Combination studies with pembrolizumab

The CTLA-4 and PD-1 pathways appear to have complementary roles in suppressing T-cell function, both in the timing of their induction and the location of their activity. CTLA-4 has its function in the early stages of immune cell activation and primarily in the lymphatic tissues, whereas PD-1 function occurs later in the immune process resulting in lymphocyte exhaustion at the site of immune impact, for example, in the tumor microenvironment. Preclinical modeling showed higher levels of antitumor efficacy when both CTLA-4 and PD-1 pathways were inhibited.38 These findings led to a series of trials evaluating the role of ipilimumab and nivolumab in combination for advanced melanoma. A Phase I trial with this combination showed a response rate of 53% in the highest tolerable dose, with all patients having deep responses of ≥80% tumor burden size reduction.39 The combination treatment in this study also resulted in an increased immune toxicity profile with grade ≥3 events in approximately half of patients. The results from this trial led to larger Phase II and Phase III randomized studies exploring this combination of checkpoint inhibitors.40,41 The Checkmate 067 Phase III trial explored the combination in untreated patients with stage III–IV unresectable melanoma. The study was designed as a double-blinded Phase III randomized trial where monotherapy with nivolumab or ipilimumab was compared with the combination of nivolumab and ipilimumab. The median PFS was 11.5 months for nivolumab and ipilimumab as compared to 2.9 months for ipilimumab alone and 6.9 months for nivolumab alone. Additionally, response rates were dramatically higher in the combination group (57.6%) than in nivolumab (43.7%) or ipilimumab (19%). Immune-related toxicity was notable, with 36% of patients discontinuing therapy due to adverse events in the combination group. This study led to the FDA approval of this drug combination in 2015 based on encouraging results using these two check point inhibitors.

Subsequently, an interest in combining pembrolizumab with ipilimumab led to the Keynote-029 trial, which was designed to evaluate standard dose pembrolizumab with lower ipilimumab dosing in order to improve the toxicity profile. Data from an expansion cohort in the KEYNOTE-029 study have been recently presented.42 This cohort included 153 patients with advanced melanoma with no active brain metastasis and no prior immune checkpoint inhibitor therapy. The treatment scheme utilized was pembrolizumab 2 mg/kg every 3 weeks and ipilimumab 1 mg/kg every 3 weeks for four doses followed by 2 mg/kg of pembrolizumab until intolerable toxicity, progression, or 2 years of therapy. Characteristics of these patients included 36% who carried the BRAF V600E mutation, 13% received ≥1 prior therapy, and 12% received a prior BRAF ± MEK inhibitor. Eighty-four percent of the patients had PD-L1-positive tumors (defined as ≥1% staining in tumor and adjacent immune cells). Adverse events related to immune activation of any grade were reported in 53% of the patients and 20% had a grade 3–4 severity. The overall response rate was 51%, with 9% of patients achieving a complete remission. Given the encouraging efficacy and lower grade 3/4 toxicity rate, further evaluation of this combination is expected.

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In addition to the combination of available immune checkpoint inhibitors, many other strategies to explore the addition of novel agents to pembrolizumab are underway. Many of these combinations are in early phase testing; however, a few combinations have made it to late phases of clinical trial testing. Pembrolizumab is being studied in combination with talimogene laherperavec (also known as Imlygic or T-VEC) in the Masterkey-265 Phase Ib/III trial. T-VEC is an oncolytic virus, based on a modified herpes simplex strain, which has been shown to be effective in the management of advanced melanoma patients with superficial metastatic disease (eg, cutaneous and superficial nodal metastases).43 The virus is directly injected into melanoma tumors where it is able to infect and replicate in the cancerous cells resulting in cell lysis. The virus also has been designed to encode the granulocyte macrophage colony stimulating factor (GM-CSF) protein, which results in additional immune stimulus in the tumor microenvironment upon cell lysis. T-VEC has been approved for patients with metastatic melanoma and superficial injectable disease. Presentation of the Phase Ib portion of the Masterkey trial combining T-VEC with pembrolizumab was presented at ASCO in 2016.44 The combination had a confirmed response rate of 48% and a 33% grade ≥3 toxicity rate. The trial has currently transitioned into a Phase III comparative study evaluating T-VEC with pembrolizumab versus pembrolizumab with placebo.

Another late phase study that has now completed enrollment and is awaiting results is the ECHO-301 trial (NCT02752074). This study is evaluating epacadostat, which is a novel immunomodulatory drug inhibiting activity of the indoleamine 2,3-dioxygenase (IDO) enzyme. IDO plays an important role in tryptophan metabolism in the tumor microenvironment and has been shown to support tumor immune escape. In a Phase I trial, epacadostat and pembrolizumab were studied in advanced solid tumors and included a melanoma cohort of patients.45 In the melanoma cohort (n=19), the response rate was 57% and a disease control rate of 73% was observed. Common toxicities included fatigue, diarrhea, rash, arthralgias, and nausea, which are similar to pembrolizumab alone toxicities. The promising results of this study have led to the ECHO-301 trial, which has enrolled advanced melanoma patients to receive either pembrolizumab with epacadostat or pembrolizumab with placebo.

A variety of other trials evaluating pembrolizumab combination treatments are underway, including combinations with BRAF and MEK inhibitors, other unique immune-checkpoint inhibitors, vaccines, cytotoxic therapies, and radiation therapy (Table 2). Recent search on reveals >70 combination studies with pembrolizumab in melanoma alone. Based on pembrolizumab’s efficacy and acceptable toxicity profile, it is easy to understand the rationale for wanting to combine it with other agents. However, identifying which are the most effective combinations and how to apply them clinically, based on individual patient tumor “immune phenotypes”, will certainly be a challenging task for years to come.

(To view a larger version of Table 2, click here.)

Pembrolizumab in the adjuvant setting

Highly effective adjuvant therapy for high-risk resected stage II and III melanoma has been lacking for decades. In the 1990s, interferon was FDA approved based on improvement in recurrence-free survival (RFS) compared to placebo; however, no OS advantage has been seen with the drug.46 Subsequent studies of interferon evaluating various dosing schedules and combinations with other agents such as vaccines and cytotoxics also have failed to improve OS outcomes in randomized trials. Additionally, interferon has a high toxicity profile with poorly tolerated flu-like symptoms being common. A PEGylated form of interferon was FDA approved in 2011 based on improved RFS compared to placebo, but still there was no improvement survival; however, this new formulation is more convenient to administer.47

In 2015, results of the EORTC 18071 randomized trial of high-dose ipilimumab (10 mg/kg) versus placebo led to FDA approval with improvement in RFS noted, although at the cost of a high toxicity profile, with frequent grade 3/4 toxicities and a discontinuation rate of ~50%.48 A subsequent update of OS showed ipilimumab demonstrating a 5-year absolute improvement in the survival of 11% compared to placebo and a 28% reduction in the risk of death hazard ratio ([HR] 0.78, P=0.001). Given the apparent superiority of the PD-1 inhibitors nivolumab and pembrolizumab over ipilimumab in trials of patients with metastatic melanoma, a series of new studies evaluating PD-1 inhibition in high-risk resected melanomas have been undertaken.

Pembrolizumab is being evaluated in two separate randomized Phase III trials. In Keynote-054, pembrolizumab is being compared to placebo in patients with IIIA (>1 mm involvement in lymph node), IIIB, and IIIC melanoma, which has been completely resected. RFS in all the subjects and in the subset of subjects with PD-1 ligand expression in the resected tumor is the primary endpoint. Secondary endpoints include distant metastatic-free survival and OS. This study has completed accrual and is awaiting data maturation for publication. In a separate adjuvant study conducted in the cooperative group setting, S1404 is evaluating pembrolizumab compared to investigator’s choice of high-dose interferon or high-dose ipilimumab for resected high-risk stage III melanoma (stages IIIA, IIIB, IIIC, and IV). Baseline PD-1 ligand testing of the tumor is being performed, and patients are being stratified by expression status. Primary endpoints include OS, RFS, and PD-L1 expression status.49 Of note, similar studies with nivolumab are also being conducted but not yet reported. Hopefully, these trials with PD-1 inhibitors will further advance outcomes for patients with high-risk melanoma who currently have limited options in this setting.