Elsevier

The Lancet Oncology

Volume 18, Issue 9, September 2017, Pages 1202-1210
The Lancet Oncology

Articles
Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial

https://doi.org/10.1016/S1470-2045(17)30428-XGet rights and content

Summary

Background

Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab.

Methods

In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged 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 Criteria 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. Patients received intravenous 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 or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity.

Findings

Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17·0 months (IQR 14·8–18·8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3–4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3–4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53–69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60–75), and estimated 1 year overall survival was 89% (95% CI 83–93).

Interpretation

Standard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway.

Funding

Merck & Co, Inc.

Introduction

Immune checkpoint blockade has become a standard of care for the treatment of advanced melanoma. The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab was the first immune checkpoint inhibitor to show a survival benefit in patients with advanced melanoma.1, 2 Subsequently, the programmed death 1 (PD-1) inhibitors pembrolizumab3, 4, 5, 6, 7 and nivolumab8, 9, 10, 11 have shown efficacy in previously untreated and ipilimumab-treated advanced melanoma. In the phase 3 KEYNOTE-006 trial,6, 12 pembrolizumab 10 mg/kg given every 2 weeks or every 3 weeks showed significantly better overall survival, progression-free survival, and objective response than did ipilimumab in patients with advanced melanoma, as well as a lower proportion of grade 3–5 treatment-related adverse events despite the longer treatment exposure of pembrolizumab than of ipilimumab.

Research in context

Evidence before this study

We searched PubMed on March 15, 2017, using the individual search terms “PD-1” OR “programmed death 1”, “PD-L1” OR “programmed death ligand 1”, “pembrolizumab” OR “MK-3475” OR “lambrolizumab” OR “keytruda”, “nivolumab” OR “BMS-936558” OR “opdivo”, “ipilimumab” OR “yervoy”, “atezolizumab” OR “MPDL3280A”, “durvalumab” OR “MEDI4736”, and “avelumab” OR “MSB0010718C”. We also did the following combination searches: “nivolumab” AND “ipilimumab” AND “combination”, “pembrolizumab” AND “ipilimumab” AND “combination”, “PD-1” AND “CTLA-4” AND “combination”, and “PD-L1” AND “CTLA-4” AND “combination”. We combined all searches with “melanoma” and did not limit them by date, but limited them to the English language. We identified three published clinical trials of nivolumab plus ipilimumab for advanced melanoma: a phase 1 dose-finding trial, the randomised controlled phase 2 CheckMate 069 study, and the randomised controlled phase 3 CheckMate 067 study.

Added value of this study

Data from this study show that combination therapy with standard-dose pembrolizumab and reduced-dose ipilimumab is tolerable and has substantial anti-tumour activity in patients with advanced melanoma. These data suggest that treatment with a standard dose of anti-programmed death 1 therapy and a reduced dose of anti-cytotoxic T-lymphocyte-associated protein 4 therapy is feasible and warrants further exploration.

Implications of all the available evidence

In this large phase 1 trial, the toxicity profile and anti-tumour activity of standard-dose pembrolizumab plus reduced-dose ipilimumab compared favourably with those observed in the phase 3 trial of reduced-dose nivolumab plus standard-dose ipilimumab. These data support use of anti-programmed death 1 and anti-cytotoxic T-lymphocyte-associated protein 4 combination therapy in patients with advanced melanoma and suggest that combination of standard-dose pembrolizumab and reduced-dose ipilimumab might be a viable treatment option for these patients.

CTLA-4 and PD-1 are inhibitory receptors that suppress anti-tumour immune activity at different stages: CTLA-4 interferes with T-cell activation at antigen presentation during the priming phase, whereas PD-1 downregulates T-cell activity at the tumour site during the effector phase.13 These non-redundant, complementary mechanisms of action led to synergistic anti-tumour activity of combined CTLA-4 and PD-1 inhibition in preclinical models.14, 15 Clinically, combination of PD-1 and CTLA-4 inhibition has shown efficacy in several clinical trials.8, 16, 17 In the phase 3 CheckMate 067 trial,8, 18 combination of reduced-dose nivolumab with standard-dose ipilimumab for four doses followed by standard-dose nivolumab alone improved overall survival, progression-free survival, and objective response compared with standard-dose ipilimumab. However, the significant improvement in efficacy was accompanied by increased toxicity, including a high proportion of grade 3–4 treatment-related adverse events, with an associated increase in treatment discontinuation. These findings raised the question of whether or not standard-dose anti-PD-1 combined with reduced-dose ipilimumab could show substantial clinical activity while avoiding severe toxicity.

In the KEYNOTE-029 trial, we assessed the safety and anti-tumour activity of standard-dose pembrolizumab given in combination with reduced-dose ipilimumab in patients with advanced melanoma. In an initial safety run-in that enrolled 22 patients with advanced melanoma or renal cell carcinoma, this combination showed an acceptable safety profile and preliminary evidence of anti-tumour activity.19 In this study, we present results from the KEYNOTE-029 expansion cohort of patients with advanced melanoma receiving standard-dose pembrolizumab plus reduced-dose ipilimumab.

Section snippets

Study design and participants

In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA into the expansion cohort (appendix p 2). Eligible patients were aged at least 18 years and had histologically confirmed, unresectable stage III or IV melanoma, excluding uveal melanoma; an Eastern Cooperative Oncology Group performance status of 0 or 1; measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1;20 adequate organ

Results

Between Jan 13, 2015, and Sept 17, 2015, we enrolled 153 patients, all of whom received at least one dose of pembrolizumab plus ipilimumab (appendix p 5) and thus were evaluable for safety and efficacy. Most patients were previously untreated and had PD-L1-positive tumours, normal serum lactate dehydrogenase concentrations, and an Eastern Cooperative Oncology Group performance status of 0 (table 1). 55 (36%) of 153 patients had BRAFV600-mutant tumours, including 13 (8%) who received previous

Discussion

In this expansion cohort of a phase 1b trial, we show that combination of standard-dose pembrolizumab with reduced-dose ipilimumab had a manageable toxicity profile and substantial anti-tumour activity.

At the time that this study was done, pembrolizumab 2 mg/kg every 3 weeks was the standard dose of pembrolizumab approved by the US Food and Drug Administration and European Medicines Agency on the basis of the results of pharmacokinetic analyses23 and randomised dose comparisons showing similar

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