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Komiya et al. J Cancer Metastasis Treat 2018;4:1 I http://dx.doi.org/10.20517/2394-4722.2017.65 Page 3 of 9

complete response, partial response, and stable disease rates. Due to retrospective analysis, repeat imaging
to confirm response was not always performed. Progression-free survival (PFS) was determined by duration
from the start of nivolumab to disease progression or death of any cause. Definition of disease progression for
the purpose of determining PFS was based on RECIST 1.1 criteria and/or on the clinical grounds (i.e., clinical
progression without formal radiologic assessment if patients were unable to perform re-staging).

Statistical analysis
The Kaplan-Meier curves were applied and the differences were assessed using the log-rank test. Univariate
and multivariable Cox proportional hazard models were used in order to assess the effects of variable(s)
on PFS of the patients. Association between anti-angiogenesis treatment and other clinical features were
carried out using Chi-squared or Fisher’s exact test. JMP software version 14 (SAS Institute, Cary, NC, USA)
was used to perform statistical analyses. For all statistical tests, significance was considered to be achieved
when two-sided P value was less than 0.05. This study was reviewed and approved by University of Kansas
Medical Center Institutional Review Board.

RESULTS
Patient characteristics according to previous anti-angiogenesis treatments are shown in Table 1. Of the 134
patients who received nivolumab, the individual dose was 3 mg/kg or 240 mg flat for 30 and 104 patients,
respectively. Sixteen patients received at least one dose of anti-angiogenesis agents prior to nivolumab. They were
previously treated with bevacizumab alone (n = 11), ramucirumab alone (n = 4), or both (n = 1). The number
of doses for anti-angiogenesis agents ranged between one and 13 with a median of six. In seven of those, no
other systemic therapy was given between anti-angiogenesis regimen and nivolumab. Of the 134 patients, seven
patients completed PD-L1 immunohistochemistry with tumor material. Only two were tested positive (≥ 1%).

As of June 10, 2017, a total of 31 patients are still being treated with nivolumab; one in the prior anti-
angiogenesis and 30 in the no prior anti-angiogenesis group. Because of the inherent limitation of
retrospective review, many patients were lost to follow-up after progression on nivolumab. Only six patients
in the no prior anti-angiogenesis group received an anti-angiogenesis agent after progression on nivolumab,
whereas none did in prior anti-angiogenesis group.

Patients in the prior anti-angiogenesis group had significantly higher likelihood of having stage IV disease,
non-squamous histology, and two or more lines of systemic therapy prior to nivolumab as compared to the
no anti-angiogenesis group. The difference in histology is expected because current regulatory approval for
bevacizumab, which is used in most patients in this group, is indicated for only non-squamous NSCLC.
There was no pseudoprogression in either group.

PFS and overall survival (OS) were investigated according to known prognostic factors as well as prior
anti-angiogenesis status. Kaplan-Meier analyses demonstrated that the prior anti-angiogenesis group had
a statistically shorter PFS as compared to the no prior anti-angiogenesis group, whereas no other factors
demonstrated statistical difference (log rank P = 0.006, Figures 1 and 2A). Multivariate analysis for PFS showed
that previous anti-angiogenesis remained statistically significant when other factors are being considered
[Table 2]. There is no dose-response relationship between the number of doses of anti-angiogenesis agent
and PFS [Figure 2B]. There is a trend in favor of the no anti-angiogenesis group in OS [Table 2] and DCR
[Table 3], although the difference was not significant.

DISCUSSION
Discovery of immune checkpoints and development of agents to enhance T cell function has led to a drastic
change in the management of advanced cancer, resulting regulatory approvals for several immunotherapy