Circadian variation in nivolumab efficacy in patients with advanced non-small cell lung cancer.

Abstract

e21585 Background: Despite efficacy of human checkpoint inhibitors, only 20 to 30% of treated patients present long term benefits. Circadian variations of the delivery of nivolumab to patients with advanced non-small-cell lung cancer (NSCLC) are proposed here as a factor potentially influencing the efficacy. Methods: A total of 1318 courses of nivolumab were administered in 57 consecutive patients with advanced NSCLC from September 2015 to December 2019 in Medical Oncology Unit of Montfermeil hospital. Percentage of total dose per patient delivered before and after 12:00 pm was computed and corelated to objective response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: Twenty eight patients (49%) received ≥ 50% of their treatment before 12:00 pm (morning group) and 29 patients (51%) after 12:00 pm (afternoon group). ORR was 53.6% in morning group and 31.0% in afternoon group; p = 0.083. Both PFS and OS were significantly longer in morning group as compared to afternoon group. Median PFS was 18.6 months [95%CL, 8.6 – 28.7] and 3.5 months [2.9 – 4.1] in morning and afternoon group respectively; p < 0.001. After a maximum follow-up of 48 months, median OS was not reached in morning group whereas it was 14.4 months [0.0 – 29.5] in afternoon group; p = 0.004. Conclusions: The significant difference in the efficacy of nivolumab between morning and afternoon group is indirect evidence of the influence of circadian rhythm on the metabolism of this checkpoint inhibitor. The application of this finding in clinical practice should allow an increase of nivolumab efficacy in patients with advanced NSCLC.

Time-Dependent Efficacy of Checkpoint Inhibitor Nivolumab: Results from a Pilot Study in Patients with Metastatic Non-Small-Cell Lung Cancer

“…We then hypothesized that circadian timing could play an important role in nivolumab’s efficacy, based on our prior trials of chronomodulated chemotherapy [ 27 , 28 , 29 ]. Strikingly, PFS and OS differences were found in an initial retrospective evaluation of efficacy as a function of morning vs. afternoon nivolumab administration in a first cohort of 57 patients [ 30 ]. We then prospectively assessed the nivolumab timing efficacy in a further 38 additional NSCLC patients in order to increase the sample size and provide independent confirmation of the initial findings.…”

Why does circadian timing of administration matter for immune checkpoint inhibitors’ efficacy?

“…In seminal clinical observations, one of us (AK) first noticed a strikingly longer follow-up for those patients who received most nivolumab infusions in the morning as compared to those treated mostly in the afternoon for metastatic non-small cell lung cancer (mNSCLC) [13]. The results suggested a possible role for the CTS on immunotherapy effects, similar to that found for chronomodulated chemotherapy [14][15][16].…”

Effect of immunotherapy-infusion time of day on survival of patients with advanced cancers: a study-level meta-analysis

“…The search found 16 studies, including 8 articles in peer-reviewed international journals 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 and 8 congress abstracts, which were presented as poster communications at major international congresses. 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 Three abstracts were discarded because the data 40 were updated in a subsequently published article, 26 or detailed HR data were not reported. 34 , 35 All 13 retained study reports consisted of retrospective evaluations of ToD ICI administration effects.…”