Factors predict survival after immunotherapy combination for HNSCC
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DALLAS — Multiple factors predicted improved survival among patients with head and neck or salivary gland cancers treated with pembrolizumab plus vorinostat, according to prospective study results.
Patients with lower pretreatment neutrophils and neutrophil-to-lymphocyte ratios — as well as those with more pretreatment lymphocytes and T helper cells — achieved longer OS and PFS, findings presented at American Head & Neck Society Annual Meeting showed.
Lower baseline neutrophil-to-lymphocyte ratios also appeared associated with reduced risk for serious adverse events.
“There is not much data available regarding peripheral blood biomarkers for immunotherapy for head and neck cancer,” Cassie Pan, MD, resident physician in the department of otolaryngology at University of Washington, told Healio. “Our results do seem to show what has been shown in other types of cancer, which is that systemic inflammation measured through peripheral blood is probably going to be a useful clinical marker for determining who is going to do better or worse with immunotherapy.”
Background
The potential of peripheral blood markers to predict outcomes after or adverse events related to immune checkpoint inhibitors in head and neck cancers has not been studied extensively.
Pan and colleagues previously published results of an open-label, single-institution phase 2 clinical trial designed to examine the anti-PD-1 therapy pembrolizumab (Keytruda, Merck) and vorinostat (Zolinza, Merck) — a histone deacetylase inhibitor — for patients with recurrent or metastatic head and neck squamous cell carcinoma or salivary gland cancer.
All patients had ECOG performance status of 0 or 1, measurable disease, and adequate bone marrow, hepatic and renal function.
Key study objectives included safety, objective response rates and survival.
At AHNS, Pan presented results of exploratory correlative blood studies conducted during the trial. Through these analyses, researchers aimed to evaluate associations between peripheral blood biomarkers and oncologic outcomes and toxicity.
Methods
The trial included 50 patients — 25 with HNSCC and 25 with salivary gland cancer — enrolled between November 2015 and August 2017.
Patients received 200 mg pembrolizumab via IV every 21 days and 400 mg oral vorinostat on a 5-days-on, 2-days-off schedule during each 21-day cycle.
Researchers collected correlative blood samples at baseline, as well as after three cycles of pembrolizumab-vorinostat.
They then performed flow cytometry on samples to characterize baseline and on-treatment peripheral T-cell phenotypes, including CD3+/CD8+ and CD3+/CD4+ T cells. They also measured PD-1 and PD-L1 expression on CD4+ and CD8+ T cells.
In addition, they assessed baseline and on-treatment neutrophils, lymphocytes, platelets and neutrophil-to-lymphocyte ratio.
Pan and colleagues performed univariable Cox regression to explore associations between a covariate of interest (eg, T-cell phenotypes) and time-to-event outcomes, such as PFS and OS. They performed logistic regression with binary outcomes, such as objective response or grade 3 or higher toxicities.
Researchers had baseline peripheral blood from 41 patients (HNSCC, n = 21; salivary gland cancer, n = 20).
Key findings
No peripheral blood biomarker appeared associated with ORR.
Results showed elevated baseline neutrophil-to-lymphocyte ratio correlated with shorter OS (HR = 1.12; 95% CI, 1.04-1.2) and PFS (HR = 1.11; 95% CI, 1.04-1.19), and higher rates of grade 3 or higher adverse events (OR = 1.09; 95% CI, 1-1.19).
Researchers also observed worse outcomes among patients with higher baseline absolute neutrophils (HR for OS = 1.43; 95% CI, 1.17-1.75; HR for PFS = 1.28; 95% CI, 1.09-1.51) and relative neutrophils (HR for OS = 1.08; 95% CI, 1.02-1.13; HR for PFS = 1.07; 95% CI, 1.02-1.12).
Number of lymphocytes (HR for OS = 0.93; 95% CI, 0.88-0.99; HR for PFS = 0.93; 95% CI, 0.87-0.98) and T helper cells (HR for OS = 0.84; 95% CI, 0.75-0.95; HR for PFS = 0.84; 95% CI, 0.75-0.94) at baseline also appeared associated with survival.
“With such significant associations with neutrophil-to-lymphocyte ratio, we generated Kaplan-Meier curves and found that patients with a neutrophil-to-lymphocyte ratio below a cutoff of 3.95 at baseline had a significant survival advantage, both for OS and PFS,” Pan said.
Next steps
Pan acknowledged study limitations, including the small sample size.
In addition, the drug combination analyzed — pembrolizumab and vorinostat — is not the standard of care.
She said these peripheral blood biomarkers merit validation in a larger study and in correlation with the validated combined positive score (CPS) biomarker, which evaluates the number of PD-L1-staining cells relative to all viable tumor cells. CPS had not been routinely collected during the era in which this study was conducted.
“Right now, even patients with a high CPS of greater than 20 still only have a 40% response rate, so it’s a very imperfect biomarker,” Pan told Healio. “It also requires technical expertise to evaluate a CPS biomarker, whereas ours would be just a simple blood draw that could be sent to any lab and compared across laboratories. It is cheap; the technology and infrastructure are there.
“If this could add some information to what we already know from CPS, even if it’s just supplementing or adding a new way to risk-stratify patients, it could have wide-reaching effects,” she added. “That’s the dream, but we have to emphasize that this is a pilot study, so we are interpreting our results with caution.”
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Pan C, et al. Abstract AHNS014. Presented at: American Head & Neck Society Annual Meeting at COSM 2022; April 27-28, 2022; Dallas.
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