Open AccessArticle
Time-Dependent Efficacy of Checkpoint Inhibitor Nivolumab: Results from a Pilot Study in Patients with Metastatic Non-Small-Cell Lung Cancer
by
1,2,*
, 1, 1, 3, 3, 3, 2,4,5, 2,6,7,8, 2,9 and 2,5,9,*
1
Medical Oncology Unit, GHT Paris Grand Nord-Est, Le Raincy-Montfermeil, 93770 Montfermeil, France
2
UPR “Chronotherapy, Cancer and Transplantation”, Medical School, Paris-Saclay University, 94800 Villejuif, France
3
Pathology Unit, GHT Paris Grand Nord-Est, Le Raincy-Montfermeil, 93370 Montfermeil, France
4
North Wales Cancer Centre, Ysbyty Gwynedd, Betsi Cadwaladr University Health Board, Bangor LL57 2PW, UK
5
Cancer Chronotherapy Team, Cancer Research Centre, Division of Biomedical Sciences, Warwick Medical School, Coventry CV4 7AL, UK
6
Medical Oncology Department, Paul Brousse Hospital, 94800 Villejuif, France
7
Medical Oncology Unit, Clinique Saint Jean L’Ermitage, 77000 Melun, France
8
Medical Oncology Unit, Clinique du Mousseau, 91000 Evry, France
9
Centre Hépato Biliaire, AP-HP, Hôpital Paul Brousse (APHP), 94800 Villejuif, France
*
Authors to whom correspondence should be addressed.
Academic Editors: Niels Reinmuth and Dirk De Ruysscher
Received: 28 December 2021
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Revised: 1 February 2022
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Accepted: 9 February 2022
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Published: 11 February 2022
Simple Summary
Initial clinical observations revealed strikingly longer follow-up for metastatic non-small-cell lung cancer (NSCLC) patients receiving nivolumab infusions predominantly in the morning as compared to those treated in the afternoon. Prior experimental and human studies have demonstrated the temporal distributions of immune cells’ proliferation, trafficking, and antigen recognition and destruction over the 24 h. Here, we hypothesized that circadian timing could play an important role in nivolumab’s efficacy, as previously shown for the toxicity and/or efficacy of chronomodulated chemotherapy in colorectal and lung cancer patients. Following project validation by an internal scientific review board, the dosing times of each of the 1818 nivolumab infusions given to 95 consecutive patients as a standard treatment for metastatic NSCLC were retrieved from the day-hospital records. Adverse events and radiologically documented tumor responses were retrieved and reviewed from patients’ clinical charts. Patients were allocated to ‘morning’ (N = 48 patients) or ‘afternoon’ (N = 47 patients) groups, according to whether they had received the majority of nivolumab infusions before or after 12:54, i.e., the median time of all infusions, respectively. ‘Morning’ nivolumab dosing nearly quadrupled median progression-free and overall survival as compared to ‘afternoon’ dosing. ‘Morning’ nivolumab was significantly more effective irrespective of age, sex, performance status, prior treatments, tumor histology, or PD-L1 expression. In contrast, nivolumab primary resistance was most often observed following ‘afternoon’ dosing. Randomized trials are warranted both to further identify the optimal timing of checkpoint inhibitors in individual cancer patients, and to determine the main mechanisms that precisely drive immunotherapy efficacy and resistance along the circadian timescale.