RESUMO
INTRODUCTION: For patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) periodic reassessment of prognostic factors provides valuable information that can aid in patient stratification. PATIENTS AND METHODS: This post hoc analysis included all patients with R/M HNSCC enrolled in the ECOG-ACRIN E1305 phase III clinical trial who received first-line treatment with platinum-containing chemotherapy doublet with or without bevacizumab. Overall survival (OS) was estimated using the Kaplan-Meier method. Prognostic factors for OS were identified using univariate and multivariable analyses. A new prognostic model for OS was built retaining the prognostic factors which were significant in the final multivariable analysis (P < 0.05). RESULTS: All 403 study participants were included in the analysis. The median OS in the whole study cohort was 11.8 months (90% confidence intervals [CI], 10.6-13.2). The new prognostic model for OS comprised four risk factors (ECOG performance status [1 versus 0], primary tumor location [other versus oropharynx], presence of bone or liver metastasis, and prior radiation to the head and neck); patients with ≤ 2 (n = 249) and > 2 risk factors (n = 154) had a median OS of 15.2 and 7.6 months, respectively (Hazard ratio, 2.14; 95% CI, 1.73-2.66; P < 0.0001). CONCLUSIONS: The new proposed model includes 4 clinical prognostic factors that can be readily assessed at baseline. Similar models have the potential to improve trial design and optimize stratification of patients with R/M HNSCC.
Assuntos
Neoplasias de Cabeça e Pescoço , Recidiva Local de Neoplasia , Humanos , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Fatores de Risco , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudos RetrospectivosRESUMO
OBJECTIVES: Certain low-level immune-related adverse events (irAEs) have been associated with survival benefits in patients with various solid tumors on immune checkpoint inhibitors (ICIs). We aimed to investigate the association between irAEs and response to neoadjuvant ICIs in patients with head and neck squamous cell carcinoma (HNSCC) and to identify differences in circulating cytokine levels based on irAE status. METHODS: This was a retrospective cohort study including three neoadjuvant clinical trials from July 2017 to January 2022: NCT03238365 (nivolumab ± tadalafil), NCT03854032 (nivolumab ± BMS986205), NCT03618654 (durvalumab ± metformin). The presence and type of irAEs, pathologic treatment response, and survival were compared. Canonical linear discriminant analysis (LDA) was performed to identify combinations of circulating cytokines predictive of irAEs using plasma sample multiplex assay. RESULTS: Of 113 participants meeting inclusion criteria, 32 (28.3%) developed irAEs during treatment or follow-up. Positive p16 status was associated with irAEs (odds ratio [OR] 2.489; 95% CI 1.069-6.119; p = 0.043). irAEs were associated with pathologic treatment response (OR 3.73; 95% CI 1.34-10.35; p = 0.011) and with higher OS in the combined cohort (HR 0.319; 95% CI 0.113-0.906; p = 0.032). Patients with irAEs within the nivolumab cohort had significant elevations of select cytokines pre-treatment. Canonical LDA identified key drivers of irAEs among all trials, which were highly predictive of future irAE status. CONCLUSIONS: irAEs are associated with response to neoadjuvant ICI therapy in HNSCC and can serve as clinical indicators for improved clinical outcomes. irAEs can be predicted by concentrations of several circulating cytokines prior to treatment.
Assuntos
Citocinas , Neoplasias de Cabeça e Pescoço , Inibidores de Checkpoint Imunológico , Terapia Neoadjuvante , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Citocinas/sangue , Idoso , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/imunologia , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêuticoRESUMO
BACKGROUND: Immune checkpoint inhibitors have been approved and currently used in the clinical management of recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. The reported benefit in clinical trials is variable and heterogeneous. Our study aims at exploring and comparing the predictive role of gene-expression signatures with classical biomarkers for immunotherapy-treated R/M HNSCC patients in a multicentric phase IIIb trial. METHODS: Clinical data were prospectively collected in Nivactor tiral (single-arm, open-label, multicenter, phase IIIb clinical trial in platinum-refractory HNSCC treated with nivolumab). Findings were validated in an external independent cohort of immune-treated HNSCC patients, divided in long-term and short-term survivors (overall survival >18 and <6 months since the start of immunotherapy, respectively). Pretreatment tumor tissue specimen from immunotherapy-treated R/M HNSCC patients was used for PD-L1 (Tumor Proportion Score; Combined Positive Score (CPS)) and Tumor Mutational Burden (Oncopanel TSO500) evaluation and gene expression profiling; classical biomarkers and immune signatures (retrieved from literature) were challenged in the NIVACTOR dataset. RESULTS: Cluster-6 (Cl6) stratification of NIVACTOR cases in high score (n=16, 20%) and low score (n=64, 80%) demonstrated a statistically significant and clinically meaningful improvement in overall survival in the high-score cases (p=0.00028; HR=4.34, 95% CI 1.84 to 10.22) and discriminative ability reached area under the curve (AUC)=0.785 (95% CI 0.603 to 0.967). The association of high-score Cl6 with better outcome was also confirmed in: (1) NIVACTOR progression-free survival (p=4.93E-05; HR=3.71, 95% CI 1.92 to 7.18) and objective-response-rate (AUC=0.785; 95% CI 0.603 to 0.967); (2) long survivors versus short survivors (p=0.00544). In multivariate Cox regression analysis, Cl6 was independent from Eastern Cooperative Oncology Group performance status, PDL1-CPS, and primary tumor site. CONCLUSIONS: These data highlight the presence of underlying biological differences able to predict survival and response following treatment with immunotherapy in platinum-refractory R/M HNSCC that could have translational implications improving treatment selection. TRIAL REGISTRATION NUMBER: EudraCT Number: 2017-000562-30.