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Complete Response to Nivolumab in Recurrent/Metastatic HPV-Positive Head and Neck Squamous Cell Carcinoma Patient After Progressive Multifocal Leukoencephalopathy: A Case Report.

ABSTRACT: In an immune-competent context nivolumab showed long-term benefit in overall survival in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC); however, in special cancer population such as these patients with immunodeficiency and viral infections, data on checkpoint inhibitors (ICI) activity are scant. Herein, we report a patient with a Human papilloma virus (HPV)-related oropharyngeal cancer (OPC) and CD4 lymphocytopenia. After a first-line treatment complete remission, the patient experienced Human Polyomavirus (JCV) infection in the brain. Consequently, to the recovery from progressive multifocal leukoencephalopathy (PML) the patient metastasized and was enrolled in a single-arm trial with nivolumab (EudraCT number: 2017-000562-30). A complete and durable response (more 3 years) was observed after 10 nivolumab injections Q2wks, interrupted for persistent drug related G2 diarrhea and a syndrome of inappropriate antidiuretic hormone secretion. We describe the circulating immune profile (before-, during-, and after nivolumab), consistent with the clinical history. Moreover, during nivolumab treatment, brain MRI evidenced the presence of small punctuate areas of contrast enhancement, reflecting a mild immune response in perivascular spaces. By cytofluorimetry, we observed that during JCV infection the CD4/CD8 ratio of the patient was under the normal values. After JCV infection recovery and before nivolumab treatment, CD4/CD8 ratio reached the normality threshold, even if the CD4⁺ T cell count remained largely under the normal values. During ICI, gene expression xCell analyses of circulating immune cells of the patient, showed a progressive normalization of the total immune profile, with significant boost in CD4⁺ and CD8⁺ T cells and a reduction in NK T, comparable to the circulating immune profile of reference tumor-free HNSCC patients. The present case supports the activity of ICI in a population of special cancer patients; whether JCV and HPV infections (alone or together) might have a possible role as immune booster(s), require further investigations.

SUBMITTER: Locati LD

PROVIDER: S-EPMC8784387 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTreatment options for patients with platinum-refractory, recurrent, metastatic head and neck squamous cell carcinoma (r/m HNSCC) are limited and prognosis is poor. The recent CheckMate 141 clinical trial demonstrated that nivolumab, an anti-programmed cell death protein 1 monoclonal antibody, was efficacious in extending the median overall survival (OS) in this patient population compared with standard therapies. We conducted a cost-effectiveness analysis to determine whether nivolumab is a cost-effective treatment in this patient population and examined various subgroups to determine for which, if any, the treatment is more cost-effective.Materials and methodsWe implemented a state transition model for HNSCC with a patient cohort who had tumor progression 6 months after the last dose of platinum-containing chemotherapy and compared the cost-effectiveness of nivolumab with docetaxel. Treatment effect estimates and adverse event rates were obtained from CheckMate 141. Costs, utilities, and other model inputs were gathered from published sources. We used a Canadian perspective, a 5-year time horizon, and a 1.5% discount rate for the analysis.ResultsNivolumab extended mean OS by 4 months compared with docetaxel and resulted in fewer treatment-related adverse events, producing an incremental effectiveness of 0.13 quality-adjusted life years (QALY). The incremental cost of treatment with nivolumab was $18,823. At a willingness-to-pay threshold of $100,000/QALY, nivolumab was not a cost-effective treatment option for r/m HNSCC, with an incremental cost-effectiveness ratio of $144,744/QALY. Nivolumab would be cost-effective if its price was reduced by 20%. Our subgroup analysis seemed to indicate that nivolumab might be cost-effective for tumors with expression of programmed death-ligand 1 >5%.ConclusionWe conclude that although nivolumab offers clinical benefit for the treatment of r/m HNSCC over current regimens, it is not cost-effective based on its list price. We have also established a value-based price estimate for nivolumab to be cost-effective in this patient population. Further study is required to draw a definitive conclusion on biomarkers for cost-effectiveness.Implications for practiceIn health care settings in which cost considerations are a constraint on choice of therapy, patient selection should be carefully considered to maintain efficiency in the system. Until a biomarker for response to therapy is identified for nivolumab, this medication is unlikely to be cost-effective for most patients with recurrent, metastatic head and neck squamous cell carcinoma.

Project description:BackgroundPatients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition.MethodsIn this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life.ResultsThe median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group.ConclusionsAmong patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636 .).

Project description:BackgroundRecurrence and/or metastasis occurs in more than half of patients with head and neck squamous cell carcinoma (HNSCC), and these events pose the greatest threats to long-term survival. We set out to identify genetic alterations that underlie recurrent/metastatic HNSCC.MethodsWhole-exome sequencing (WES) was performed on genomic DNA extracted from fresh-frozen whole blood and patient-matched tumor pairs from 13 HNSCC patients with synchronous lymph node metastases and 10 patients with metachronous recurrent tumors. Mutational concordance within and between tumor pairs was used to analyze the spatiotemporal evolution of HNSCC in individual patients and to identify potential therapeutic targets for functional evaluation.ResultsApproximately 86% and 60% of single somatic nucleotide variants (SSNVs) identified in synchronous nodal metastases and metachronous recurrent tumors, respectively, were transmitted from the primary index tumor. Genes that were mutated in more than one metastatic or recurrent tumor, but not in the respective primary tumors, include C17orf104, inositol 1,4,5-trisphosphate receptor, type 3 (ITPR3), and discoidin domain receptor tyrosine kinase 2 (DDR2). Select DDR2 mutations have been shown to confer enhanced sensitivity to SRC-family kinase (SFK) inhibitors in other malignancies. Similarly, HNSCC cell lines harboring endogenous and engineered DDR2 mutations were more sensitive to the SFK inhibitor dasatinib than those with WT DDR2.ConclusionIn this WES study of patient-matched tumor pairs in HNSCC, we found synchronous lymph node metastases to be genetically more similar to their paired index primary tumors than metachronous recurrent tumors. This study outlines a compendium of somatic mutations in primary, metastatic, and/or recurrent HNSCC cancers, with potential implications for precision medicine approaches.FundingNational Cancer Institute, American Cancer Society, Agency for Science, Technology and Research of Singapore, and Gilead Sciences Inc.

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Complete Response to Nivolumab in Recurrent/Metastatic HPV-Positive Head and Neck Squamous Cell Carcinoma Patient After Progressive Multifocal Leukoencephalopathy: A Case Report.

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