Randomised phase 2 study of pembrolizumab plus CC-486 versus pembrolizumab plus placebo in patients with previously treated advanced non-small cell lung cancer

Benjamin P. Levy, Giuseppe Giaccone, Benjamin Besse, Enriqueta Felip, Marina Chiara Garassino, Manuel Domine Gomez, Pilar Garrido, Bilal Piperdi, Santiago Ponce-Aix, Daniel Menezes, Kyle J. MacBeth, Alberto Risueño, Ruta Slepetis, Xiaoling Wu, Abderrahim Fandi, Luis Paz-Ares

Research output: Contribution to journalArticle

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Abstract

Introduction: Preclinical and early clinical studies suggest that combining epigenetic agents with checkpoint inhibitors can potentially improve outcomes in patients with previously treated advanced non-small cell lung cancer (NSCLC). This phase 2 trial examined second-line pembrolizumab + CC-486 (oral azacitidine) in patients with advanced NSCLC. Methods: Patients with one prior line of platinum-containing therapy were randomised in a ratio of 1:1 to CC-486 or placebo, on days 1–14, in combination with pembrolizumab on day 1 of a 21-day cycle. The primary end-point was progression-free survival (PFS). Key secondary end-points included overall survival (OS), overall response rate (ORR) and safety. Results: Among 100 patients randomised (pembrolizumab + CC-486: 51; pembrolizumab + placebo: 49), most were male (57.0%), were white (87.0%) and had Eastern Cooperative Oncology Group performance status 1 (68.0%). No significant difference in PFS was observed between the pembrolizumab + CC-486 and pembrolizumab + placebo arms (median, 2.9 and 4.0 months, respectively; hazard ratio [HR], 1.374; 90% confidence interval [CI], 0.926–2.038; P = 0.1789). Median OS was 11.9 months versus not estimable (HR, 1.375; 90% CI, 0.830–2.276; P = 0.2968); ORR was 20% versus 14%. Median treatment duration was shorter (15.0 versus 24.1 weeks), and the number of cycles was lower (5.0 versus 7.0) with pembrolizumab + CC-486 versus pembrolizumab + placebo. No new safety signals for CC-486 or pembrolizumab were detected. Treatment-emergent adverse events were more common in the pembrolizumab + CC-486 arm, particularly gastrointestinal, potentially impacting treatment feasibility. Conclusions: No improvement in PFS was observed with pembrolizumab + CC-486 versus pembrolizumab + placebo. Decreased treatment exposure due to adverse events may have impacted efficacy with pembrolizumab + CC-486.

Original languageEnglish (US)
Pages (from-to)120-128
Number of pages9
JournalEuropean Journal of Cancer
Volume108
DOIs
StatePublished - Feb 1 2019
Externally publishedYes

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Non-Small Cell Lung Carcinoma
Placebos
Disease-Free Survival
pembrolizumab
Confidence Intervals
Therapeutics
Safety
Azacitidine
Survival
Platinum
Epigenomics

Keywords

  • Azacitidine
  • CC-486
  • Epigenetics
  • Non-small cell lung cancer
  • Pembrolizumab

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Randomised phase 2 study of pembrolizumab plus CC-486 versus pembrolizumab plus placebo in patients with previously treated advanced non-small cell lung cancer. / Levy, Benjamin P.; Giaccone, Giuseppe; Besse, Benjamin; Felip, Enriqueta; Garassino, Marina Chiara; Domine Gomez, Manuel; Garrido, Pilar; Piperdi, Bilal; Ponce-Aix, Santiago; Menezes, Daniel; MacBeth, Kyle J.; Risueño, Alberto; Slepetis, Ruta; Wu, Xiaoling; Fandi, Abderrahim; Paz-Ares, Luis.

In: European Journal of Cancer, Vol. 108, 01.02.2019, p. 120-128.

Research output: Contribution to journalArticle

Levy, BP, Giaccone, G, Besse, B, Felip, E, Garassino, MC, Domine Gomez, M, Garrido, P, Piperdi, B, Ponce-Aix, S, Menezes, D, MacBeth, KJ, Risueño, A, Slepetis, R, Wu, X, Fandi, A & Paz-Ares, L 2019, 'Randomised phase 2 study of pembrolizumab plus CC-486 versus pembrolizumab plus placebo in patients with previously treated advanced non-small cell lung cancer', European Journal of Cancer, vol. 108, pp. 120-128. https://doi.org/10.1016/j.ejca.2018.11.028
Levy, Benjamin P. ; Giaccone, Giuseppe ; Besse, Benjamin ; Felip, Enriqueta ; Garassino, Marina Chiara ; Domine Gomez, Manuel ; Garrido, Pilar ; Piperdi, Bilal ; Ponce-Aix, Santiago ; Menezes, Daniel ; MacBeth, Kyle J. ; Risueño, Alberto ; Slepetis, Ruta ; Wu, Xiaoling ; Fandi, Abderrahim ; Paz-Ares, Luis. / Randomised phase 2 study of pembrolizumab plus CC-486 versus pembrolizumab plus placebo in patients with previously treated advanced non-small cell lung cancer. In: European Journal of Cancer. 2019 ; Vol. 108. pp. 120-128.
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abstract = "Introduction: Preclinical and early clinical studies suggest that combining epigenetic agents with checkpoint inhibitors can potentially improve outcomes in patients with previously treated advanced non-small cell lung cancer (NSCLC). This phase 2 trial examined second-line pembrolizumab + CC-486 (oral azacitidine) in patients with advanced NSCLC. Methods: Patients with one prior line of platinum-containing therapy were randomised in a ratio of 1:1 to CC-486 or placebo, on days 1–14, in combination with pembrolizumab on day 1 of a 21-day cycle. The primary end-point was progression-free survival (PFS). Key secondary end-points included overall survival (OS), overall response rate (ORR) and safety. Results: Among 100 patients randomised (pembrolizumab + CC-486: 51; pembrolizumab + placebo: 49), most were male (57.0{\%}), were white (87.0{\%}) and had Eastern Cooperative Oncology Group performance status 1 (68.0{\%}). No significant difference in PFS was observed between the pembrolizumab + CC-486 and pembrolizumab + placebo arms (median, 2.9 and 4.0 months, respectively; hazard ratio [HR], 1.374; 90{\%} confidence interval [CI], 0.926–2.038; P = 0.1789). Median OS was 11.9 months versus not estimable (HR, 1.375; 90{\%} CI, 0.830–2.276; P = 0.2968); ORR was 20{\%} versus 14{\%}. Median treatment duration was shorter (15.0 versus 24.1 weeks), and the number of cycles was lower (5.0 versus 7.0) with pembrolizumab + CC-486 versus pembrolizumab + placebo. No new safety signals for CC-486 or pembrolizumab were detected. Treatment-emergent adverse events were more common in the pembrolizumab + CC-486 arm, particularly gastrointestinal, potentially impacting treatment feasibility. Conclusions: No improvement in PFS was observed with pembrolizumab + CC-486 versus pembrolizumab + placebo. Decreased treatment exposure due to adverse events may have impacted efficacy with pembrolizumab + CC-486.",
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T1 - Randomised phase 2 study of pembrolizumab plus CC-486 versus pembrolizumab plus placebo in patients with previously treated advanced non-small cell lung cancer

AU - Levy, Benjamin P.

AU - Giaccone, Giuseppe

AU - Besse, Benjamin

AU - Felip, Enriqueta

AU - Garassino, Marina Chiara

AU - Domine Gomez, Manuel

AU - Garrido, Pilar

AU - Piperdi, Bilal

AU - Ponce-Aix, Santiago

AU - Menezes, Daniel

AU - MacBeth, Kyle J.

AU - Risueño, Alberto

AU - Slepetis, Ruta

AU - Wu, Xiaoling

AU - Fandi, Abderrahim

AU - Paz-Ares, Luis

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Introduction: Preclinical and early clinical studies suggest that combining epigenetic agents with checkpoint inhibitors can potentially improve outcomes in patients with previously treated advanced non-small cell lung cancer (NSCLC). This phase 2 trial examined second-line pembrolizumab + CC-486 (oral azacitidine) in patients with advanced NSCLC. Methods: Patients with one prior line of platinum-containing therapy were randomised in a ratio of 1:1 to CC-486 or placebo, on days 1–14, in combination with pembrolizumab on day 1 of a 21-day cycle. The primary end-point was progression-free survival (PFS). Key secondary end-points included overall survival (OS), overall response rate (ORR) and safety. Results: Among 100 patients randomised (pembrolizumab + CC-486: 51; pembrolizumab + placebo: 49), most were male (57.0%), were white (87.0%) and had Eastern Cooperative Oncology Group performance status 1 (68.0%). No significant difference in PFS was observed between the pembrolizumab + CC-486 and pembrolizumab + placebo arms (median, 2.9 and 4.0 months, respectively; hazard ratio [HR], 1.374; 90% confidence interval [CI], 0.926–2.038; P = 0.1789). Median OS was 11.9 months versus not estimable (HR, 1.375; 90% CI, 0.830–2.276; P = 0.2968); ORR was 20% versus 14%. Median treatment duration was shorter (15.0 versus 24.1 weeks), and the number of cycles was lower (5.0 versus 7.0) with pembrolizumab + CC-486 versus pembrolizumab + placebo. No new safety signals for CC-486 or pembrolizumab were detected. Treatment-emergent adverse events were more common in the pembrolizumab + CC-486 arm, particularly gastrointestinal, potentially impacting treatment feasibility. Conclusions: No improvement in PFS was observed with pembrolizumab + CC-486 versus pembrolizumab + placebo. Decreased treatment exposure due to adverse events may have impacted efficacy with pembrolizumab + CC-486.

AB - Introduction: Preclinical and early clinical studies suggest that combining epigenetic agents with checkpoint inhibitors can potentially improve outcomes in patients with previously treated advanced non-small cell lung cancer (NSCLC). This phase 2 trial examined second-line pembrolizumab + CC-486 (oral azacitidine) in patients with advanced NSCLC. Methods: Patients with one prior line of platinum-containing therapy were randomised in a ratio of 1:1 to CC-486 or placebo, on days 1–14, in combination with pembrolizumab on day 1 of a 21-day cycle. The primary end-point was progression-free survival (PFS). Key secondary end-points included overall survival (OS), overall response rate (ORR) and safety. Results: Among 100 patients randomised (pembrolizumab + CC-486: 51; pembrolizumab + placebo: 49), most were male (57.0%), were white (87.0%) and had Eastern Cooperative Oncology Group performance status 1 (68.0%). No significant difference in PFS was observed between the pembrolizumab + CC-486 and pembrolizumab + placebo arms (median, 2.9 and 4.0 months, respectively; hazard ratio [HR], 1.374; 90% confidence interval [CI], 0.926–2.038; P = 0.1789). Median OS was 11.9 months versus not estimable (HR, 1.375; 90% CI, 0.830–2.276; P = 0.2968); ORR was 20% versus 14%. Median treatment duration was shorter (15.0 versus 24.1 weeks), and the number of cycles was lower (5.0 versus 7.0) with pembrolizumab + CC-486 versus pembrolizumab + placebo. No new safety signals for CC-486 or pembrolizumab were detected. Treatment-emergent adverse events were more common in the pembrolizumab + CC-486 arm, particularly gastrointestinal, potentially impacting treatment feasibility. Conclusions: No improvement in PFS was observed with pembrolizumab + CC-486 versus pembrolizumab + placebo. Decreased treatment exposure due to adverse events may have impacted efficacy with pembrolizumab + CC-486.

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