Improved Survival With Nivolumab vs DTIC in Treatment-Naive Pts With Advanced Melanoma Without a BRAF Mutation: CheckMate 066 Slideset on: Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2014;372:320-330. This activity is supported by educational grants from Bristol-Myers Squibb and Genentech.

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Case A 58-yr-old gentleman with history of CAD s/p CABG X4 and ICD placement in 2007, history of biventricular block and tachycardia with pacemaker, hypertension, diabetes, and hyperlipidemia Newly diagnosed metastatic melanoma, initially presenting with persistent productive cough with CT scan showing lymphadenopathy in the chest and liver lesions LN biopsy and core biopsy of liver lesion both revealed metastatic melanoma No primary lesion identified BRAF negative CABG, coronary artery bypass graft surgery; CAD, coronary artery disease; CT, computed tomography; ICD, implantable cardioverter defibrillators; LN, lymph node; s/p, status post.

What treatment options can we offer this patient with newly diagnosed metastatic melanoma?

Nivolumab in Previously Untreated Melanoma Without BRAF Mutation

Background: Nivolumab in Metastatic Melanoma Global incidence of unresectable, advanced, or metastatic melanoma increasing and mortality remains high Nivolumab: fully human IgG4 monoclonal antibody against PD-1 Blocks interaction with PD-1 ligands, PD-L1 and PD-L2, allowing T-cell activation and proliferation Has shown clinical activity in treatment-experienced pts with advanced solid tumors, including melanoma Phase I: 28.0% to 30.8% ORR and 6.0% SD at 24 wks with favorable safety profile Phase III in pts with advanced melanoma not responding to ipilimumab: higher ORR compared with chemotherapy (32% vs 11%) ORR, objective response rate; SD, stable disease. Robert C, et al. N Engl J Med. 2014;372:320-330.

CheckMate 066: Study Schema Stratified by PD-L1 status (positive vs negative/ indeterminate) and metastasis stage (M0/M1a/M1b vs M1c) Nivolumab 3 mg/kg IV q2w + Placebo IV q3w (n = 210) Dacarbazine 1000 mg/m2 q3w + Placebo IV q2w (n = 208) Unresectable, treatment-naive stage III or IV melanoma, wild-type BRAF, ECOG PS 0-1, 18 yrs of age or older (N = 418) Treatment continued until disease progression* or unacceptable toxicity ECOG, Eastern Cooperative Oncology Group; IV, intravenous; OS, overall survival; PS, performance status; q2w, every 2 weeks; q3w, every 3 weeks. *Treatment permitted after disease progression at investigator’s discretion in pts experiencing clinical benefit. Primary objective: OS Robert C, et al. N Engl J Med. 2014;372:320-330.

CheckMate 066: OS and PFS All pt subsets had OS benefit from nivolumab HR for death: 0.42 (99.79% CI: 0.25-0.73; P < .001) HR for death or disease progression: 0.43 (95% CI: 0.34-0.56; P < .001) 100 100 90 90 80 Nivolumab 80 mPFS (95% CI) 70 70 Nivolumab Dacarbazine 5.1 mos (3.5-10.8) 2.2 mos (2.1-2.4) 60 Dacarbazine 60 Overall Survival (%) 50 Progression-free Survival (%) 50 40 OS, overall survival; PFS, progression-free survival 40 30 30 Nivolumab mOS (95% CI) 20 20 Nivolumab Dacarbazine Not reached 10.8 mos (9.3-12.1) Dacarbazine 10 10 3 6 9 12 15 18 3 6 9 12 15 18 Mos Mos Robert C, et al. N Engl J Med. 2014;372:320-330.

CheckMate 066: Duration of Response ORR significantly higher with nivolumab vs dacarbazine (40.0% vs 13.9%, respectively; P < .001) 100 90 Nivolumab 80 70 60 Dacarbazine Pts With ORR (%) 50 40 DoR, duration of response; ORR, objective response rate. 30 Median DoR (95% CI) 20 Nivolumab Dacarbazine Not reached 6.0 mos (3.0-not reached) 10 3 6 9 12 15 Mos Robert C, et al. N Engl J Med. 2014;372:320-330.

CheckMate 066: Most Common AEs AEs, n (%) Nivolumab (n = 206) Dacarbazine (n = 205) Any Grade Grade 3/4 Any 192 (93.2) 70 (34.0) 194 (94.6) 78 (38.0) Treatment-related AE 153 (74.3) 24 (11.7) 155 (75.6) 36 (17.6) Fatigue 41 (19.9) 30 (14.6) 2 (1.0) Pruritus 35 (17.0) 1 (0.5) 11 (5.4) Nausea 34 (16.5) 85 (41.5) Diarrhea 33 (16.0) Vomiting 13 (6.3) 43 (21.0) Serious treatment- related AE 19 (9.2) 12 (5.8) 18 (8.8) 12 (5.9) AE, adverse event. Robert C, et al. N Engl J Med. 2014;372:320-330.

Strengths and Weaknesses of the Study First study to assess anti–PD-1 antibody in pts who were previously untreated, likely bringing checkpoint blockade to frontline for melanoma Demonstrates superior efficacy of nivolumab to standard chemotherapy Provide evidence of pseudoprogression by allowing pts who experienced PD by RECIST to remain on study Weaknesses Up to 38% of patients in dacarbazine arm received ipilimumab at PD, which may skew OS data (impact of this is unclear) Unclear how nivolumab compares with other checkpoint inhibitors and BRAF/MEK inhibitors in the first-line setting OS, overall survival data; PD, progressive disease. Robert C, et al. N Engl J Med. 2014;372:320-330.

Future Directions Optimal sequence of immunotherapy approach and BRAF/MEK inhibition yet to be determined[1] Several trials exploring various combinations and sequences of treatment ongoing or in development[2,3] Further exploration of “pseudoprogression” phenomenon Need to differentiate between true and false negatives with PD-L1 expression to identify which pts will truly benefit from PD-1 inhibitor therapy Head-to-head comparison to determine if nivolumab is superior to ipilimumab in frontline setting is ongoing Phase III CheckMate 067[3] 1. Robert C, et al. N Engl J Med. 2014;372:320-330. 2. ClinicalTrials.gov. NCT02224781. 3. ClinicalTrials.gov. NCT01844505.

Conclusions Nivolumab confers significant survival benefit for pts with previously untreated advanced melanoma compared with dacarbazine Median OS not yet reached in pts taking nivolumab (vs 10.8 mos w/DTIC) 1-yr survival rate of 73% with nivolumab PFS significantly longer with nivolumab vs DTIC (5.1 vs 2.2 mos; P < .001) Survival advantage with nivolumab regardless of PD-L1 expression across all pt subgroups ORR, CR, and PR all higher in nivolumab arm Median DOR not yet reached with nivolumab (vs 6.0 mos with DTIC) Among pts treated beyond PD, 8.1% achieved ≥ 30% reduction in tumor burden of target lesion with nivolumab vs 3.8% with DTIC CR, complete response; DOR, duration of response; DTIC, dacarbazine; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response. Robert C, et al. N Engl J Med. 2014;372:320-330.

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