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Supplements The Role of Immuno-Oncology in the Treatment of Advanced Melanoma

Current Landscape of Immuno-Oncology in Advanced Melanoma

Dabrafenib, another selective BRAF inhibitor, was studied in an open-label, multicenter, phase 3 trial in patients with unresectable stage III or IV melanoma who had not received antitumor therapy other than IL-2 (N = 250).

Patients were randomized 3:1 to receive dabrafenib (n = 187) or dacarbazine (n = 63). Results were reviewed by a masked independent review committee.17 Dabrafenib showed significant improvement over dacarbazine with an objective response rate (ORR) of 50% (95% CI, 42.4%-57.1%) versus 6% (95% CI, 1.8%-15.5%), respectively, and a median PFS of 5.1 versus 2.7 months, respectively (HR, 0.30; 95% CI, 0.18-0.51; P <.0001). AEs with dabrafenib occurring in at least 5% of patients were cutaneous AEs, fever, fatigue, headache, and joint pain. AEs with dacarbazine in at least 5% of patients were nausea, vomiting, fatigue, and neutropenia. Grade 3 and 4 events were not common in either group.17

As BRAF signaling is dependent on activation of MEK, the success of BRAF inhibitors spurred development of MEK inhibitors. The first FDA-approved MEK inhibitor was trametinib,13 which was evaluated in an international, prospective, open-label phase 3 trial in patients with unresectable stage III or IV melanoma with V600E or V500K BRAF mutations (N = 322). Patients were randomized 2:1 to receive either trametinib (n = 214) or chemotherapy (dacarbazine or paclitaxel; n = 108).18 Trametinib demonstrated an ORR of 22% (95% CI, 17%-28%) versus 8% (95% CI, 4%-15%) with chemotherapy (P <.01). The median PFS with trametinib versus chemotherapy was 4.8 versus 1.5 months, respectively (HR, 0.45; 95% CI, 0.33-0.63; P <.001).13 The most common AEs with trametinib were rash, diarrhea, peripheral edema, fatigue, and dermatitis acneiform. In patients receiving chemotherapy, common AEs included fatigue, nausea, constipation, vomiting, and alopecia. AEs led to dose reductions in 27% of patients receiving trametinib and 10% of patients receiving chemotherapy.18

Combination BRAF Plus MEK Inhibition

Concurrent with the development of vemurafenib and trametinib, investigators researching the MAPK pathway observed downstream activation in BRAF signaling. Consequently, additional studies in combined BRAF inhibition plus MEK inhibition were conducted.13,19

In an international double-blind phase 3 trial, BRAF inhibition plus MEK inhibition was evaluated in patients with unresectable stage IIIC or IV melanoma with BRAF Val600Glu or Val600Lys mutations (N = 423) who had no previous systemic treatment for metastatic disease. Patients were randomized 1:1 to receive either dabrafenib plus trametinib (n = 211) or dabrafenib plus placebo (n = 212).20 The ORR with combination therapy was 69% (95% CI, 62%-75%) versus 53% (95% CI, 46%-69%) for dabrafenib alone (P = .0014). The median PFS with dabrafenib plus trametinib was 11.0 months (95% CI, 8.0-13.9) versus 8.8 months (95% CI, 5.9-9.3) with dabrafenib alone (HR 0.67; 95% CI, 0.53-0.84; P = .0004), and median overall survival (OS) was 25.1 months (95% CI, 19.2-not reported) versus 18.7 months (95% CI, 15.2-23.7), respectively (HR, 0.71; 95% CI, 0.55-0.92; P = .0107). The most common treatment-related AEs observed with combination therapy were fever, chills, fatigue, rash, and nausea; in patients receiving dabrafenib alone, hyperkeratosis, fatigue, alopecia, fever, hand-foot syndrome, and joint pain. Fewer patients receiving dabrafenib plus trametinib experienced cutaneous AEs compared with dabrafenib alone, while more patients receiving dabrafenib experienced fever compared with patients receiving combination therapy.

Discontinuation due to AEs occurred in 11% of patients receiving combination therapy versus 14% of patients receiving dabrafenib alone.20

BRAF plus MEK inhibition was evaluated against BRAF inhibition alone in an international open-label phase 3 trial. Patients with unresectable stage IIIC or IV melanoma with BRAF V600E or V600K mutations (N = 704) were randomized 1:1 to receive dabrafenib plus trametinib (n = 352) or vemurafenib monotherapy (n = 352).21 The ORR with dabrafenib plus trametinib was 64% (95% CI, 59%-69%) versus 51% (95% CI, 46%-57%) with vemurafenib (P <.001). The median PFS was 11.4 versus 7.3 months, respectively (HR, 0.56; 95% CI, 0.46-0.69; P <.001), and the OS at 12 months was 72% (95% CI, 67%-77%) versus 65% (95% CI, 59%-70%), respectively. In patients receiving dabrafenib plus trametinib, the most common AEs were fever, nausea, vomiting, diarrhea, chills, headache, and fatigue. In patients receiving vemurafenib, the most common AEs were joint pain, rash, alopecia, diarrhea, nausea, and fatigue. Fever occurred more frequently in patients receiving combination therapy compared with vemurafenib (53% vs 21%, respectively) and was the most common reason for dose interruption and reduction (33% and 14%, respectively). In patients receiving vemurafenib, rash was the most common reason for dose interruption or reduction (14% and 11%, respectively).21

Cobimetinib, another FDA-approved MEK inhibitor, was studied in an international phase 3 trial in treatment-naïve patients with unresectable, locally advanced, stage IIIC or IV melanoma with BRAF V600 mutations (N = 495). Patients were randomized 1:1 to receive vemurafenib plus cobimetinib (n = 247) or vemurafenib plus placebo (n = 248).22 The ORR was significantly higher with vemurafenib plus cobimetinib at 70% (95% CI, 63.5%-75.3%) versus 50% (95% CI, 43.6%-56.4%) with vemurafenib alone (P <.0001). The median OS for patients receiving combination therapy was 22.3 months (95% CI, 20.3-not estimable) versus 17.4 months (95% CI, 15.0-19.8) with vemurafenib alone (HR, 0.70; 95% CI, 0.55-0.90; P = .005), and the 1-year OS was 74.5% (95% CI, 68.9%-80.2%) versus 63.8% (95% CI, 57.6%-70.0%), respectively.22 Serious AEs occurred in 36% of patients receiving vemurafenib plus cobimetinib and 28% of patients receiving vemurafenib alone. Pyrexia and dehydration were the most common serious AEs reported with combination therapy. MEK-inhibitor–specific AEs reported in the combination therapy group and vemurafenib-only group included serious retinopathy (any grade, 27% vs 4%, respectively), decreased left ventricular ejection fraction (grade ≥2, 11% vs 5%), and increased creatine phosphokinase (grade ≥3, 12% vs <1%). Discontinuations due to AEs occurred in 14% of patients receiving vemurafenib plus cobimetinib and 11% of patients receiving vemurafenib alone.22

Results from these pivotal clinical trials have established combination therapy with a BRAF inhibitor plus a MEK inhibitor as the standard of care in targeted treatment for BRAF-mutant melanoma.13


Recent breakthroughs in targeted therapies (eg, BRAF inhibitors and MEK inhibitors) have improved outcomes over chemotherapy in patients with advanced melanoma; however, treatment challenges remain for patients who relapse or do not respond to these agents. Immunotherapies are effective in advanced melanoma regardless of mutation status, aiming to interrupt processes in the tumor microenvironment that allow tumors to grow uncontrolled. Standard treatments that generally target the immune system (cytokines, interferon-α and IL-2) are accompanied by significant toxicities.13,23-26 With the development of monoclonal antibodies (mAbs), which bind to only 1 substance,27 immunotherapy has transitioned from broad-based treatment to specific antibody-mediated blockade of cytotoxic T-lymphocyte–antigen-4 (CTLA-4) and shows promise in combination with programmed cell death protein 1 (PD-1) inhibitors in mediating immune checkpoints.13

CTLA-4 Inhibitors

CTLA-4, expressed on activated T cells, tends to stop the antitumor response. Ipilimumab is the first anti–CTLA-4 antibody approved for patients with melanoma.26 The efficacy of ipilimumab was evaluated in 2 phase 3 trials using 2 dosages. In a multinational double-blind study of 403 patients with stage III or IV melanoma who had been on a previous therapy, patients were randomized 3:1:1 to either ipilimumab 3 mg/kg plus a cancer vaccine (glycoprotein 100 [gp100]; n = 403), ipilimumab 3 mg/kg alone (n = 137), or gp100 alone (n = 136).28 The highest median OS of 10.1 months was observed in patients receiving ipilimumab alone (95% CI, 8.0-13.8) compared with 10.0 months for patients receiving ipilimumab plus gp100 (95% CI, 8.5-11.5) and 6.4 months with gp100 alone (95% CI, 5.5-8.7). The HR for death with ipilimumab alone versus gp100 alone was 0.66 (P <.003). At 12 months, the OS was also highest with ipilimumab alone, at 45.6%, compared with 43.6% for ipilimumab plus gp100 and 25.3% for gp100 alone.28

Common AEs in this study were immune related and usually affected the skin and GI tract. Grade 3 or 4 AEs occurred in 10% to 15% of patients who received ipilimumab and in 3% of patients who received gp100 alone. The most common AE of any grade with ipilimumab was diarrhea. In patients surviving through the 2-year follow-up, residual effects included injection site reaction, vitiligo, and diarrhea or colitis; ongoing events included grade 1 or 2 rash, pruritus, diarrhea, anorexia, and fatigue, and grade 3 leukocytosis.

There were 14 deaths related to the study drug, half of which were associated with immune-related AEs (irAEs).28

Ipilimumab was also studied in combination with dacarbazine in patients with stage III or IV melanoma. In this multinational double-blind study, 502 patients were randomized 1:1 to receive ipilimumab plus dacarbazine (n = 250) or dacarbazine alone (n = 252).29 The median OS with ipilimumab plus dacarbazine was 11.2 months (95% CI, 9.4-13.6) compared with 9.1 months (95% CI, 7.8-10.5) for patients receiving dacarbazine alone. Estimated 1-year survival rates for ipilimumab plus dacarbazine and dacarbazine alone were 47.3% and 36.3%, respectively; at 2 years, 28.5% and 17.9%; and at 3 years, 20.8% and 12.2%, respectively (HR, 0.72; P <.001). The most common AEs were immune related. AEs occurring more frequently with ipilimumab plus dacarbazine than with dacarbazine alone included increased alanine aminotransferase (33.2% vs 5.2%, respectively), increased aspartate aminotransferase (29.1% vs 5.6%), diarrhea (36.4% vs 24.7), pruritus (29.6% vs 8.8%), and rash (24.7% vs 6.8%). There were no deaths related to ipilimumab plus dacarbazine treatment.29

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