Abstract
Background:
Associations between peripheral blood biomarkers and oncologic outcomes were explored in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HN) and salivary gland cancer (SGC) treated with pembrolizumab and vorinostat on a phase II trial (NCT02538510).
Experimental Design:
Twenty-five HN and 25 SGCs were treated with pembrolizumab and vorinostat. Baseline peripheral blood was available in 21 HN and 20 SGCs and evaluated for associations with grade ≥3 adverse events (G≥3AE) by CTCAEv4, objective response rate (ORR), overall survival (OS), and progression-free survival (PFS).
Results:
Higher pretreatment neutrophil-to-lymphocyte ratio (NLR) and neutrophils, as well as lower pretreatment lymphocytes and T helper cells correlated with worse OS and PFS. Higher NLR further predicted increased rates of G≥3AEs. No correlations with ORR were observed.
Conclusions:
In a prospectively evaluated cohort of HN and SGCs treated with pembrolizumab and vorinostat, we observed novel associations between peripheral blood biomarkers and oncologic outcomes and toxicities.
Keywords: peripheral blood biomarkers, immunotherapy, pembrolizumab, head and neck cancer, salivary gland cancer
Introduction
In recent years, the emergence of immune checkpoint inhibitors (ICI) has expanded treatment options and improved survival for recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HN).1–4 Despite these advances, prognosis of R/M HN remains poor, with objective response rates (ORR) of 13–36% among patients in large clinical trials.2,5,6 The efficacy of ICIs in recurrent metastatic salivary gland cancers (SGC) is not well studied, and there is no current role for ICIs in standard of care treatment. Appropriate patient selection for ICIs is critical, as these drugs come at a significantly higher cost than cytotoxic therapy and can result in severe immune-related adverse events, including colitis, pneumonitis, endocrinopathies, and hepatitis.7 With only a fraction of patients receiving benefit from immune checkpoint inhibitors, further work is urgently needed to identify and understand prognostic biomarkers of immunotherapy for head and neck cancers.
PD-L1 expression by combined positive score (CPS) is currently used to guide patient selection in R/M HN as a companion diagnostic for the use of pembrolizumab in this population. Even in the biomarker enriched population of CPS ≥ 20, the demonstrated ORR of pembrolizumab monotherapy and pembrolizumab combined with chemotherapy in the landmark Keynote-048 study was 23% and 43% respectively.3 Since CPS is an imperfect biomarker, research efforts are ongoing to identify additional molecular biomarkers predictive of response to ICIs, including defects in mismatch repair proteins and tumor mutational burden.8 However, costs and available technological infrastructure have limited the use of these biomarkers in the clinical setting. In contrast, peripheral blood biomarkers are cost-effective, easily obtainable, and routinely measured. They rely on laboratory values such as those obtained from complete blood counts, which require only standard laboratory equipment to process and can be compared across laboratories.
Peripheral blood biomarkers with prognostic significance in immunotherapy have been found in a variety of solid tumors, including melanoma and non-small cell lung cancer (NSCLC), where poor outcomes are associated with elevated baseline peripheral neutrophils, decreased lymphocytes, and increased neutrophil-to-lymphocyte ratio (NLR).8 High peripheral neutrophils and low peripheral lymphocytes represent systemic inflammation and reflect an immune-suppressive tumor microenvironment in which tumor-associated neutrophils promote tumor growth and metastasis.9–15 Furthermore, as ICIs exert their effects through lymphocyte reactivation and release of suppression of host anti-tumor immune response, peripheral blood parameters such as neutrophils, lymphocytes, and NLR are compelling potential biomarkers for predicting response to ICI treatment. However, data examining peripheral blood biomarkers in head and neck immunotherapy is scarce.
This work presents previously unexplored peripheral blood biomarkers in R/M HN and SGC treated with a combination of pembrolizumab and vorinostat, a histone deacetylase inhibitor, on a phase II clinical trial published by our group (Clin Cancer Res 2020, NCT02538510).16 The synergy between epigenetic modification and PD-1 inhibition provided the rationale for this drug combination in head and neck malignancies in this trial.16 This combination demonstrated activity in HN and fewer, but durable, responses in SGC, as well as higher rates of high-grade toxicities compared to PD-1 inhibition alone. Correlative blood samples were prospectively collected on this study, and correlations between outcomes and circulating mononuclear and T-cell populations based on PD-L1 or PD-L2 phenotypes have been published.16 In this study, we explore associations between additional peripheral blood biomarkers and oncologic outcomes and toxicity with mature follow-up times.
Methods
Study Design and population
Phase II open-label, single institution study that enrolled patients with progressing incurable HN and SGC (NCT02538510). Eligibility required age ≥ 18 years at enrollment, Eastern Cooperative Oncology Group performance status ≤ 1, RECIST 1.1 measurable disease, and adequate organ function. Ineligibility criteria included inability to swallow the vorinostat pills and/or gastrostomy tube dependence, uncontrolled central nervous system involvement, prior treatment with an anti–PD-1 inhibitor and/or vorinostat, and autoimmune disease requiring systemic immunosuppression in the 3 years prior.
The primary study objectives for both HN and SGC groups were (i) safety according to Common Terminology Criteria for Adverse Events version 4 (CTCAEv4) and (ii) ORR using RECIST 1.1. Secondary objectives included progression-free survival (PFS) and overall survival (OS). Exploratory endpoints included tissue and peripheral blood correlative studies. This study was reviewed and approved by the Fred Hutchinson Cancer Research Institutional Review Board and was in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients enrolled.
Patients received pembrolizumab 200 mg intravenously every 21 days and vorinostat 400 mg by mouth daily, 5 days on, 2 days off during each 21-day cycle, at least 2 hours prior to the pembrolizumab infusion. Adverse events were assessed prior to each treatment cycle and graded according to CTCAEv4. RECIST 1.1 assessments of response were made every 9 weeks with images read by an independent radiologist. Full details of study design and results have been previously published.16
Correlative blood sample collection
Correlative blood samples were collected at baseline within 24 hours prior to starting treatment. The following peripheral blood parameters were collected: lactate dehydrogenase (LDH), neutrophils, lymphocytes, platelets, and neutrophil-to-lymphocyte ratio (NLR). Neutrophil-to-lymphocyte ratio is calculated as absolute neutrophil count divided by absolute lymphocyte count. Additionally, flow cytometry (using a modified LSRII flow cytometer; BD Biosciences) was performed on these samples and the data was analyzed using Woodlist 3.1 software (courtesy of Brent L. Wood) to characterize baseline peripheral T cell immunophenotypes, including CD3+/CD4+ (helper) and CD3+/CD8+ (cytotoxic) T cells. Combined positive score (CPS) was not routinely obtained during this time. HN and SGC groups were analyzed together for all correlative blood investigations.
Statistical Analysis
Summary statistics for continuous measures included sample size and median. Responses were summarized as frequencies and percentages. Univariable Cox regression was performed to explore associations between a covariate of interest (e.g., T-cell phenotypes) and time-to-event outcomes, such as OS, PFS, and grade ≥ 3 toxicities (G≥3AE) based on CTCAEv4. Logistic regression was performed with binary outcomes, such as ORR based on RECIST 1.1 criteria. For statistical tests, a p-value of < 0.05 was considered statistically significant and 95% confidence intervals were reported. Kaplan-Meier survival curves were generated for NLR at the cutoff derived from the R function surv_cutpoint, which determines the optimal cut-point for continuous variables in survival analyses.
Results
This trial enrolled 25 HN and 25 SGCs between 11/2015 and 8/2017. Follow-up continued until 12/21/2021. Patient demographic and clinical characteristics, as well as outcome results were previously published.16 Table 1 summarizes outcomes observed according to group. Among the 25 patients in the HN group, there were 8 (32%) partial responses (PR), with median PFS of 4.5 (95% CI, 4.1–8.4) months and median OS of 12.6 [95% CI, 8.1-not reached (NR)] months. Among the 25 SGCs, there were 4 (16%) PRs, with median PFS of 6.9 (95% CI, 4.1-NR) months and median OS of 14.0 (95% CI, 8.5-NR) months. Grade ≥ 3 adverse events occurred in 9 (36%) HN and 9 (36%) SGC.
Table 1.
Responses and outcomes
| HN | SGC | |
|---|---|---|
| Responses and outcomes | N= 25 (%) | N= 25 (%) |
| RECIST 1.1 response | ||
| CR | 0 | 0 |
| PR | 8 (32) | 4 (16) |
| SD | 4 (16) | 14 (56) |
| PD | 10 (40) | 7 (28) |
| Median | ||
| Follow-up (survivors only) | 12.6 mo | 13.1 mo |
| Overall survival | 12.6 mo (95% CI, 8.1–NR) | 14.0 mo (95% CI, 8.5–NR) |
| Progression-free survival | 4.5 mo (95% CI, 4.1–8.4) | 6.9 mo (95% CI, 4.1–NR) |
Baseline peripheral blood was available in 21 HN and 20 SGCs. Correlations between peripheral blood parameters and ORR, OS, PFS, and grade ≥ 3 adverse events are shown in Tables 2, 3, 4, and 5, respectively. No association between ORR and any peripheral biomarker was observed. Lower baseline NLR correlated with improved OS (p = 0.001), PFS (p = 0.001), and lower rates of G≥3AE (p = 0.04). Kaplan-Meier survival analysis is shown in Figure 1 for patients above and below the NLR cutoff of 3.95, demonstrating the significant survival advantage of low pretreatment NLR.
Table 2.
Associations of peripheral blood parameters with objective response rate
| Objective Response Rate | |||
|---|---|---|---|
| Baseline blood parameter | OR | 95% CI | p-value |
| CD3+/CD4+ T cells (%) | 1.22 | 1.01–1.52 | 0.055 |
| CD3+/CD8+ T cells (%) | 1.14 | 0.92–1.47 | 0.233 |
| Lactate dehydrogenase | 1.00 | 0.98–1.00 | 0.456 |
| Platelets | 1.00 | 0.98–1.01 | 0.489 |
| Neutrophils (%) | 0.93 | 0.82–1.03 | 0.190 |
| Neutrophils (absolute) | 0.53 | 0.21–0.99 | 0.107 |
| Lymphocytes (%) | 1.09 | 0.97–1.24 | 0.158 |
| Lymphocytes (absolute) | 1.54 | 0.29–7.29 | 0.580 |
| Neutrophil-to-lymphocyte ratio | 0.71 | 0.36–1.01 | 0.182 |
Table 3.
Associations of peripheral blood parameters with overall survival
| Overall Survival | |||
|---|---|---|---|
| Baseline blood parameter | HR | 95% CI | p-value |
| CD3+/CD4+ T cells (%) | 0.84 | 0.75–0.95 | 0.005 |
| CD3+/CD8+ T cells (%) | 0.89 | 0.77–1.04 | 0.134 |
| Lactate dehydrogenase | 1.00 | 1.00–1.00 | 0.111 |
| Platelets | 1.00 | 0.99–1.01 | 0.992 |
| Neutrophils (%) | 1.08 | 1.02–1.13 | 0.004 |
| Neutrophils (absolute) | 1.43 | 1.17–1.75 | 0.0005 |
| Lymphocytes (%) | 0.93 | 0.88–0.99 | 0.021 |
| Lymphocytes (absolute) | 0.86 | 0.35–2.15 | 0.749 |
| Neutrophil-to-lymphocyte ratio | 1.12 | 1.04–1.20 | 0.001 |
Table 4.
Associations of peripheral blood parameters with progression-free survival
| Progression-Free Survival | |||
|---|---|---|---|
| Baseline blood parameter | HR | 95% CI | p-value |
| CD3+/CD4+ T cells (%) | 0.84 | 0.75–0.94 | 0.002 |
| CD3+/CD8+ T cells (%) | 0.85 | 0.73–0.99 | 0.035 |
| Lactate dehydrogenase | 1.00 | 1.00–1.00 | 0.113 |
| Platelets | 1.01 | 1.00–1.01 | 0.181 |
| Neutrophils (%) | 1.07 | 1.02–1.12 | 0.005 |
| Neutrophils (absolute) | 1.28 | 1.09–1.51 | 0.003 |
| Lymphocytes (%) | 0.93 | 0.87–0.98 | 0.007 |
| Lymphocytes (absolute) | 0.59 | 0.23–1.49 | 0.263 |
| Neutrophil-to-lymphocyte ratio | 1.11 | 1.04–1.19 | 0.001 |
Table 5.
Associations of peripheral blood parameters with serious adverse events
| Grade ≥3 Adverse Events | |||
|---|---|---|---|
| Baseline blood parameter | HR | 95% CI | p-value |
| CD3+/CD4+ T cells (%) | 0.99 | 0.88–1.13 | 0.923 |
| CD3+/CD8+ T cells (%) | 1.01 | 0.89–1.15 | 0.866 |
| Lactate dehydrogenase | 1.00 | 1.00–1.00 | 0.715 |
| Platelets | 0.99 | 0.99–1.00 | 0.243 |
| Neutrophils (%) | 1.04 | 0.97–1.11 | 0.258 |
| Neutrophils (absolute) | 1.12 | 0.85–1.47 | 0.413 |
| Lymphocytes (%) | 0.96 | 0.89–1.04 | 0.305 |
| Lymphocytes (absolute) | 0.97 | 0.32–3.02 | 0.964 |
| Neutrophil-to-lymphocyte ratio | 1.09 | 1.00–1.19 | 0.040 |
Figure 1:
Kaplan-Meier estimates on OS (A) and PFS (B)
Lower baseline absolute and percent neutrophils, higher baseline precent lymphocytes, and higher baseline CD3+/CD4+ (helper) T cells were associated with superior OS and PFS. Elevated baseline CD3+/CD8+ (cytotoxic) T cells correlated with improved PFS. Pretreatment LDH, platelets, and absolute lymphocytes were not significantly associated with any outcome measure.
Discussion
Expanding indications for ICIs in recurrent metastatic head and neck malignancies necessitate a deeper understanding of their utility in order to prognosticate treatment, limit toxicities, and control costs. Peripheral blood biomarkers with prognostic significance in ICIs have been described in a variety of solid tumors, including melanoma and NSCLC, where poor outcomes are associated with elevated pretreatment peripheral neutrophils, platelets, monocytes, LDH, decreased lymphocytes, and increased NLR.8,17
Literature has recently emerged examining the impact of these biomarkers among patients with head and neck malignancies receiving ICIs. In a 2018 abstract, Foster et al. studied a cohort of 114 patients with metastatic head and neck cancer receiving anti-PD-1 therapy and found that high baseline NLR was inversely correlated with OS and PFS.18 In a small retrospective review, Nishikawa et al. observed that baseline elevated percent neutrophils and decreased percent lymphocytes were associated with poor prognosis in treatment of platinum-refractory R/M HN with nivolumab.19 Our work corroborates and adds to the growing body of literature supporting the prognostic importance of peripheral blood markers of inflammation among larger populations of solid tumor patients receiving ICIs. Our clinical trial design, while limited in ways we discuss below, allowed for uniform treatment and follow-up, prospective collection of routine and specialized (e.g. T cell phenotypes) peripheral blood biomarkers, and standardized assessments of response and toxicity.
With prior work supporting our observation of baseline NLR being inversely correlated with survival, we adapted this finding into a clinically-applicable measure by identifying an NLR cutoff of 3.95, above which OS and PFS significantly decline. This finding encourages further investigations to determine the optimal NLR cutoff value to appropriately select for and counsel patients to undergo ICI treatment.
Our observations support previous findings that in R/M head and neck cancers, circulating hematologic cells represent systemic as well as local (tumor microenvironment) inflammation.15,20 Neutrophils promote tumor growth, invasion, and metastasis through multiple avenues. They secrete proteases that facilitate invasion and metastasis of tumor cells and produce cytokines and growth factors, including interleukin (IL)-6, IL-8, vascular endothelial growth factor, and epidermal growth factor, that lead to tumor cell activation and spread.21 In contrast, decreased lymphocytes, which includes B cells, CD4+ helper T cells, CD8+ cytotoxic T cells, and natural killer cells, results in attenuation of monitoring by the host immune response through decreased release of cytokines that promote apoptosis of tumor cells.22–24 These mechanisms are of particular importance in ICI treatment as these agents exert their anti-tumor effects primarily through reactivation of lymphocytes.
To our knowledge, this work is the first to observe an association between NLR and high-grade toxicities for ICI treatment in head and neck malignancies, suggesting potential utility of peripheral blood biomarkers foridentification of patients who may merit closer monitoring for treatment-related toxicities. Little data exists on predictors for toxicity for solid tumors, although Liu et al. demonstrated higher NLR to be predictive of toxicity in head and neck cancer patients receiving induction docetaxel-containing regimens.25 The underlying mechanism for this is not well elucidated and caution in the interpretation among our small sample size with combination therapy should be taken.
Additionally, we demonstrated that peripheral CD4+ helper T cells and CD8+ cytotoxic T cells are associated with improved PFS. These are novel findings for immunotherapy-treated head and neck malignancies and are consistent with prior reports in melanoma.26 We speculate that these results may relate to the favorable prognostic role of regulatory T cell infiltration, which correlates strongly with local CD4+ and CD8+ T cell populations in head and neck tumors.27 Although less readily obtained than standard peripheral blood results from CBCs, this may indicate a potential biomarker for research in prospective studies.
Our work has several limitations, foremost being the small sample size of a heterogenous population of R/M HN and SGC. The heterogeny between these two histologic groups, as well as the differences among HN subsites, was not analyzed in this pilot study but warrant investigation in future studies. These observations in a select group enrolled in a clinical trial may introduce survival bias for adverse events. This, together with the administration of a novel non-FDA approved therapeutic combination may make our observations non-generalizable to patients receiving standard regimen ICI monotherapy or other PD-1 inhibitor treatment regimens. Without validation in a larger group of preferably prospectively studied patients, applicability to a general patient population is cautioned, as this study comprised a clinical trial cohort with favorable performance status and limited comorbidities. With our small sample size and our select phase II trial population, we report only on our univariate analysis. We intend to adjust for known prognostic variables via a multivariable analysis in our ongoing studies in a larger group of patients with head and neck squamous cell carcinoma treated with standard of care immunotherapy. Finally, this trial predated the routine use of the CPS biomarker, which was not available for this cohort. Associations between NLR and CPS remain unknown, and we intend to investigate this in future studies.
Conclusions
In a small prospectively evaluated cohort of HN and SGCs treated with a combination of pembrolizumab and vorinostat, lower pretreatment NLR and neutrophils as well as higher pretreatment lymphocytes and T helper cells were associated with improved OS and PFS. Lower baseline NLR was further predictive of lower rates of serious AEs. Peripheral blood biomarkers represent an emerging frontier in improving patient selection for immunotherapy through routine and cost-effective laboratory tests. These results merit validation in a larger population treated with the current therapeutic standards and correlation with the validated CPS biomarker.
Financial support:
National Institutes of Health T32 DC000018 (Dr. Pan)
Conflict of Interest Disclosures:
Dr. Futran reported educational consultancy role for Stryker Corporation. Dr. Rodriguez reported receipt of institutional research funding from AstraZeneca, Ayala, Bristol Myers Squibb, Ignyta, and Merck, and reported advisory board membership for Cue Biopharma. The other authors declare no potential conflicts of interest.
Footnotes
This article was presented as an oral presentation at the American Head and Neck Society Annual Meeting in Dallas, TX on April 27, 2022.
Clinical trial registration: NCT02538510
Data availability statement:
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.