Pembrolizumab adjuvant therapy: significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up
May 16, 2021
Summary
Background:
The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43–0·74], p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results.
Methods:
This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.
Findings:
Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5–45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9–69·5] in the pembrolizumab group vs 49·4% [44·8–53·8] in the placebo group; HR 0·60 [95% CI 0·49–0·73]; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8–71·2) in the pembrolizumab group and 51·6% (46·6–56·4) in the placebo group (HR 0·61 [95% CI 0·49–0·76]; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3–64·1) than the placebo group 41·4% (37·0–45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 [95% CI 0·49–0·70]) and in those with PD-L1-positive tumours 61·4% (56·3–66·1) in the pembrolizumab group and 44·1% (39·2–48·8) in the placebo group (HR 0·59 [95% CI 0·49–0·73]).
Interpretation:
Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma.
Source:
Alexander M M Eggermont, Christian U Blank, Mario Mandalà, Georgina V Long, Victoria G Atkinson, Stéphane Dalle, Andrew M Haydon, Andrey Meshcheryakov, Adnan Khattak, Matteo S Carlino, Shahneen Sandhu, James Larkin, Susana Puig, Paolo A Ascierto, Piotr Rutkowski, Dirk Schadendorf, Rutger Koornstra, Leonel Hernandez-Aya, Anna Maria Di Giacomo, Alfonsus J M van den Eertwegh, Jean-Jacques Grob, Ralf Gutzmer, Rahima Jamal, Paul C Lorigan, Alexander C J van Akkooi, Clemens Krepler, Nageatte Ibrahim, Sandrine Marreaud, Michal Kicinski, Stefan Suciu, Caroline Robert, Alex Menzies, Thierry Lesimple, Michele Maio, Gerald Linette, Michael Brown, Peter Hersey, Inge Marie Svane, Laurent Mortier, Jacob Schachter, Catherine Barrow, Ragini Kudchadkar, Xinni Song, Caroline Dutriaux, Pietro Quaglino, Friedegund Meier, Paola Queirolo, Daniil Stroyakovskiy, Lars Bastholt, Bernard Guillot, Claus Garbe, Pablo Luis Ortiz Romero, Florent Grange, Peter Mohr, Alain Algazi, Oliver Bechter, Micaela Hernberg, Jean-Philippe Arnault, Philippe Saiag, Carmen Loquai, Frank Meiss, Jan-Christoph Simon, Gil Bar-Sela, Vanna Chiarion Sileni, Bernard Fitzharris, Mike McCrystal, Phillip Parente, Jean-Francois Baurain, Patrick Combemale, Célèste Lebbe, Axel Hauschild, Naoya Yamazaki, Reinhard Dummer, Mohammed Milhem, Marcin Dzienis, John Walker, Lionel Geoffrois, Marie-Thérèse Leccia, Lutz Kretschmer, Daniel Hendler, Michal Lotem, Andrzej Mackiewicz, Lidija Sekulovic, Elaine Dunwoodie, Christoph Hoeller, Laurent Machet, Jessica Hassel, Geke A.P. Hospers, Maria-Jose Passos, Max Levin, Martin Fehr, Philippa Corrie, Ashita Waterston, Sigrun Hallmeyer, Henrik Schmidt, Vincent Descamps, Jean-Philippe Lacour, Carola Berking, Felix Kiecker, Pier Francesco Ferrucci, Kenji Yokota, Maureen Aarts, Michael Jameson, Anna Katharina Winge-Main, Paula Ferreira, Kevin Kim, Catriona McNeil, Reiner Hofmann-Wellenhof, Joseph Kerger, François Aubin, Jochen Utikal, Virginia Ferraresi, Takashi Inozume, Yoshio Kiyohara, Gerard Groenewegen, Helena Kapiteijn, Suzana Matkovic, Wolf-Henning Boehncke, Richard Casasola, Timothy Crook, Ernest Marshall, Tanja Skytta, Marie-Francoise Avril, Thomas Jouary, Rüdiger Hein, Patrick Terheyden, Jun Aoi, Tatsuya Takenouchi, Oddbjorn Straume, César Martins, Guzel Mukhametshina, Paul Nathan, Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial, The Lancet Oncology, Volume 22, Issue 5, 2021, Pages 643-654, ISSN 1470-2045, https://doi.org/10.1016/S1470-2045(21)00065-6.