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Page 2 of 9 Komiya et al. J Cancer Metastasis Treat 2018;4:1 I http://dx.doi.org/10.20517/2394-4722.2017.65

Keywords: Non-small cell lung cancer, nivolumab, angiogenesis, immunotherapy

INTRODUCTION
Systemic treatment for advanced cancer had been primarily cytotoxic chemotherapy until modern systemic
modalities were recently developed. Now we know that targeted therapies for selected advanced cancer such
as oncogene-driven malignancy provide better outcomes than traditional chemotherapy. For instance, small
molecule kinase inhibitors are available for advanced non-small cell lung cancer (NSCLC) with a somatic
mutation in the catalytic domain of epidermal growth factor receptor gene (EGFR) or gene rearrangement
in anaplastic leukemic kinase gene (ALK) . More recently, inhibitors for immune checkpoints that
[1-4]
negatively regulate anti-cancer immunity have become clinically available with improved survival outcome
for the treatment of advanced NSCLC, head/neck, melanoma, bladder, and renal cell carcinomas [5-11] .

The mortality rate for lung cancer, however, has not changed dramatically over the last several decades .
[12]
Although recently developed cancer immunotherapy, such as anti-PD-1 therapy, has made a significant
impact on daily practice for advanced NSCLC, most patients who are treated with such agents still succumb
[13]
to the disease within five years . Continued efforts to enhance activity of cancer immunotherapy are
required to further improve outcome.

Recently researchers have been conducting clinical trials to determine if the combination of immunotherapy
and other treatments may have additive clinical activity in this disease. Anti-angiogenesis agents such as
bevacizumab have been developed and achieved regulatory approval for several cancer types [14,15] . These
agents are also being investigated in various diseases in combination with immunotherapy . Rationale
[16]
for the combination is that suppression of neoangiogenesis, remodeling on distorted microvasculature,
[16]
and resultant improved tumor perfusion are expected to enhance anti-cancer immunity . Because
bevacizumab has a relatively long half-life (approximately 20 days) and lasting biological effect , previous
[15]
anti-angiogenesis treatment might positively influence the efficacy of anti-cancer immunotherapy.
Several studies have indicated that withdrawal of anti-angiogenesis agents results in an increase in tumor
aggressiveness due to rebound angiogenesis in the tumor microenvironment [17,18] . We therefore conducted
a retrospective study to determine if prior use of anti-angiogenesis therapy can impact progression-free
survival in advanced NSCLC patients who were treated with anti-PD-1 therapy.

METHODS
Patient selection
A total of 801 advanced and metastatic NSCLC patients were registered at University of Kansas Cancer
Center between January 2015 and June 2016. Review of their medical records identified 141 patients who
were treated with at least one dose of the anti-PD-1/PD-L1 inhibitors at University of Kansas Cancer
Center. A majority (n = 133) of patients were treated with nivolumab alone, whereas others were treated
with nivolumab and atezolizumab (n = 1), atezolizumab alone (n = 1), pembrolizumabalone (n = 4), or other
investigational agentalone (n = 2). All of these agents were intravenously given every two weeks (nivolumab)
or every three weeks (atezolizumab and pembrolizumab) according to standard dosing schedules.

Because most patients were treated with nivolumab (n = 134), we decided to focus on patients who received
it for recurrent or metastatic disease. They were grouped based on presence or absence of previous anti-
angiogenesis treatment which included bevacizumab and ramcirumab. None of the patients received other
anti-angiogenesis agents prior to nivolumab. Information about clinical demographics was collected as well.
The two groups (prior anti-angiogenesis vs. no prior anti-angiogenesis) were compared for the differences
in clinical demographics and outcome. Tumor response was determined according to Response Evaluation
Criteria in Solid Tumors (RECIST) 1.1 criteria, and disease control rate (DCR) was defined as the sum of