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: 7 th most common cancer in Canada; 19th in the world. Incidence is rising. o The 15-49 age group is most affected, with melanoma being 4 th most common cancer in this group. - Mortality:14 th most common cause of cancer death in Canada in men, and 15 th in 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 o MEK inhibitors (e.g.: trametinib, cobimetinib, binimetinib). 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 8 th edition 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 Stage IIIc T0-2a T1-2a T2b-3a T0 T1a-3a T3b-4a N1b-c N2b N1a-2b N2b-c, N3b-c N2c-N3c Any N M0 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 (20x10 6 U/m2/d IV 5 days/week x4 weeks, followed by 10x10 6 U/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 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 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. 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 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 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
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) Adjuvant IFNalpha Primary Endpoint Disease-free survival, Overall survival Inclusion/Exclusion AJCC Stage II-III resected cutaneous melanoma 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%). 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.) 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 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 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. 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) 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 Nivolumab: fully human IgG4 PD-1 checkpoint inhibitor, selectively of Experimental Drug blocks PD-1 receptor. Primary Endpoint Recurrence free survival Inclusion/Exclusion Inclusion: 15 years or older, stage 3B, 3C or resected stage 4 (AJCC 7 th 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 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) Arm 1: Dabrafenib 150mg twice daily + trametinib 2mg once daily for up to 12 months Arm 2: Placebo Mechanism of Action Dabrafenib: oral BRAF inhibitor. Trametinib: oral MEK inhibitor of Experimental Drug Primary Endpoint Relapse free survival Inclusion/Exclusion Inclusion: 18 years or older, resected stage 3A (lymph node metastasis of at least 1mm), 3B, 3C (AJCC 7 th 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 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) Arm 1: Pembrolizumab 200mg q 3 weeks for up to 18 doses Arm 2: Placebo Mechanism of Action Pembrolizumab: monoclonal antibody against PDL-1 of Experimental Drug Primary Endpoint Recurrence free survival in PDL-1 positive tumors Inclusion/Exclusion Inclusion: 18 years or older, stage 3A (if N1a had to have a micrometastasis of at least 1mm), 3B, or 3C (AJCC 7 th edition), no intransit 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 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 1 st line 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 1 st line 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. 2 nd line: If immunotherapy used 1 st line, choose alternate immunotherapy or targeted agents if BRAF V600 positive. If ipilimumab used 1 st line and response maintained for at least 6 months can re-challenge with ipilimumab. If targeted agents used first line, use immunotherapy 2 nd line. 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) 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 Trametinib: oral MEK inhibitor Experimental Drug Primary Endpoint PFS Inclusion/Exclusion Inclusion: BRAF Val600Lys or Val600Glu mutation-positive 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. 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) 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 Trametinib: oral MEK inhibitor Experimental Drug Vemurafenib: oral BRAF inhibitor Primary Endpoint OS Inclusion/Exclusion Inclusion: BRAF V600E or V600K mutation-positive unresectable 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. 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) 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 Vemurafenib: oral BRAF inhibitor Experimental Drug Primary Endpoint Investigator assessed PFS Inclusion/Exclusion Inclusion: BRAF V600 mutation-positive unresectable 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) 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. 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) Mechanism of Experimental Drug Primary Endpoint Inclusion/Exclusion [Original BRIM-3 publication: Chapman, NEJM 2011, p 2507-2516] Arm 1: Vemurafenib 960 mg po BID 2 Arm 2: Dacarbazine 1000mg/mIV q3wk Vemurafenib: oral BRAF inhibitor Dacarbazine: IV alkylating agent, prodrug of MTIC activated by demethylation in liver. Co-primary endpoints: OS and PFS, analyzed in ITT Inclusion: BRAF V600E and V600K mutation-positive unresectable 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. Vemurafenib improves survival in patients with BRAF V600E and V600K mutations. Other Comments Open label study Mechanism of Experimental Drug Primary Endpoint Inclusion/Exclusion BREAK-3 (Hauschild, Lancet, 2012, p 358-365) Arm 1: Dabrafenib 150 mg po BID 2 Arm 2: Dacarbazine 1000 mg/mq3wks Dabrafenib: reversible ATP-competitive inhibitor that selectively inhibitors BRAF V600E kinase, part of the MAPK pathway. Dacarbazine: IV alkylating agent, prodrug of MTIC activated by demethylation in liver. Investigator-assessed PFS analyzed by ITT Inclusion: BRAF V600E mutation-positive unresectable 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) 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. Dabrafenib significantly improves PFS compared to dacarbazine. Other Comments Open label study METRIC (Flaherty, NEJM, 2012, 107-114) 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. 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 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. 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) 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 (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 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. 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) 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 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 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. 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) Mechanism of 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. Nivolumab: fully human IgG4 PD-1 checkpoint inhibitor, selectively
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. 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. 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) 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 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 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).
Toxicity Other Comments 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. Grade 3/4 in >4% pts: Ipi+DTIC: diarrhea, increased LFTs. DTIC: none. Ipilimumab with dacarbazine improved OS compared to dacarbazine in previously untreated melanoma. PFS was similar at the 12 week assessment, but afterwards curves separated. Ipilimumab in metastatic melanoma (Hodi, NEJM, 2010, 711-723) 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 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 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. 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) Mechanism of Experimental Drug 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) Nivolumab: fully human IgG4 PD-1 checkpoint inhibitor, selectively blocks PD-1 receptor 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. ECOG 0-1. Exclusion: active brain mets, autoimmune disease, ocular melanoma. Size (N) 945 patients Survival: 3year OS: NI: 58%, N: 52%, I: 34%. HR 0.55 for comparison Results 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. 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) 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 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 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. 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 had responded to PD-1 REFERENCES 1. Uptodate. (2015). at <http://www.uptodate.com.myaccess.library.utoronto.ca/contents/the-molecularbiology-of- melanoma?source=search_result&search=melanoma+molecular&selected Title=1%7E150> 2. Dummer, R., Hauschild, A., Lindenblatt, N., Pentheroudakis, G. & Keilholz, U. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 26, v126-v132 (2015).
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