Research Article ISSN 2639-8478

Research Article Cancer Science & Research

Plasma Cell-free RNA PD-L1 and Survival with Immune Checkpoint

Inhibitor Therapy in Metastatic Non-Small Cell Lung Cancer
Paul Walker¹,²*, Mahvish Muzaffar¹, Sriraksha Jayananda¹, Praveen Namireddy4, Nitika Sharma5,
Teresa Parent³, Cynthia Cherry³ and Richard Lanman²
¹Division of Hematology/Oncology, Brody School of Medicine at
East Carolina University,
Greenville, NC, 27834 USA. *
Correspondence:
Paul R. Walker, MD, FACP, Division of Hematology/Oncology,
²Circulogene, Birmingham, AL, 35209 USA. Brody School of Medicine at East Carolina University,
Greenville, NC 27834, USA. E-mail: [email protected].
³ECU Health Medical Center, Greenville, NC, 27834 USA.
Received: 01 May 2023; Accepted: 03 Jun 2023; Published: 08 Jun 2023
⁴Wake Med Cancer Care. Raleigh, NC 27610, USA.

⁵Cancer Treatment Centers of America, Newman, GA, 30265 USA.

Citation: Walker P, Muzaffar M, Jayananda et al. Plasma Cell-free RNA PD-L1 and Survival with Immune Checkpoint Inhibitor
Therapy in Metastatic Non-Small Cell Lung Cancer. Cancer Sci Res. 2023; 6(1): 1-6.

ABSTRACT
Background: Tissue programmed death-ligand 1 (PD-L1) protein expression is predictive of immune checkpoint
inhibitor (ICI) benefit. However, tissue testing can be fraught with tissue acquisition and heterogeneity limitations.
Plasma testing can overcome these limitations. However, the overall survival predictive benefit of plasma PD-L1
assays have not been well characterized.

Methods: Patients with stage IV non-small cell lung cancer (NSCLC) and plasma cell free RNA PD-L1 by
polymerase chain reaction (PCR) expression were identified and assessed for overall survival. Sixteen patients
treated with front-line ICI-based regimens were assessed and represented a real-world patient population with
over half with a performance status of 2 or greater. Ten contemporaneous patients at the same institution treated
with chemotherapy alone were also identified and assessed.

Results: With a median follow-up of 33 months, median overall survival was 13 months with a 30% 3-year OS
for the ICI treated patients compared to a median OS of 3 months and a 10% 3- year OS for those treated with
chemotherapy alone. Comparative log-rank test p-value = 0.014 and a hazard ratio 0.376 (95%-CI 0.134-1.057).

Conclusions: A plasma cell free RNA PD-L1 by PCR assay was associated with a statistically significant survival
benefit from ICI-based treatment compared to chemotherapy in the first line treatment of a real-world patient
population of advanced NSCLC.

Keywords checkpoint inhibitor (ICI) based therapy benefit compared to

Plasma PD-L1, Predictive immune biomarker, Liquid biopsy, standard chemotherapy in advanced non-small cell lung carcinoma
cfRNA. (NSCLC).

Introduction However, as with any tissue biomarker testing, tissue PD-L1

Tissue programmed death-ligand 1 (PD-L1) protein expression is protein testing can be fraught with tissue acquisition limitations,
the recognized predictive immune biomarker of front-line immune tissue site sampling heterogeneity, monoclonal antibody assay

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variability, pathologist interpretation variability, and imprecise and PD-L1 protein by the same three IHC assays, concluding PCR
predictive cut-off levels of immunohistochemical (IHC) staining PD-L1 RNA is not equivalent to IHC assays, but can identify PD-
[1-5]. L1 IHC negative patients [17].

A liquid biopsy immune biomarker predictive of ICI benefit Tissue PD-L1 mRNA expression is suggestive of ICI treatment
would not be constrained by these tissue-testing limitations and benefit. Conroy et al. concluded PD-L1 mRNA expression is
could also easily allow dynamic assessment of PD-L1 expression comparable to PD-L1 protein expression by IHC both analytically
with treatment and upon cancer recurrence and/or progression. and clinically in predicting ICI response in NSCLC [14]. In
However, prior plasma PD-L1 assays of soluble PD-L1 by enzyme- another study, tissue mRNA qPCR was stated to have only
linked immunosorbent assays have not been predictive of ICI weak correlation with tissue PD-L1 protein. However, high PD-
benefit. Elevated levels of soluble protein PD-L1 were associated L1 mRNA expression was associated with improved long-term
with poorer survival with ICI treatment [6,7]. Secreted PD-L1 benefit of ICI treatment, whereas low PD-L1 RNA levels had a
proteins have also been shown to contain decoy PD-L1 variants high negative predictive value of 0.92 for absence of long-term
as a mediator of ICI treatment resistance (8). Circulating tumor benefit emphasizing the need for further validation of PD-L1
cell PD-L1 expression has also not been a helpful plasma-based mRNA [18].
immune biomarker. It has an overall poor correlation with tissue
PD-L1 expression and has not been associated with predictive ICI Plasma cell free mRNA (cfRNA) testing can be difficult because
treatment benefit [9-10]. of RNA fragility and poor extraction efficiency. However,
advances in liquid biopsy technology have successfully brought
A notable exception of an effective plasma-based immune plasma RNA testing into the clinic [19,-20]. Ishiba et al. reported
biomarker is extracellular vesicle (EV) PD-L1 expression. An plasma cfRNA PD-L1 by PCR detectable across various cancers
EV PD-L1 protein research assay demonstrated that the dynamic with no reported detection in the tested healthy individuals [21].
changes in the EV PD-L1 protein were predictive of ICI treatment In the twelve patients in that study with parallel plasma and tissue
durability. Increasing EV PD-L1 was associated with non- samples available, there was concordance between the plasma
responders with a decrease seen in patients with an ICI response cfRNA PD-L1 expression and the tissue PD-L1 protein expression
[11]. PD-L1 mRNA expression by droplet digital PCR in plasma- and stated to be predictive of ICI response, however, OS benefit
derived exosomes has also demonstrated a similar dynamic was not reported [21]. Raez et al. reported cfRNA PD-L1
change correlating with ICI response [12]. This emphasizes the expression by PCR in a variety of metastatic cancers, including 52
potential of a plasma-based PD-L1 assay having longitudinal ICI NSCLC patients. That study noted dynamic changes in the cfRNA
predictive benefit, however neither PD-L1 EV assay was evaluated PD-L1 expression with ICI treatment response, but due to lack of
as a pre-treatment predictor of ICI benefit, just having a dynamic follow up with the COVID pandemic, survival outcomes were not
correlation with response. reported [22].

mRNA PD-L1 expression is a potential predictive immune Our aim was to evaluate the association of plasma cfRNA PD-
biomarker. The use of mRNA for PD-L1 testing carries the potential L1 expression and treatment based clinical outcomes in metastatic
for a more precise standardization without the confounding IHC NSCLC patients. In this retrospective real-world patient
interpretation variability or protein expression heterogeneity. experience, we report the median and landmark 3-year OS in
Correlation between tissue PD-L1 mRNA and tissue PD-L1 metastatic NSCLC patients who demonstrated positive plasma
protein expression has yielded conflicting findings. Levels of cfRNA PD-L1 expression and were treated with ICI-based therapy
tissue mRNA expression correlated with PD-L1 protein tumor cell compared to chemotherapy alone.
expression with the Dako 28-8 monoclonal antibody IHC staining
percentages in NSCLC [13]. There was a similar tissue PD-L1 Methods
RNA expression correlation with the Dako 22C3 monoclonal This is a single-institution, retrospective observational study
antibody IHC staining in NSCLC and other solid tumors [14]. performed at the Brody School of Medicine at East Carolina
However, other studies have identified low concordance. University (Greenville, NC, USA) with patients treated at the
Vidant Medical Center (now ECU Health Medical Center). In
There was only 59% concordance between tissue mRNA PD-L1 order to assess a landmark 3-year OS, patients with pathologically
in-situ hybridization compared to tissue PD-L1 protein [15]. In confirmed NSCLC and positive plasma cfRNA PD-L1 expression
a study comparing tissue RNA PD-L1 by PCR with IHC PD-L1 by PCR were identified through the institutional thoracic oncology
protein 22C3, SP263, and SP 142 assays, 51 of the 167 patient program database from November 2018 through July 2019 (n =
samples tested were discordant with no tumor cell PD-L1 staining 92). Patients with stage I/II/III NSCLC, stage unknown, or with
yet RNA PD-L1 expression. Of those patients without tumor cell the presence of a targetable oncogenic driver mutation/fusion were
staining, 57% demonstrated immune cell PD-L1 protein expression excluded. There were no other clinical or laboratory exclusion
[16]. In the CLOVER study of 437 NSCLC patients across all criteria. Patients were treated based upon the current available
stages, there was low agreement between PD-L1 RNA by PCR standard of care during that time period with the local treating

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oncologist making the final treatment decision. Patients with stage metastases, and one-third with bone metastases, all predictors of
IV NSCLC meeting these criteria and who received their treatment poor ICI and chemotherapy treatment benefit (Table 1).
at Vidant Medical Center (now ECU Health Medical Center) were
identified and utcomes assessed based upon receiving either ICI- Table 1: Clinical presentations of the IO cohort and ChemoRx cohort
based treatment or chemotherapy alone treatment. The Brody treated patients with plasma cfRNA PD-L1 expression.
School of Medicine at East Carolina University Institutional IO COHORT (N = 16) CHEMORX COHORT (N = 10)
GENDER 8 Females/8 males 10 males
Review Board approved this study.
Median age 65 (range
AGE Median age 69 (range 42-81)
55-85)
The ‘IO cohort’ consisted of sixteen patients with metastatic 75% non-squamous 70% non-squamous
NSCLC who demonstrated plasma cfRNA PD-L1 expression and HISTOLOGY
25% squamous 30% squamous
were treated with first-line ICI-based therapies. Thirteen patients ECOG PS 1 = 8 ECOG PS 1 = 4
ECOG PS
received combination anti-PD-1/PD-L1 ICI plus chemotherapy ECOG PS ≥2 = 8 ECOG PS ≥2 = 6
regimens and three patients anti-PD-1/L1 ICI alone. No patients BRAIN
5 (31%) 2 (20%)
METASTASES
received definitive concurrent chemoradiation therapy or thoracic
BONE
radiation therapy (RT). Palliative RT with either whole brain RT METASTASES
7 (44%) 3 (30%)
or Gamma Knife radiosurgery, or palliative stereotactic body
RT were undertaken as indicated upon the recommendation of The IO treated cohort had a statistically improved OS compared to
the treating oncologist. The ‘ChemoRx cohort’ consisted of ten the ChemoRx treated cohort. The IO cohort patients had a median
contemporaneously identified metastatic NSCLC patients with OS of thirteen months with a 30% 3-year OS. In comparison, the
plasma cfRNA PD-L1 expression who received first-line platinum- ChemoRx cohort had a median OS of three months and 3-year OS
based doublet chemotherapy alone. Median and 3-year landmark of 10%.
OS outcomes in the IO cohort were compared to the ChemoRx
cohort. Comparative log-rank test p-value = 0.014 HR of 0.376 (95%
CI, 0.14-1.057) (Figure 1). There was no OS difference in the IO
Plasma for testing was collected before any treatment. Blood cohort whether tissue PD-L1 was positive, negative, or unknown.
was collected in a single 10-ml EDTA tube. The cfRNA PD-L1 Given the clinically known poorer OS differences of both ICI and
expression testing was performed at the Circulogene CLIA/CAP chemotherapy treatment in patients with an ECOG PS of 2 or worse
accredited laboratory (Birmingham, AL, USA). Circulogene is a compared to ECOG PS of 0 or 1, OS was compared between the
commercial liquid biopsy vendor with a proprietary patented pre- ECOG PS 2 or greater patients and the ECOG PS 1 patients in the
analytical linear-in-situ-amplification technology. The cfRNA PD- IO cohort. There was no difference in OS between the IO cohort
L1 Gene Expression assay is a real-time PCR-based assay with PD- patients of ECOG PS 2 or greater and ECOG PS 1 (Figure 2).
L1 specific PCR primers. The demonstrated limit of detection for
cfRNA PD-L1 was 1.0 copy/uL. Tissue PD-L1 protein expression
testing with the Dako 22C3 monoclonal antibody was requested
in all patients.

Ten patients in the IO cohort did have simultaneous plasma and

tissue PD-L1 expression results. Tissue PD-L1 was reported as ≥
50% in six patients and ≥ 1% in four patients. Six of the total IO
cohort of sixteen patients (37%) were either tissue PD-L1 negative
or unknown due to tissue quantity not sufficient for testing.

OS was assessed from the date of diagnosis and either death

or censored follow-up. Median follow-up was 33 months. OS
analysis was performed by AnalystSoft StatPlus Kaplan-Meier
and log-rank test p-value and hazard ratio (HR) survival analysis.
The pre-specified endpoint was median and 3-year OS.

Results
The IO cohort and ChemoRx cohort had similar advanced Figure 1: Overall survival of the IO cohort compared to the ChemoRx
NSCLC histology and clinical presentations. As typical of a real- cohort treated patients with plasma cfRNA PD-L1 expression (p-value
world advanced NSCLC patient population, half had an ECOG = 0.014).
performance status (PS) of 2 or greater, 20-30% symptomatic brain

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 Health database in non-squamous NSCLC patients with an ECOG
PS of ≥2 and tissue PD-L1 expression of ≥ 50% treated with ICI
alone, reports a median OS of 5.2 months and 3-year KM estimated
OS of 16.7%. In ICI-chemotherapy treated non-squamous NSCLC
patients with an ECOG PS ≥ 2, median OS was 6.3 months with a
KM estimated 3-year OS of just 10.3%. Both median OS and KM
estimated 3-year OS approach only half of ECOG PS 0 or 1 patient
survivals treated with ICI-based regimens [29]. Bone metastases
are associated with a cold tumor immune microenvironment and
has become a recognized unfavorable metastatic compartment of
ICI treatment outcome benefit irrespective of ECOG PS or liver
metastases [30]. Over 40% of patients in our patient population
had bone metastases further emphasizing the potential unfavorable
ICI treatment outcomes of our real-world experience.

In our population, over half had an ECOG PS of 2 or greater and

one-third symptomatic brain metastases, such that only one-third of
our patients would have been eligible for a pharma sponsored ICI
clinical trial limited to asymptomatic or minimally symptomatic
Figure 2: Overall survival of ICI treated patients ECOG PS 1 versus ECOG PS of 0 or 1 patients and excluding those with untreated
ECOG PS 2 or greater (p-18 value = 0.8289). symptomatic brain metastases. The expected poor outcomes in the
ChemoRx cohort would not account for the comparative difference
Discussion as the IO cohort clinical presentations were similar with poor ICI
Just as in the pharma sponsored ICI clinical trials demonstrating benefit prognostic factors. Even with these unfavorable ICI benefit
tissue PD-L1 protein expression was predictive of an improved patients in our IO cohort, the ICI-based treatment OS outcomes
OS of ICI compared to chemotherapy in first-line therapy [23,24], in the ECOG PS 2 patients associated with plasma cfRNA PD-L1
plasma cfRNA PD-L1 by PCR expression was associated with an expression was not inferior to our ECOG PS 1 patients or clinical
improved OS of ICI-based treatment compared to chemotherapy in trial outcomes data and was better than reported real-world data in
our symptomatic metastatic NSCLC population. Within this real- the Flatiron Health database.
world patient experience and an expected poorer OS, the clinical
outcomes of our ICI- based treated patients with plasma cfRNA We felt that a landmark OS with prolonged follow-up would best
PD-L1 expression demonstrated a similar median OS and 3-year reflect the clinical utility of plasma cfRNA PD-L1 expression
OS of 30% as the large prospective ICI clinical trials based on and ICI treatment outcome. Response rates and progression free
tissue PD-L1 protein expression. Even when 37% of patients were survival have been inconsistent early surrogates of ICI treatment
either tissue PD-L1 negative or unknown, patients with positive OS, and a lack of an early response does not preclude an ICI OS
plasma cfRNA PD-L1 expression still achieved an improved ICI benefit [31-33]. A pooled analysis of first-line ICI randomized
treatment benefit. trials failed to show a strong correlation between PFS or response
rates with OS emphasizing the importance of having mature OS
Real-world data invariably shows poorer clinical outcomes than data as the most important endpoint for first- line ICI trials [34,35].
clinical trial outcomes. That becomes most evident in patients
with an ECOG PS of 2. What data is available with chemotherapy There are limitations of this reported patient experience. It is a
studies, ECOG PS 2 patients demonstrated a median OS of 3.9 retrospective collection of outcomes data treated at a single
months and 6% 2- year OS such that this four-chemotherapy institution and not a prospective multi-institutional randomized
regimen phase III trial amended the ongoing protocol excluding comparison. Our presented outcomes data also only reflects
ECOG PS 2 patients [25]. This supports an expected OS difference patients with plasma cfRNA PD-L1. Similar outcomes data with
between the chemotherapy treated patients in clinical trials limited ICI-based treated patients who were plasma PD-L1 negative
to an ECOG of 0 or 1 with our chemotherapy treated population treated at our institution was not captured in this comparative
with over half of the patients with an ECOG of 2 or greater. cohort study. That comparison is being assessed in another cohort
comparison. Even with these limitations and the modest patient
There remains an open debate whether any NSCLC ECOG PS 2 sample size, to our knowledge it does represent the largest patient
patients without a targetable mutation or fusion should even be experience of plasma cfRNA PD-L1 expression and ICI-based
treated with ICI since they were not represented in any of the treatment compared to chemotherapy alone OS outcomes.
pharma sponsored ICI clinical trials leaving oncologists without
any outcomes data in that symptomatic patient population compared Conclusions
to chemotherapy and what data there is, indicates a much poorer In a real-world patient experience of symptomatic metastatic
outcome than patients with a PS of 0 or 1 [26-28]. The Flatiron NSCLC patients, plasma cfRNA PD-L1 expression was associated

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with a statistically significant and clinically meaningful median 10. Moran J, Adams D, Edelman M, et al. Monitoring PD-
and 3-year landmark OS benefit with ICI-based systemic treatment L1 Expression on Circulating Tumor-Associated Cells in
compared to chemotherapy. Plasma cfRNA PD-L1 expressing Recurrent Metastatic Non-Small-Cell Lung Carcinoma
patients still received the outcome benefit of ICI treatment whether Predicts Response to Immunotherapy with radiation Therapy.
tissue PD-L1 was negative or unknown. Our data lends support JCO Precis Oncol. 2022; 6: e2200457.
for needed further and expanded study of the potential predictive 11. Del Re M, Marconi R, Pasquini G, et al. PD-L1 mRNA
benefit and clinical utility of plasma cfRNA PD-L1 as a predictive expression in plasma-derived exosomes is associated with
immune biomarker. response to anti-PD-1 antibodies in melanoma and NSCLC.
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