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

Current Landscape of Immuno-Oncology in Advanced Melanoma

Adjuvant treatment with ipilimumab was evaluated in a multinational double-blind phase 3 trial in high-risk patients with stage IIIA, IIIB, or IIIC melanoma with no in-transit metastasis (N = 951) and following complete regional lymph node dissection. Patients were randomized 1:1 to receive ipilimumab (n = 475) or placebo (n = 476).30 Recurrence-free survival (RFS) with ipilimumab was significantly longer compared with placebo (HR, 0.75; 95% CI, 0.64-0.90). In patients receiving ipilimumab, the median RFS was 26.1 months (95% CI, 19.3-39.3) versus 17.1 months (95% CI, 13.4-21.6) with placebo; the 3-year RFS rate was 46.5% (95% CI, 41.5%-51.3%) versus 34.8% (95% CI, 30.1%-39.5%), respectively (P = .0013). In the ipilimumab group, 54% of patients experienced grade 3 or 4 AEs compared with 25% in the placebo group. irAEs were reported more often in patients receiving ipilimumab versus placebo and most commonly (grade 3 or 4) were related to the GI, hepatic, or endocrine system. Discontinuation due to AEs occurred in 52% of patients receiving ipilimumab versus 4% for placebo.30

Healthcare providers should be informed about the  diagnosis and management of ipilimumab-specific AEs, especially those that have been observed across clinical studies with the agent. Proper management requires a multidisciplinary approach. In a pooled analysis of patients receiving 10 mg/kg ipilimumab every 3 weeks for 4 cycles (N = 325), treatment-related AEs were seen in 84.6% of patients and irAEs were seen in 72.3% of patients.31 After an average of 3.6 weeks, 47% to 68% of patients experienced maculopapular rash with intense itch. For grade 3 immune-related skin reactions, withholding a dose of ipilimumab and administering oral corticosteroids is recommended; permanent discontinuation is recommended for life-threatening toxicity. Diarrhea was reported in 44% of patients and can be associated with symptoms of colitis (which can further lead to bowel obstruction and perforation). In patients with grade 3 or 4 diarrhea (18%), ipilimumab should be discontinued and intravenous steroids, electrolytes, and hydration should be administered. Immune-related hepatotoxicity was reported in 3% to 9% of patients. Ipilimumab should be discontinued in patients with grade 3 or 4 hepatotoxicity.31 One percent to 6% of patients treated with ipilimumab experienced hypophysitis, which must be differentiated from the occurrence of new brain metastases. To monitor for hypophysitis, thyroid function tests and clinical chemistry profiles should be assessed in all patients before the start of treatment and before each dose.31 Less than 1% of patients experienced episcleritis and uveitis, commonly co-occurring with diarrhea or colitis. In patients with grade 3 or 4 episcleritis or uveitis, ipilimumab should be discontinued. Immune-related pancreatitis occurred in less than 1.5% of patients. In patients whose pancreatic enzymes increase to grade 3 or 4 toxicity, ipilimumab should be discontinued. Less than 1% of patients experienced transient sensory or motor peripheral neuropathies. For mild neuropathies, a dose of ipilimumab can be withheld; for grade 3 or 4 neuropathy, treatment should be discontinued. Lymphadenopathy and sarcoid-like syndrome have been described in anecdotal reports.31

PD-1 Inhibitors

PD-1 receptor activation is another immune checkpoint that can interfere with the antitumor response. Melanoma tumors suppress cytotoxic T-cell activity by expressing PD-1 ligand (PD-L1). Researchers have identified anti–PD-1 antibodies that block PD-L1 from activating PD-1 receptors, potentially reversing T-cell suppression and inducing durable responses in patients with advanced melanoma.26,32

Nivolumab, a fully human, immunoglobulin G4 (IgG4) anti–PD-1 mAb, was evaluated in an international, double-blind, phase 3 study in treatment-naïve patients with unresectable stage III or IV melanoma without a BRAF mutation (N = 418). Patients were randomized 1:1 to receive either nivolumab (n = 210) or dacarbazine (n = 208), plus matched placebo.32 At 1 year, the OS with nivolumab was 72.9% (95% CI, 65.5%-78.9%) compared with 42.1% (95% CI, 33.0%-50.9%) with dacarbazine and at a significant benefit over the latter (HR, 0.42; 99.79% CI, 0.25-0.73; P <.001). The median PFS was 5.1 months (95% CI, 3.5-10.8) versus 2.2 months (95% CI, 2.1-2.4), respectively. Nivolumab demonstrated an ORR of 40.0% (95% CI, 33.3%-47.0%) compared with 13.9% (95% CI, 9.5%-19.4%) with dacarbazine (OR, 4.06; P <.001). The incidence rate of treatment-related AEs was similar between groups (74.3% and 75.6%, respectively), although grade 3 to 4 AEs

were less frequent in patients receiving nivolumab (11.7% vs 17.6%, respectively). The most common treatment-related AEs with nivolumab were fatigue, pruritus, and nausea, and with dacarbazine, GI and hematologic events. This study showed a consistent benefit in OS versus dacarbazine chemotherapy.32

Nivolumab was evaluated against chemotherapy in another open-label phase 3 trial in patients with unresectable phase IIIC or IV melanoma. Patients were randomized 2:1 to receive nivolumab (n = 405) or investigator’s choice of chemotherapy (ICC) (dacarbazine or carboplatin plus paclitaxel; n = 268). For patients receiving nivolumab, the median OS was 15.7 months (95% CI, 12.9-19.9) compared with 14.4 months (95% CI, 11.7-18.2) for ICC (HR, 0.95; 95.54% CI, 0.73-1.24). In the nivolumab group, 1-year survival was 58.9% (95% CI, 52.8%-64.5%) versus 55.1% (95% CI, 46.1-63.3) with ICC, and 2-year survival was 38.7% (95% CI, 32.8%-44.5%) and 33.9% (95% CI, 25.8%-42.1%), respectively. Grade 3 or 4 AEs occurred in 14% of patients receiving nivolumab versus 34% of patients receiving ICC. The most common treatment-related AE was fatigue (32% and 39%, respectively), and those that were possibly immune related occurred in the skin, GI, and hepatic systems. Treatment-related AEs leading to discontinuation occurred in 5% of patients receiving nivolumab and 11% of those receiving ICC.33

Pembrolizumab is a humanized, igG4-κ anti–PD-1 mAb that blocks PD-1 from interacting with PD-L1 and PD-L2.34 The antitumor activity and safety of pembrolizumab were evaluated using data pooled from an international, open-label, multiple-cohort, phase 1 clinical trial in patients with advanced melanoma (N = 655). Patients in these cohorts were randomized and nonrandomized, ipilimumab-naïve and ipilimumab-experienced, and therapy naïve. In the primary pooled analysis, 581 patients meeting Response Criteria In Solid Tumors (RECIST) criteria were evaluated. Pembrolizumab demonstrated an ORR of 33% (95% CI, 30%-37%), with a complete response (CR) rate of 8% (95% CI, 6%-11%) and a disease control rate (DCR) of 51% (95% CI, 47%-55%).

In a subgroup analysis of patients who were ipilimumab naïve (n = 277), the ORR was 39% (95% CI, 33%-45%; n = 107) compared with 29% (95% CI, 24%-34%; n = 87) in patients who previously received ipilimumab (n = 304). In patients who received no previous therapy (n = 133), the ORR was 45% (95% CI, 36%-54%; n = 60), the CR rate was 14% (95% CI, 8%-21%;  n = 18), and the DCR was 61% (95% CI, 52%-69%; n = 81).

Investigators observed no dose- or regimen-related toxicities with pembrolizumab, which was shown to be generally well tolerated. Grade 3 or 4 treatment-related toxicities occurred in 14% of patients, the most common of which was fatigue, at 1.8%; all others occurred in less than 1% of patients. The most common serious treatment-related AEs were colitis, pyrexia, and pneumonitis. Discontinuations due to treatment-related AEs occurred in 4% of patients, and no treatment-related deaths were reported.35

In a separate pooled analysis of the same multiple-cohort phase 1 trial in patients with advanced melanoma (N = 655), the antitumor activity of pembrolizumab relative to PD-L1 expression was evaluated. Again, patients in these cohorts were randomized and nonrandomized, ipilimumab-naïve and ipilimumab-experienced, and therapy naïve. Of these patients, 451 were evaluable for PD-L1 expression using the melanoma (MEL) scale of 0-5 (0 is negative and 2-5 are positive for PD-L1). Tumor response was also evaluated by RECIST criteria. Of the 405 patients evaluable for both PD-L1 and tumor response, the ORR was 33% (95% CI, 28%-37%). Patients with higher MEL scores had significantly better ORRs: 57% in those with MEL 4 versus 8% for those with MEL 0, showing that PD-L1 expression is positively correlated with improved tumor response. Higher PD-L1 MEL scores were also associated with increased PFS (HR, 0.76; 95% CI, 0.71-0.82;

P <.001) and OS (HR, 0.76; 95% CI, 0.69-0.83; P <.001).36

Combination PD-1/PD-L1 Inhibtion Plus CTLA-4 Inhibition

PD-1 inhibitors and CTLA-4 inhibitors target distinct mechanisms in T-cell activation. Nivolumab and pembrolizumab demonstrated significant clinical efficacy against PD-L1, and ipilimumab was shown to improve outcomes when targeting CTLA-4; therefore, researchers evaluated the potential impact of treatment with these agents in combination.24

In an international, open-label, phase 3 trial (N =834), patients with unresectable stage III or IV melanoma with or without BRAF mutations who had not had more than 1 systemic therapy for advanced disease were randomized 1:1:1 to receive pembrolizumab every 2 weeks (n = 279), pembrolizumab every 3 weeks (n = 277), or ipilimumab (n = 278).24 OS rates for both pembrolizumab groups were superior to the ipilimumab group, and the study was stopped early to allow patients receiving ipilimumab to receive pembrolizumab, if desired. Estimated survival at 1 year was 74.1% for patients receiving pembrolizumab every 2 weeks (HR vs ipilimumab, 0.63; 95% CI, 0.47-0.83; P <.0005), 68.4% with pembrolizumab every 3 weeks (HR vs ipilimumab, 0.69; 95% CI, 0.52-0.90; P = .0036), and 58.2% with ipilimumab. Pembrolizumab demonstrated significantly improved response rates over ipilimumab (11%) both with pembrolizumab every 2 weeks (33.7%; P <.001) and every 3 weeks (32.9%; P <.001). More patients receiving ipilimumab (9.4%) discontinued the study due to AEs compared with pembrolizumab every 2 weeks (4.0%) and pembrolizumab every 3 weeks (6.9%). Grade 3 to 5 treatment-related AEs occurred in 13.3% of patients receiving pembrolizumab every 2 weeks, 10.1% receiving pembrolizumab every  3 weeks, and 19.0% receiving ipilimumab. The most common treatment-related AEs (any grade) observed with pembrolizumab and ipilimumab were fatigue, diarrhea, rash, and pruritus. In this study, both regimens of pembrolizumab improved OS compared with ipilimumab.24

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