) at 5 years

Toxicity ● Grade 3/4: diarrhea, colitis, hepatotoxicity, hypophysitis. 1% of patients died due to toxicity.

Conclusion ● Adjuvant ipilimumab significantly improved recurrence-free survival in this group of patients. Risk-benefit ratio requires further assessment based on distant metastasis-free survival and overall survival.

Other Comments ● 29% of patients received at least 7 doses (1 year) of ipilimumab. ● In post-hoc analyses, benefit of ipilimumab more pronounced in stage IIIC, ulcerated melanomas, and macroscopic lymph node involvement.

CheckMate-238 (Weber, NEJM, 2017, p1824-1835) Regimen • Arm 1: Nivolumab 3mg/kg q 2 weeks for up to 1 year

• Arm 2: Ipilimumab 10mg/kg q 3 weeks x4 and then q 12 weeks for up to 1 year

Mechanism of Action of Experimental Drug

• Nivolumab: fully human IgG4 PD-1 checkpoint inhibitor, selectively blocks PD-1 receptor.

Primary Endpoint • Recurrence free survival Inclusion/Exclusion Criteria

• Inclusion: 15 years or older, stage 3B, 3C or resected stage 4 (AJCC 7th edition), ECOG 0-1. Randomization within 12 weeks of surgery. Brain mets were allowed

• Exclusion: uveal melanoma, history of autoimmune disease, previous nonmelanoma cancer without complete remission for more than 3 years, systemic use of glucocorticoids, previous systemic therapy for melanoma

Size (N) • 906 patients Results • Recurrence free survival: At 12 months 70.5 vs 60.8% and at 18

months 66.4 vs 52.7% both favoring Nivolumab. HR = 0.65 (95% C.I 0.51-0.83)

• HR for RFS in PDL-1 <5% 0.71. HR for RFS in PDL-1 >5% 0.50. Both statistically significant.

• Survival: not reported Toxicity • Grade 3-4 adverse events in 14.4% of Nivolumab treated patients vs

45.9% of Ipilimumab treated patients • Deaths: 0 in nivolumab group and 2 in ipilimumab group • Most common grade 3-4 AE in Nivolumab group: diarrhea, fatigue,

rash, increased ALT, hypophysitis Conclusion • Recurrence free survival was improved with Nivolumab compared

to Ipilimumab with lower adverse events. Improvement seen in PDL-1 expression above or below 5%

Other Comments

Combi-AD (Long, NEJM, 2017, p1813-1823) Regimen • Arm 1: Dabrafenib 150mg twice daily + trametinib 2mg once daily for up

to 12 months • Arm 2: Placebo

Mechanism of Action of Experimental Drug

• Dabrafenib: oral BRAF inhibitor. Trametinib: oral MEK inhibitor

Primary Endpoint • Relapse free survival Inclusion/Exclusion Criteria

• Inclusion: 18 years or older, resected stage 3A (lymph node metastasis of at least 1mm), 3B, 3C (AJCC 7th edition), BRAF V600K/V600E positive, randomization within 12 weeks of surgery, ECOG 0-1

• Exclusion: previous systemic therapy for melanoma Size (N) • 870 patients Results • Relapse free survival: At 12 months 88 vs 56%, and at 3 years 58 vs

39% favoring Dabrafenib/trametinib. HR= 0.47 (95% C.I 0.39-0.58) • Overall survival (interim analysis): At 12 months 97 vs 94%, and at 3

years 86 vs 77% favoring Dabrafenib/trametinib. HR = 0.57, however not significant because did not cross interim boundary

Toxicity • Grade 3-4 adverse events in 41% of those on Dabrafenib/trametinib • Most common grade 3-4 adverse events: hypertension, pyrexia, fatigue,

increased ALT/AST Conclusion • Adjuvant Dabrafenib/trametinib for resected stage 3 melanoma

with a BRAF mutation improves relapse free survival and overall survival over placebo

Other Comments

EORTC-1325 / Keynote-054 (Eggermont, NEJM, 2018) Regimen • Arm 1: Pembrolizumab 200mg q 3 weeks for up to 18 doses

• Arm 2: Placebo Mechanism of Action of Experimental Drug

• Pembrolizumab: monoclonal antibody against PDL-1

Primary Endpoint • Recurrence free survival in PDL-1 positive tumors Inclusion/Exclusion Criteria

• Inclusion: 18 years or older, stage 3A (if N1a had to have a micrometastasis of at least 1mm), 3B, or 3C (AJCC 7th edition), no in-transit lesions, randomization within 13 weeks of surgery, ECOG 0-1

• Exclusion: autoimmune disease, uncontrolled infections, use of systemic glucocorticoids, previous systemic therapy for melanoma

Size (N) • 1019 patients Results • Recurrence free survival: At 12 months 75.4 vs 61%, and at 18 months

71.4 vs 53.2% favoring pembrolizumab. HR= 0.57 (95% C.I 0.43-0.74) • Benefit in RFS seen in all subgroups including PDL-1 positive and

negative • Survival: not reported

Toxicity • Grade 3-4 adverse events occurred in 14.7% of patients treated with pembrolizumab

• Most common grade 3-4 events: T1DM, fatigue, diarrhea, rash, pneumonitis, hepatitis, hypophysitis

• 1 pembrolizumab related death due to myositis Conclusion • In patients with resected, high-risk stage III melanoma,

pembrolizumab was associated with a rate of recurrence-free survival at 1 year that was significantly higher than that with placebo

Other Comments

RECURRENT / METASTATIC DISEASE

- Bottom Line General Approach for Unresectable Stage III or IV: Clinical trial participation encouraged. Consider targeted BRAF/MEK therapy if eligible, otherwise immunotherapy. Optimal sequencing of targeted and immunotherapy remains unknown. Few receive chemotherapy.

BRAF V600 mutation positive 1stline options: - Combination of BRAF and MEK inhibitor

● Vemurafenib 960 mg po BID plus cobimetinib 60 mg po daily x 21d on, 7d off ● Dabrafenib 150 mg po bid plus trametinib 2 mg po daily ● Patients with an elevated LDH and multiple metastatic sites /bulky disease at diagnosis

may do worse with TKI therapy vs immunotherapy. However TKI can be considered upfront to debulk if funding available

- Immunotherapy (anti-PD-1 preferred to Ipilimumab): ● Anti-PD-1: Pembrolizumab 2mg/kg IV q3 wks or Nivolumab 3mg/kg IV q2 wks ● Anti-CTLA4: Ipilimumab 3 mg/kg IV q3 wks x4 doses ● Combined ipilimumab 3mg/kg IV and nivolumab 1mg/kg IV q3 wks x4, then

maintenance nivolumab 3mg/kg IV q2 wks BRAF mutation negative 1stline options:

- Immunotherapy (anti-PD-1 preferred to Ipilimumab): ● Pembrolizumab 2 mg/kg IV q3 wk or Nivolumab 3mg/kg IV q2 wks for 2 years ● Ipilimumab 3 mg/kg IV q3 wks x4 doses ● Combined ipilimumab 3mg/kg IV and nivolumab 1mg/kg IV q3 wks x4, then

maintenance nivolumab 3mg/kg IV q2 wks Studies are examining combined targeted and immunotherapy treatment, low dose ipi-Nivo treatment to improve toxicity, and sequencing strategies for BRAF positive tumours. 2ndline: If immunotherapy used 1stline, choose alternate immunotherapy or targeted agents if BRAF V600 positive. If ipilimumab used 1stline and response maintained for at least 6 months can re-challenge with ipilimumab. If targeted agents used first line, use immunotherapy 2ndline. If C-kit mutated: Imatinib may be funded on case-by case basis. Chemotherapy: dacarbazine, temozolomide, paclitaxel, nab-paclitaxel, carboplatin-paclitaxel. Chemotherapy has not shown overall survival benefit. DTIC has been a standard comparator in trials, but has never been studied versus placebo. Check with local provincial authority for approvals. Radiation: palliative for local control of symptomatic metastases. Stereotactic radiosurgery is preferred over whole brain radiation for brain metastases when possible. Surgery for resectable stage IV disease: Consider resection as a primary treatment, followed by adjuvant systemic therapy. No clear phase III data to support this approach but standard of care for completely resected met disease is to offer adjuvant treatment - Local recurrence/in-transits/satellites: Surgical consultation for excision, or possible intralesional injections (IL-2, Talimogene laherparepvec- T-vec), regional therapy (isolated limb perfusion with melphalan and/or TNF-a), or other experimental agents. Prognosis: 3yr OS in checkmate 067 ipi+nivo is 58% with tail on the curve suggesting some patients may be curatively treated. Ongoing follow-up needed Important Phase III Clinical Trials:

TARGETED THERAPY

COMBI-d (Long, Lancet, 2015, p 444-451)

Regimen ● Arm 1: Dabrafenib 150 mg po BID plus Trametinib 2 mg po daily ● Arm 2: Dabrafenib 150 mg po BID plus placebo

Mechanism of ● Dabrafenib: oral BRAF inhibitor Action of ● Trametinib: oral MEK inhibitor Experimental Drug Primary Endpoint ● PFS Inclusion/Exclusion ● Inclusion: BRAF Val600Lys or Val600Glu mutation-positive Criteria unresectable stage III or stage IV melanoma. No previous systemic

treatment for advanced or metastatic cancer. If had brain mets, must have been definitively treated and stable for minimum 12 weeks.

Size (N) ● 423 patients Results ● Survival:Median OS 25.1 mos vs 18.7 mos, HR 0.71 (95% CI

0.55-0.92, p=0.0107). ● PFS:Median PFS 11.0 mos vs 8.8 mos, HR 0.67 (95% CI 0.53-0.84, p=0.004). ● Overall response rate: 69% (95% CI 62-75) vs 53% (95% CI 46-60), p=0.0014. ● Quality of Life: not reported

Toxicity ● Grade 3/4 in >4% pts: Combo: Pyrexia. Dabrafenib: cutaneous squamous cell carcinoma.

Conclusion ● OS improvement establishes dabrafenib plus trametnib as standard targeted therapy for BRAF Val600 mutant advanced melanoma.

Other Comments ●

COMBI-v (Robert, NEJM, 2015, p 30-39)

Regimen ● Arm 1: Dabrafenib 150 mg po BID plus Trametinib 2 mg po daily ● Arm 2: Vemurafenib 960 mg po BID

Mechanism of ● Dabrafenib: oral BRAF inhibitor Action of ● Trametinib: oral MEK inhibitor Experimental Drug ● Vemurafenib: oral BRAF inhibitor Primary Endpoint ● OS Inclusion/Exclusion ● Inclusion: BRAF V600E or V600K mutation-positive unresectable Criteria stage III or stage IV melanoma. No previous systemic treatment for

advanced or metastatic cancer. If had brain mets, must be stable for minimum 12 weeks. ECOG 0-1.

Size (N) ● 704 patients Results ● Survival:OS at 12 mos 72% (95% CI 67-77%) vs 65% (95% CI

59-70%), HR 0.69 (95% CI 0.53-0.89, p=0.005). ● PFS:Median PFS 11.4 mos vs 7.3 mos, HR 0.56 (95% CI 0.46-0.69, p<0.001). ● Objective response rate:64% (95% CI 59.1-69.4) vs 51% (46.1-56.8), p<0.001. ● Quality of Life: not reported

Toxicity ● Grade 3/4 in >4% pts: Combo: Pyrexia, decreased ejection fraction. Vemurafenib: rash, cutaneous squamous cell carcinoma.

Conclusion ● Dabrafenib plus trametinib significantly improved OS compared with vemurafenib in BRAF mutant metastatic melanoma.

Other Comments ● Open-label study

coBRIM (Larkin, NEJM, 2014, p 1867-1876)

Regimen ● Arm 1: Vemurafenib 960 mg po BID plus Cobimetinib 60 mg po daily x21d, 7 d off. ● Arm 2: Vemurafenib 960 mg po BID plus placebo

Mechanism of ● Cobimetinib: oral MEK inhibitor Action of ● Vemurafenib: oral BRAF inhibitor Experimental Drug Primary Endpoint ● Investigator assessed PFS Inclusion/Exclusion ● Inclusion: BRAF V600 mutation-positive unresectable stage IIIc or Criteria stage IV melanoma. No previous systemic treatment for advanced or

metastatic cancer. If had brain mets, must be stable for minimum 12 weeks. ECOG 0-1.

Size (N) ● 495 patients Results ● Survival:OS interim analysis: 9 month rates 81% (95% CI 75-87%)

vs 73% (95% CI 65-80%). ● PFS:Median PFS 9.9 mos vs 6.2 mo (HR 0.51, 95% CI 0.39-0.68, p<0.001). ● Overall response rate:68% (61-73) vs 45% (95% CI 38-51), p<0.001 ● Quality of Life: not reported

Toxicity ● Grade 3/4 in >4% pts: Combo: diarrhea, rash, fatigue, increase ALT/AST/CK. Vemurafenib: rash, arthralgia, increased ALT, cutaneous SCC, keratoacanthoma.

Conclusion ● Cobimetinib plus vemurafenib is associated with significant PFS improvement, with some increase in toxicity.

Other Comments ● OS had not crossed prespecified hazard-ratio boundary for significance at the time of this analysis.

BRIM-3 long-term follow-up (McArthur, Lancet Oncol, 2014, p 323-332)

[Original BRIM-3 publication: Chapman, NEJM 2011, p 2507-2516] Regimen ● Arm 1: Vemurafenib 960 mg po BID 2 ● Arm 2: Dacarbazine 1000mg/mIV q3wk Mechanism of ● Vemurafenib: oral BRAF inhibitor Action of ● Dacarbazine: IV alkylating agent, prodrug of MTIC activated by Experimental Drug demethylation in liver. Primary Endpoint ● Co-primary endpoints: OS and PFS, analyzed in ITT Inclusion/Exclusion ● Inclusion: BRAF V600E and V600K mutation-positive unresectable Criteria stage IIIc or stage IV melanoma. No previous systemic treatment for advanced or metastatic cancer. If had brain mets, must be stable for minimum 12 weeks. ECOG 0-1. Size (N) ● 675 patients Results ● Survival:Median OS 13.6 mos (95% CI 12.0-15.2) vs 9.7 mos (7.9-12.8); HR 0.70 (95% CI 0.57-0.87; p=0.0008).

● PFS:Median PFS 6.9 mos (95% CI 6.1-7.0) vs 1.6 mos (95% CI 1.6-2.1); HR 0.38 (95% CI 0.32-0.46; p<0.0001). ● Objective response rate:57% vs 8.6 % (From online appendix). ● Quality of Life: not reported. Toxicity ● Grade 3/4 in >4% pts: cutaneous SC, keratoacanthomas, rash, abnormal liver function tests. For Dacarbazine: neutropenia. ● Grade 5 events in 2% of both groups. Conclusion ● Vemurafenib improves survival in patients with BRAF V600E and V600K mutations. Other Comments ● Open label study

BREAK-3 (Hauschild, Lancet, 2012, p 358-365)

Regimen ● Arm 1: Dabrafenib 150 mg po BID

2 ● Arm 2: Dacarbazine 1000 mg/mq3wks

Mechanism of ● Dabrafenib: reversible ATP-competitive inhibitor that selectively Action of inhibitors BRAF V600E kinase, part of the MAPK pathway. Experimental Drug ● Dacarbazine: IV alkylating agent, prodrug of MTIC activated by

demethylation in liver. Primary Endpoint ● Investigator-assessed PFS analyzed by ITT Inclusion/Exclusion ● Inclusion: BRAF V600E mutation-positive unresectable stage IIIc or Criteria stage IV melanoma. No previous systemic treatment for advanced or

metastatic melanoma, except IL-2. If had brain mets, must be stable for minimum 3 months after surgery/SRS. ECOG 0-1.

Size (N) ● 250 patients Results ● Survival:not reported.

● PFS:Median PFS 5.1 mos vs 2.7 mos. HR 0.30 (95% CI 0.18-0.51; p<0.0001). ● Overall response rate:50% (95% CI 42.4-57.1) vs 6% (95% CI 1.8-15.5) ● Quality of Life: not reported.

Toxicity ● Grade 3/4 in >4%: Dabrafenib: SCC/keratoacanthomas. Dacarbazine: neutropenia.

Conclusion ● Dabrafenib significantly improves PFS compared to dacarbazine.

Other Comments ● Open label study METRIC (Flaherty, NEJM, 2012, 107-114)

Regimen ● Arm 1: Trametinib 2 mg po daily

● 2

Arm 2: Chemotherapy: Dacarbazine 1000 mg/mIV q3 wks OR 2 Paclitaxel 175 mg/mIV q3wk

Mechanism of ● Trametinib: Small molecular selective inhibitor of MEK1 and MEK2. Action of ● Dacarbazine: IV alkylating agent, prodrug of MTIC activated by

Experimental Drug demethylation in liver. ● Paclitaxel: taxane, microtubule inhibitor. ● Cisplatin: platinum, crosslinks DNA.

Primary Endpoint ● PFS Inclusion/Exclusion ● Inclusion: BRAF V600E and V600K mutation-positive unresectable Criteria stage IIIc or stage IV melanoma. No previous systemic treatment for

advanced or metastatic melanoma, except IL-2. If had brain mets, must be stable for minimum 3 months after surgery/SRS. ECOG 0-1.

Size (N) ● 322 patients Results ● Survival:6 month OS 81% vs 67% (HR 0.54, 95% CI 0.32-0.92;

p=0.01). Median OS not reached. ● PFS: 4.8 mos vs 1.5 mos (HR 0.45, 95% CI 0.33-0.63; p<0.001). ● Overall response Rate:22% (95% CI 17-28) vs 8% (95% CI 4-15) p=0.01. ● Quality of Life:

Toxicity ● Grade 3/4 in >4%: Trametinib: rash, fatigue, hypertension, decreased ejection fraction, cardiac-related events. Chemotherapy: none meeting this criteria.

Conclusion ● Trametinib improved PFS and OS compared to chemotherapy in BRAF V600E or V600K mutated metastatic melanoma.

Other Comments ● Open label study

IMMUNOTHERAPY Keynote-006 (Robert, NEJM, 2015, 2521-2532)

Regimen ● Arm 1: Pembrolizumab 10 mg/kg IV q2wks (P2) ● Arm 2: Pembrolizumab 10 mg/kg IV q3wks (P3) ● Arm 3: Ipilimumab 3 mg/kg IV q3wks (IPI) Mechanism of ● Pembrolizumab: monoclonal antibody to programmed cell death-1 Action of (PD-1), a checkpoint of the effector stage of the immune system Experimental Drug ● Ipilimumab: fully human IgG1 to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint molecule Primary Endpoint ● Co-primary endpoints: PFS and OS Inclusion/Exclusion ● Inclusion: unresectable stage III or IV melanoma; had no more than Criteria one previous systemic therapy for advanced disease. ECOG 0-1. ● Exclusion: previous CTLA-4, PD-1 or PD-L1 treatment; ocular melanoma; active brain mets; history of serious autoimmune disease. ● If BRAF positive were required to have previous BRAF inhibitor if abnormal LDH and clinically significant symptoms or rapidly progressive disease. Size (N) ● 834 patients Results ● Survival:12-month OS rates: 74.1% (P2) vs 68.4% (P3) vs 58.2% (IPI). HR 0.63 (95% CI 0.47-0.83, p=0.0005 for P2); HR 0.69 (95%CI 0.52-0.90, p=0.0036). ● PFS: 6month PFS rates: 47.3% (P2) vs 46.4% (P3) vs 26.5% (IPI). HR 0.58, (95% CI 0.46-0.72 and 0.47-0.72) p<0.001 (for P2 and P3 vs IPI). ● Response Rate:33.7% (95% CI 28.2-39.6) (P2) vs 32.9% (95% CI 27.4-38.7) (P3) vs 11.9 (95% CI 8.3 -16.3) (IPI). P<0.001 for P2 and

P3 vs IPI. ● Quality of Life: Not reported. Toxicity ● Grade 3/4 in >4% pts: P2 none, P3 none. IPI: colitis. Conclusion ● Pembrolizumab prolongs PFS and OS and has less high-grade toxicity compared to ipilimumab in advanced melanoma. Other Comments ● Open label study CHECKMATE-066 (Robert, NEJM, 2015, p 320-330)

Regimen ● Arm 1: Nivolumab 3 mg/kg IV q2wk plus dacarbazine-matched placebo q3wk 2 ● Arm 2: Dacarbazine 1000mg/mIV q3wk plus nivolumab-matched placebo q2wk

Mechanism of ● Nivolumab: fully human IgG4 PD-1 checkpoint inhibitor, selectively Action of blocks PD-1 receptor. Experimental Drug ● Dacarbazine: IV alkylating agent, prodrug of MTIC activated by

demethylation in liver. Primary Endpoint ● OS Inclusion/Exclusion ● Inclusion: Unresectable stage III or IV melanoma. No previous Criteria treatment for advanced disease. ECOG 0-1.

● Exclusion: active brain mets, uveal melanoma, history of serious autoimmune disease.

Size (N) ● 418 patients Results ● Survival:12 month OS rate: 72.9% (95% CI 65.5-78.9) vs 42.1%

(95% CI 33.0-50.9). HR 0.42 (99.79% CI 0.25-0.73; p<0.001) ● PFS/TTP:Median PFS 5.1 mos vs 2.2 mos (HR 0.43, 95% CI 0.34-0.56; p<0.001). ● Objective response rate:40.0% (95% CI 33.3-47.0) vs 13.9 (95% CI 9.5-19.4). OR 4.06; p<0.001. ● Quality of Life: not reported.

Toxicity ● Grade 3/4 in >4% pts: Nivolumab: none. Dacarbazine: thrombocytopenia, neutropenia.

Conclusion ● Nivolumab has significant improvement in OS and PFS compared to dacarbazine in previously untreated metastatic melanoma that is BRAF-mutation negative.

Other Comments ● Survival benefit seen across all subgroups of PD-L1 staining.

Checkmate 037 (Weber, Lancet Oncol, 2015, 375-384)

Regimen ● Arm 1: Nivolumab 3 mg/kg IV q2 wks 2 ● Arm 2: Chemotherapy. Option of: Dacarbazine 1000 mg/mIV q3 wks 2 or paclitaxel 175 m/mplus carboplatin AUC 6 IV q3wks.

Mechanism of ● Nivolumab: fully human IgG4 PD-1 checkpoint inhibitor, selectively

Action of blocks PD-1 receptor. Experimental Drug ● Dacarbazine: IV alkylating agent, prodrug of MTIC activated by

demethylation in liver. ● Paclitaxel: taxane, microtubule inhibitor. ● Cisplatin: platinum, crosslinks DNA.

Primary Endpoint ● Co-primary endpoints: Objective response rate and OS Inclusion/Exclusion ● Included: Unresectable stage IIIC or IV metastatic melanoma. Criteria Progressed on anti-CTLA-4 if BRAF negative. If BRAF positive, have

progressed on BRAF inhibitor and anti-CTLA-4. ● Excluded: active brain or leptomeningeal mets, history of autoimmune disease, previous anti-PD-1/anti-PD-L1/anti-PD-L2.

Size (N) ● 272 patients Results ● Survival:not reported. Minimum # of events has not been reached.

● PFS:No sig’t difference. Median PFS 4.7 mos (95% CI 2.3-6.5) vs 4.2 mos (95% CI 2.1-6.3) [ITT population]. ● Response Rate:31.7% (95% CI 23.5-40.8) vs 10.6% (95% CI 3.5-23.1) [per-protocol population]. ● Quality of Life: not reported.

Toxicity ● Grade 3/4 in >4% pts: Nivolumab: none. ● Chemotherapy: neutropenia, thrombocytopenia, anemia.

Conclusion ● Nivolumab had higher objective response rates and fewer side effects compared to chemotherapy for melanoma progressed on ipilimumab. There was no difference in PFS.

Other Comments ● Open label study ● Authors discussed possible reasons for lack of difference in PFS: imbalance in prognostic factors favouring chemo group, immature data, false-positive progression in nivolumab when using RECIST v1.1 instead of immune-related response criteria.

Ipilimumab plus dacarbazine metastatic first line (Robert, NEJM, 2011, p 2517-2526)

Regimen 2 ● Arm 1: Ipilimumab 10 mg/kg plus dacarbazine 850 mg/mq3 wks 2 ● Arm 2: Dacarbazine (DTIC) 850 mg/mplus placebo. Given wk 1,4,7,10 and then dacarbazine alone q3wks to week 22. Mechanism of ● Ipilimumab: fully human IgG1 to the cytotoxic Action of T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint molecule Experimental Drug ● Dacarbazine: IV alkylating agent, prodrug of MTIC activated by demethylation in liver. Primary Endpoint ● OS Inclusion/Exclusion ● Inclusion: unresectable stage III or IV melanoma. ECOG 0-1. No prior Criteria treatment in metastatic setting. ● Exclusion: autoimmune disease, treatment with immunosuppressants or long-term steroids. Evidence of brain mets on imaging, ocular/mucosal melanoma. Size (N) ● 502 patients Results ● Survival:Median OS 11.2 mos (95% CI 9.4-13.6) vs 9.1 mos (95% CI 7.8 - 10.5). HR 0.72, p<0.001).

● PFS:24% reduction in risk of progression, HR 0.76, p=0.006. ● Overall response rate:15.2% vs 10.3% ● Quality of Life: not reported. Toxicity ● Grade 3/4 in >4% pts: Ipi+DTIC: diarrhea, increased LFTs. DTIC: none. Conclusion ● Ipilimumab with dacarbazine improved OS compared to dacarbazine in previously untreated melanoma. Other Comments ● PFS was similar at the 12 week assessment, but afterwards curves separated.

Ipilimumab in metastatic melanoma (Hodi, NEJM, 2010, 711-723)

Regimen ● Arm 1: Ipilimumab 3 mg/kg IV q3 wks (up to 4 doses) + gp100 (IG) ● Arm 2: Ipilimumab 3 mg/kg IV q3 wks (up to 4 doses) (I) ● Arm 3: gp100 (G)

Mechanism of ● Ipilimumab: fully human IgG1 to the cytotoxic Action of T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint molecule Experimental Drug ● Gp100: vaccine comprised of HLA-A*0201-restricted peptides derived

from gp100, a melanosomal protein. Primary Endpoint ● OS Inclusion/Exclusion ● Inclusion: unresectable stage III or IV melanoma, and received a Criteria previous treatment containing one or more of: dacarbazine,

temozolomide, carboplatin, IL-2, fotemustine. ECOG 0-1. Positive HLA-A*0101. ● Exclusion: previous anti-CTLA4 treatment, autoimmune disease, untreated CNS mets, use of immunosuppression/steroids.

Size (N) ● 403 patients Results ● Survival:Median OS 10.0 mos (IG) vs 6.4 mos (G); HR 0.68,

p<0.001. Median OS 10.1 mos (I); HR 0.66 p=0.003 (compared w/G). No difference OS between IG and I. ● PFS:Median PFS 2.76 mos (95% CI 2.73-2.79) (IG) vs 2.86 mos (95% CI 2.76-3.02) (I) vs 2.76 mos (95% CI 2.73-2.83) (G). ● PFS rate at week 12: 49.1% 49.1% (95% CI, 44.1 to 53.9) (IG) vs 57.7% (95% CI, 48.9 to 65.5) (I) vs 48.5% (95% CI, 39.6 to 56.7) (G) ● 19% reduction in risk of progression w IG vs G (HR 0.81, p<0.05). 36% reduction in risk w I vs G (HR 0.64; p<0.001). Reduction in risk w IG was less than I (HR 1.25, p=0.04). ● Overall response rate:5.7% (95% CI 3.7–8.4) (IG) vs 10.9% (95% CI 6.3–17.4) (I) vs 1.5% (95% CI 0.2–5.2) (G). ● Quality of Life: not reported.

Toxicity ● Grade 3/4 in >4% pts: IG: diarrhea, fatigue. I: diarrhea, fatigue, colitis. G: abdominal pain, dyspnea, anemia. ● 7 deaths associated with immune-related adverse events in the IG or I groups. Of those, most related to bowels, 1 liver failure, 1 GBS.

Conclusion ● Ipilimumab with or without gp100 improves OS in previously treated metastatic melanoma compared to gp100 alone. Side effects are severe and/or long-lasting, but most can be reversed.

Other Comments ● PFS was similar at the 12 week assessment, but afterwards curves

separated.

Checkmate 067 (Wolchok et al October 5, 2017 N Engl J Med 2017; 377:1345-1356)

Regimen ● Arm 1: Nivolumab 3mg/kg IV q2 wks alone (N)

● Arm 2: Nivolumab 1mg/kg IV q3 wks + ipilimumab 3mg/kg IV q3wks x4 doses, followed by Nivo 3 mg/kg IV q2wks for cycles >=3 (NI) ● Arm 3: Ipilimumab 3mg/kg IV q3 wks x4 doses alone (I)

Mechanism of ● Nivolumab: fully human IgG4 PD-1 checkpoint inhibitor, selectively Action of blocks PD-1 receptor Experimental Drug ● Ipilimumab: fully human IgG1 to the cytotoxic

T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint molecule

Primary Endpoint ● Co-primary end points: PFS and OS Inclusion/Exclusion ● Inclusion: previously untreated unresectable stage III or IV melanoma. Criteria ECOG 0-1.

● Exclusion: active brain mets, autoimmune disease, ocular melanoma. Size (N) ● 945 patients

Results ● Survival: 3year OS: NI: 58%, N: 52%, I: 34%. HR 0.55 for comparison NI to I. HR 0.65 for comparison N to I

● PFS:median PFS 6.9mos (95% CI 4.3-9.5) (N) vs 11.5 mos (95% CI 8.9-16.7) (NI) vs 2.9 (95% CI 2.8-3.4) (I), HR 0.42 (99.5% CI 0.31-0.57; p<0.001) for comparison NI to I. HR 0.57 (99.5% CI 0.43-0.76, p<0.001) for comparison N to I. HR 0.74 (95% CI 0.60-0.92) for comparison N to NI.* ● Objective response rate: N: 44%, NI: 58% I: 19.0% OR for comparison to I: N= 3.40 (95% CI 2.02–5.72), p<0.001. NI= 6.11 (95% CI 3.59–10.38), p<0.001. ● Quality of Life: not reported.

Toxicity ● Grade 3/4 in >4% pts: NI= diarrhea, fatigue, rash, increased ALT & AST, colitis. N= none. I= diarrhea, colitis.

Conclusion ● Nivolumab alone or combined with ipilimumab results in significantly longer PFS compared to ipilimumab alone. For PD-L1 negative tumors, combination was most effective.

Other Comments ● *Not designed for formal statistical comparison of N vs NI, but numerically NI showed higher PFS and response rates. ● PD-L1 negative tumours: longer PFS with combination than with nivo alone (11.2 mo vs 5.3 mo).

Keynote 029 (Long et al. Lancet 2017, 18(9): 1202-1210) Regimen • Arm 1: pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg

every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years

• Phase 1b trial single arm Mechanism of Action ● Pembrolizumab: monoclonal antibody to programmed cell death-1

of Experimental Drug (PD-1), a checkpoint of the effector stage of the immune system ● Ipilimumab: fully human IgG1 to the cytotoxic

T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint molecule Primary Endpoint • Safety and tolerability Inclusion/Exclusion Criteria

● Inclusion: at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy

Size (N) • N=153 Results • 1 year OS 89%

• 1 year PFS 69% • ORR 61%

Toxicity • Grade 3-4 ADE in 45%, no treatment related deaths • Grade 3-4 immune related ADE in 27%, most common immune aDE

was thyroid abnormalities. Conclusion • Combination pembrolizumab and low dose Ipilimumab has

tolerable side effect profile with anti-tumor effect in melanoma Other Comments Acquired Resistance to PD -1 blockade in melanoma - Jesse M. Zaretsky et al. NEJM n engl j med 375;9 nejm.org September 1, 2016

• Looked at 4 patients that had 6 mths of response to PD-1 blockade and then progressed • Used next generation sequencing to indentify novel mutation expressed in the

progressing tumors • Found 2 paitents had muations in JAK1 or JAK2 – causing loss of response of tumor

to Interferon gamma • One patient had loss of beta-2-microglobulin (required for stable expression of MHC I

complex at cell surface) • One patient mechanism of resistance remained obscure • Paper identifies potential reasons of treatment failure and progression in paitents that

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