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Clinical Trial
. 2021 Oct 1;27(19):5280-5288.
doi: 10.1158/1078-0432.CCR-21-0793.

Standard-Dose Pembrolizumab Plus Alternate-Dose Ipilimumab in Advanced Melanoma: KEYNOTE-029 Cohort 1C, a Phase 2 Randomized Study of Two Dosing Schedules

Georgina V Long  1 , Caroline Robert  2 , Marcus O Butler  3 , Felix Couture  4 , Matteo S Carlino  5 , Steven O'Day  6 , Victoria Atkinson  7 , Jonathan S Cebon  8 , Michael P Brown  9 , Stéphane Dalle  10 , Andrew G Hill  11 , Geoffrey T Gibney  12 , Steven McCune  13 , Alexander M Menzies  1 , Cuizhen Niu  14 , Nageatte Ibrahim  15 , Blanca Homet Moreno  15 , Adi Diab  16
Affiliations
Clinical Trial

Standard-Dose Pembrolizumab Plus Alternate-Dose Ipilimumab in Advanced Melanoma: KEYNOTE-029 Cohort 1C, a Phase 2 Randomized Study of Two Dosing Schedules

Georgina V Long et al. Clin Cancer Res. .

Abstract

Purpose: Standard-dose pembrolizumab plus alternative-dose ipilimumab (1 mg/kg Q3W for 4 doses) were tolerable and had robust antitumor activity in advanced melanoma in cohort B of the phase 1 KEYNOTE-029 study. Cohort C evaluated standard-dose pembrolizumab with two other alternative ipilimumab regimens.

Patients and methods: Patients with treatment-naive unresectable stage III/IV melanoma were randomly assigned 1:1 to pembrolizumab 200 mg Q3W for ≤24 months plus ipilimumab 50 mg Q6W for 4 doses (PEM200+IPI50), or the same pembrolizumab regimen plus ipilimumab 100 mg Q12W for 4 doses (PEM200+IPI100). Primary end points were incidence of grade 3-5 treatment-related adverse events (TRAE) and objective response rate (ORR) per RECIST v1.1 by independent central review. Per protocol-defined thresholds, grade 3-5 TRAE incidence ≤26% indicated meaningful toxicity reduction and ORR ≥48% indicated no decrease in efficacy versus data reported for other PD-1 inhibitor/ipilimumab combinations.

Results: Median follow-up on February 18, 2019, was 16.3 months in PEM200+IPI50 (N = 51) and 16.4 months in PEM200+IPI100 (N = 51). Grade 3-5 TRAEs occurred in 12 (24%) patients in PEM200+IPI50 and 20 (39%) in PEM200+IPI100. One patient in PEM200+IPI50 died from treatment-related autoimmune myocarditis. Immune-mediated AEs or infusion reactions occurred in 21 (42%) patients in PEM200+IPI50 and 28 (55%) in PEM200+IPI100. ORR was 55% in PEM200+IPI50; 61% in PEM200+IPI100.

Conclusions: Pembrolizumab 200 mg Q3W plus ipilimumab 50 mg Q6W or 100 mg Q12W demonstrated antitumor activity above the predefined threshold; pembrolizumab plus ipilimumab 50 mg Q6W had lower incidence of grade 3-5 TRAEs than the predefined threshold, suggesting a reduction in toxicity. See related commentary by Jameson-Lee and Luke, p. 5153.

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Figures

Figure 1. Best percentage change from baseline in target lesion size (RECIST, version 1.1, by central review) in patients in PEM200+IPI50 (pembrolizumab 200 mg Q3W + ipilimumab 50 mg Q6W; A) and PEM200+IPI100 (pembrolizumab 200 mg Q3W + ipilimumab 100 mg Q12W; B). Abbreviations: Q3W, every 3 weeks; Q6W, every 6 weeks; Q12W, every 12 weeks.
Figure 1.
Best percentage change from baseline in target lesion size (RECIST, version 1.1, by central review) in patients in PEM200+IPI50 (pembrolizumab 200 mg Q3W + ipilimumab 50 mg Q6W; A) and PEM200+IPI100 (pembrolizumab 200 mg Q3W + ipilimumab 100 mg Q12W; B). Abbreviations: Q3W, every 3 weeks; Q6W, every 6 weeks; Q12W, every 12 weeks.
Figure 2. Duration of treatment and response in patients in PEM200+IPI50 (pembrolizumab 200 mg Q3W + ipilimumab 50 mg Q6W; A) and PEM200+IPI100 (pembrolizumab 200 mg Q3W + ipilimumab 100 mg Q12W; B). Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; Q3W, every 3 weeks; Q6W, every 6 weeks; Q12W, every 12 weeks.
Figure 2.
Duration of treatment and response in patients in PEM200+IPI50 (pembrolizumab 200 mg Q3W + ipilimumab 50 mg Q6W; A) and PEM200+IPI100 (pembrolizumab 200 mg Q3W + ipilimumab 100 mg Q12W; B). Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; Q3W, every 3 weeks; Q6W, every 6 weeks; Q12W, every 12 weeks.
Figure 3. Kaplan–Meier estimates of (A) duration of response, (B) progression-free survival, and (C) overall survival in PEM200+IPI50 (pembrolizumab 200 mg Q3W + ipilimumab 50 mg Q6W) and PEM200+IPI100 (pembrolizumab 200 mg Q3W + ipilimumab 100 mg Q12W) arms. *From Kaplan–Meier method. Abbreviations: DOR, duration of response; NR, not reached; Q3W, every 3 weeks; Q6W, every 6 weeks; Q12W, every 12 weeks.
Figure 3.
Kaplan–Meier estimates of (A) duration of response, (B) progression-free survival, and (C) overall survival in PEM200+IPI50 (pembrolizumab 200 mg Q3W + ipilimumab 50 mg Q6W) and PEM200+IPI100 (pembrolizumab 200 mg Q3W + ipilimumab 100 mg Q12W) arms. *From Kaplan–Meier method. Abbreviations: DOR, duration of response; NR, not reached; Q3W, every 3 weeks; Q6W, every 6 weeks; Q12W, every 12 weeks.
See this image and copyright information in PMC

Comment in

  • Ipilimumab Combination Dosing: Less is More.
    Jameson-Lee M, Luke JJ. Jameson-Lee M, et al. Clin Cancer Res. 2021 Oct 1;27(19):5153-5155. doi: 10.1158/1078-0432.CCR-21-2406. Clin Cancer Res. 2021. PMID: 34341015 Free PMC article.

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