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Prognostic Biomarkers of Salvage Chemotherapy Following Nivolumab Treatment for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.

ABSTRACT: Recent studies have suggested the benefit of salvage chemotherapy (SCT) after immune checkpoint inhibitor (ICI) treatment for recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). We retrospectively examined the outcome of SCT and the usefulness of the serum C-reactive protein level (CRP) and neutrophil-to-lymphocyte ratio (NLR) as prognostic biomarkers. Thirty-nine patients with R/M HNSCC were enrolled in this study. Twenty-five patients (64.1%) received combination chemotherapy of weekly paclitaxel and cetuximab (PC) as SCT, and 14 patients (35.9%) received tegafur-gimestat-otastat potassium (S1), an oral fluoropyrimidine. In all patients, the response rate, disease control rate, median progression-free survival (PFS), and median overall survival (OS) were 45.2%, 85.7%, 6.5 months, and 13.5 months, respectively. No chemotherapy-related deaths were observed. These PC groups had low CRP (<1.2 mg/dL) or low NLR (<7.0) values at the time of SCT induction, which was significantly associated with an improved OS (p = 0.0440, p = 0.0354). A multivariate analysis also showed that a lower CRP value was significantly associated with a better OS (p = 0.0078). We clarified the usefulness of the PC and S1 regimens as SCT. In addition, SCT with the PC regimen showed a better prognosis with a lower CRP or NLR at induction than a higher CRP or NLR. This is the first report on biomarkers of SCT in R/M HNSCC.

SUBMITTER: Wakasaki T

PROVIDER: S-EPMC7463840 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Prognostic Biomarkers of Salvage Chemotherapy Following Nivolumab Treatment for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.

Wakasaki Takahiro T Yasumatsu Ryuji R Masuda Muneyuki M Takeuchi Toranoshin T Manako Tomomi T Matsuo Mioko M Jiromaru Rina R Uchi Ryutaro R Komune Noritaka N Noda Teppei T Nakagawa Takashi T

Cancers 20200815 8

Recent studies have suggested the benefit of salvage chemotherapy (SCT) after immune checkpoint inhibitor (ICI) treatment for recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). We retrospectively examined the outcome of SCT and the usefulness of the serum C-reactive protein level (CRP) and neutrophil-to-lymphocyte ratio (NLR) as prognostic biomarkers. Thirty-nine patients with R/M HNSCC were enrolled in this study. Twenty-five patients (64.1%) received combination chemot ...[more]

PMID: 32824226

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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:BACKGROUND:Patients 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. METHODS:In 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. RESULTS:The 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. CONCLUSIONS:Among 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:Salvage surgery in recurrent head and neck squamous cell carcinoma has a poor outcome, both in terms of survival and quality of life. Therefore, the identification of pre-operative prognostic factors to improve the selection of patients who could benefit the most from salvage surgery is clinically relevant. The present study is a single-center retrospective analysis of 164 patients treated with salvage surgery after recurrence of head and neck cancer. Progression free survival and overall survival were calculated through Kaplan-Meier method. Hazard risk (HR) and corresponding confidence intervals (CI) were estimated through Cox proportional hazard model, adjusting for potential confounders. Significant predictors were combined into a prognostic score, attributing one point to each factor. Progression-free survival and overall survival were respectively 50.3% and 56.5% at 2 years, and 36.6% and 44.2% at 5 years. Four pre-operative factors were independently associated with poor prognosis: age > 70 years (HR = 2.18; 95% CI 1.27-3.73), initial stage IV (HR = 2.37; 95% CI 1.18-4.76), disease free interval < 12 months (HR = 1.72; 95% CI 1.01-2.94), and loco-regional recurrence (HR = 2.22; 95% CI 1.22-4.04). No post operative factor was associated with oncologic outcomes. Patients with 3-4 unfavorable factors showed a 5-year overall survival of 0.0% compared to 65.7% in those with 0-1 unfavorable factors (HR = 5.61; 95% CI 2.89-10.92). Despite the low number of patients, 3-4 unfavorable factors were associated to worse prognosis in all sub-sites. In conclusion, age > 70 years, initial stage IV, disease-free interval < 12 months, and loco-regional recurrence are strong independent pre-operative predictors of poor outcome in patients undergoing salvage surgery. Patients with two or more of these factors should be informed about the low success rate after salvage surgery and alternative treatments should be considered.

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.

Dataset Information

Prognostic Biomarkers of Salvage Chemotherapy Following Nivolumab Treatment for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.

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Prognostic Biomarkers of Salvage Chemotherapy Following Nivolumab Treatment for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.

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