Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03486119 |
| Other study ID # |
4-2017-0788 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
February 5, 2018 |
| Est. completion date |
July 7, 2020 |
Study information
| Verified date |
October 2020 |
| Source |
Yonsei University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The study aimed to elucidate predictive immune related biomarker to the responsiveness to the
PD-1 blockade and evaluate the dynamics of immune cells in peripheral blood from NSCLC
patients during nivolumab treatment.
Hypothesis that The ratio of MDSC after 1st or 2nd cycle can predict the response to
nivolumab in NSCLC patients earlier than the tumor assessment by imaging scan.
The primary objective is to determine whether myeloid-derived suppressor cell (MDSC) ratio
after 1st or 2nd cycle of nivolumab can be accurate predictive biomarkers of nivolumab in
advanced NSCLC.
Description:
Non-small cell lung cancer (NSCLC) is the leading cause of cancer related mortality
worldwide. Immune checkpoint blockade has emerged as a promising treatment modality in NSCLC.
More recently, Programmed Cell Death 1 (PD-1) inhibitor was approved by FDA as ≥ second line
treatment, which are major paradigm shift in NSCLC treatment.
Subsequently two randomized phase III trials, comparing the overall survival (OS) of
nivolumab with that of docetaxel as second line therapy, were completed. CheckMate-017
included squamous cell lung cancer patients and CheckMate-057 did non-squamous cell lung
cancer patients. In both trials, nivolumab showed improvement of OS in all-comers regardless
of PD-L1 expression. As a result of retrospective analysis, PD-L1 positivity was not
predictive factor for the efficacy in squamous cell histology, but predictive factor for
non-squamous histology. Finally, nivolumab was approved the all-comer NSCLC patients
regardless of PD-L1 expression after failure to platinum based chemotherapy.
Although tumor PD-L1 expression is currently the best predictive biomarker for PD-1
blockades, the prediction accuracy is not high enough to solidify the drug efficacy.
Actually, PD-L1 negative patients can still respond to PD-1 blockades and some of PD-L1
positive patients do not respond to these therapy. Interestingly, the responders among PD-L1
negative patients showed comparable duration of response in those with PD-L1 positive in
Checkmate 057 trial.
Therefore, we need to select patients who are most likely to benefit from anti-PD-1 therapy
and identify the better biomarker to predict the response to PD-1 blockades in NSCLC patients
earlier than tumor assessment by imaging scan. To maximize the benefit of nivolumab in NSCLC
patients, nivolumab should apply to all-comers, but we need to early decide to go or stop
depending on predictive biomarker after 1st or 2nd cycle.
It is well known that various immune suppressive mechanisms including an accumulation and
activation of myeloid derived suppressor cells (MDSC) and regulatory T cells (Tregs) exist in
tumor microenvironment of cancer patients. MDSC are one of the major components of the tumor
microenvironment, demonstrating their potentials, such as tumor progression by promoting
tumor cell survival, angiogenesis, invasion of healthy tissue by tumor cells, and metastases.
Recent studies show that MDSC as a heterogenous group of myeloid progenitors with immuno
suppressive function could be used as one of the promising biomarker candidate for cancer
immunotherapies. Ipilimumab could affect the immune cells in peripheral blood from melanoma
patients. This study demonstrated that responder to ipilimumab showed early increase of
eosinophil counts, whereas non-responders presented that elevated monocytic MDSC increased
serum levels of S100A8/A9 and HMGB1 that attract and activate MDSCs. This result suggests
that measurement of MDSCs could be a predictive immune related biomarker to ipilimumab
treatment. On the other hand, we do not know how PD-1 blockade affects the immune suppressive
cells such as MDSC or Tregs and makes difference between responder and non-responder.
Recently, we conducted pilot trial to compare the T lymphocytes and MDSC population in
peripheral blood between responder and non-responder to nivolumab. Interestingly, our
preliminary data demonstrated that after 1st cycle of the therapy CD11b+CD33+MDSC/CD45+ or
CD14- ratio has significantly decreased in responder compared to non-responder. The cut-off
value of peripheral MDSC ratio could be reliable biomarker for accurate prediction of
nivolumab therapy in NSCLC patients. To validate our finding, we need to expand this study in
NSCLC patients who will be treated with nivolumab.
