Elevated basal antibody-dependent cell-mediated cytotoxicity (ADCC) and high epidermal growth factor receptor (EGFR) expression predict favourable outcome in patients with locally advanced head and neck cancer treated with cetuximab and radiotherapy

Lattanzio, Laura; Denaro, Nerina; Vivenza, Daniela; Varamo, Chiara; Strola, Giuliana; Fortunato, M.; Chamorey, Emmanuel; Comino, Alberto; Monteverde, Martino; Nigro, Cristiana Lo; Milano, Gérard; Merlano, Marco

doi:10.1007/s00262-017-1960-8

Cited by 45 publications

(41 citation statements)

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“…It is also reasonable to propose that “priming” antitumor immune responses with cetuximab prior to the administration of other immunotherapies might augment a patient’s responsiveness to treatment (31, 36). Contribution of ADCC to the antitumor activity of cetuximab have not been widely tested in clinical trials, but recent studies has suggested a correlation between cetuximab efficacy and high ADCC (37, 38). …”

Section: Available Targeted Therapies In Scchnmentioning

confidence: 99%

Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck

et al. 2017

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The major development of the past decade in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) was the introduction of cetuximab in combination with platinum plus 5-fluorouracil chemotherapy (CT), followed by maintenance cetuximab (the “EXTREME” regimen). This regimen is supported by a phase 3 randomized trial and subsequent observational studies, and it confers well-documented survival benefits, with median survival ranging between approximately 10 and 14 months, overall response rates between 36 and 44%, and disease control rates of over 80%. Furthermore, as indicated by patient-reported outcome measures, the addition of cetuximab to platinum-based CT leads to a significant reduction in pain and problems with social eating and speech. Conversely, until very recently, there has been a lack of evidence-based second-line treatment options, and the therapies that have been available have shown low response rates and poor survival outcomes. Presently, a promising new treatment option in R/M SCCHN has emerged: immune checkpoint inhibitors (ICIs), which have demonstrated favorable results in second-line clinical trials. Nivolumab and pembrolizumab are the first two ICIs that were approved by the US Food and Drug Administration. We note that the trials that showed benefit with ICIs included not only patients who previously received ≥1 platinum-based regimens for R/M SCCHN but also patients who experienced recurrence within 6 months after combined modality therapy with a platinum agent for locally advanced disease. In this review, we outline the available clinical and observational evidence for the EXTREME regimen and the initial results from clinical trials for ICIs in patients with R/M SCCHN. We propose that these treatment options can be integrated into a new continuum of care paradigm, with first-line EXTREME regimen followed by second-line ICIs. A number of ongoing clinical trials are comparing regimens with ICIs, alone and in combination with other ICIs or CT, with the EXTREME regimen for first-line treatment of R/M SCCHN. As we eagerly await the results of these trials, the EXTREME regimen remains the standard of care for the first-line treatment of R/M SCCHN.

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Section: Available Targeted Therapies In Scchnmentioning

confidence: 99%

Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck

et al. 2017

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“…All of these treatments, including surgery, may have contributed to modifying the immune microenvironment of the tumor, making it more sensitive to immunotherapy. [14][15][16][17][18][19][20] After an initial major response, our patient's tumor slowly progressed in two locations during nivolumab treatment. Although radiological pseudoprogression seems to be infrequent in head and neck cancer, caution should be applied when using 18 F-FDG PET scans for tumor reevaluation in patients receiving immunotherapy, as increases in metabolic uptake can occur due to inflammatory cell infiltration and be confounded with tumor progression.…”

Section: Discussionmentioning

confidence: 78%

“…Our patient underwent a laryngectomy 6 months prior to receiving cetuximab in combination with paclitaxel and cisplatin. All of these treatments, including surgery, may have contributed to modifying the immune microenvironment of the tumor, making it more sensitive to immunotherapy …”

Section: Discussionmentioning

confidence: 99%

Durable intracranial and extracranial response to nivolumab with appearance of secondary resistance in a heavily pretreated patient with head and neck cancer

et al. 2019

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Background Recently, nivolumab was approved in the second‐line setting of squamous cell cancer of the head and neck (SCCHN). The benefits of PD‐(L)1 inhibitors in PD‐L1(−) tumors are unclear, and no reports exist on the activity of these agents in brain metastases from SCCHN. Little is known regarding the mechanisms underlying acquired resistance to PD‐(L)1 inhibition. Methods A patient with PD‐L1(−) metastatic SCCHN progressing to cetuximab‐based chemotherapy received third‐line nivolumab. T cell infiltration and mRNA expression of immune‐related genes were compared in prenivolumab and postnivolumab biopsies from a progressing tumor lesion. Results An exceptional local and systemic response was achieved, including complete devitalization of brain metastases that lasted for more than a year. Increased T cell infiltration and upregulation of genes related to T cell exhaustion and resistance to PD‐1 inhibition were found. Conclusion Durable responses to PD‐(L)1 inhibitors may be observed in biomarker‐negative SCCHN. Mechanisms of resistance should be studied.

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“…Apart from cell line and mouse models, the importance of ADCC was recently corroborated in patients with LA-SCCHN. In a retrospective analysis [22], high baseline ADCC predicted OS in patients who received radiation concurrently with cetuximab ( n = 28), but not in patients treated with cisplatin ( n = 15). In the bioradiation-treated group, patients with high baselines of ADCC (lactate dehydrogenase release, Cytotoxic 96® cytotoxicity assay) and EGFR 3+ (immunohistochemistry) had significantly more complete responses and longer OS than the others.…”

Section: Introductionmentioning

confidence: 99%

Immunotherapy in head and neck cancer: aiming at EXTREME precision

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2017

BMC Med

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BackgroundLocoregionally advanced, recurrent, and metastatic squamous cell carcinomas of the head and neck (SCCHN) remain difficult to treat disease entities, in which systemic treatment often forms an integral part of their management. Immunotherapy is based on functional restoration of the host immune system, helping to counteract various tumour evasion strategies. Broadly, immunotherapeutic approaches encompass tumour-specific antibodies, cancer vaccines, cytokines, adoptive T-cell transfer, and immune-modulating agents. Until 2015, the epidermal growth factor receptor inhibitor cetuximab, a tumour-specific antibody, represented the only Food and Drug Administration (FDA)-approved targeted therapy for SCCHN. Subsequently, in 2016, the results from two prospective trials employing the immune-modulating antibodies nivolumab and pembrolizumab heralded a new era of anticancer treatment.DiscussionNivolumab and pembrolizumab are monoclonal antibodies against programmed cell death protein-1 (PD-1), an ‘immune checkpoint’ receptor. Found on the surface of T-cells, PD-1 negatively regulates their activation and can thus be exploited during carcinogenesis. The second-line phase III trial CheckMate-141 randomly assigned 361 patients with recurrent and/or metastatic SCCHN in a 2:1 ratio to receive either single-agent nivolumab (3 mg/kg intravenously every 2 weeks) or standard monotherapy (methotrexate, docetaxel, or cetuximab). Nivolumab improved the objective response rate (13% versus 6%) and median overall survival (OS; 7.5 versus 5.1 months, p = 0.01) without increasing toxicity. Exploratory biomarker analyses indicated that patients treated with nivolumab had longer OS than those given standard therapy, regardless of tumour PD-1 ligand (PD-L1) expression or p16 status. In the non-randomised, multicohort phase Ib study KEYNOTE-012, treatment with pembrolizumab achieved comparable results. Importantly, most of the responding patients had a long-lasting response.ConclusionBased on recent results, nivolumab and pembrolizumab have been approved by the FDA as new standard-of-care options for the second-line treatment of recurrent and/or metastatic SCCHN. Generally well tolerated, these novel drugs demonstrated modest response rates, with tumour regressions usually being durable, even in platinum-resistant/refractory cases. The next step will be to extend the observed benefit to first-line treatment, currently dominated by the EXTREME regimen (platinum/5-fluorouracil/cetuximab), and to the locoregionally advanced setting, where concurrent chemoradiation with cisplatin is standard. Regimens combining immunotherapy with other modalities will probably further improve outcomes.

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Elevated basal antibody-dependent cell-mediated cytotoxicity (ADCC) and high epidermal growth factor receptor (EGFR) expression predict favourable outcome in patients with locally advanced head and neck cancer treated with cetuximab and radiotherapy

Abstract: In this study, patients treated with cetuximab and radiotherapy, showing high baseline of both ADCC and EGFR3+, have significant higher probability of achieving a complete response and a long overall survival compared to the others.

Cited by 45 publications

References 11 publications

Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck

Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck

Durable intracranial and extracranial response to nivolumab with appearance of secondary resistance in a heavily pretreated patient with head and neck cancer

Immunotherapy in head and neck cancer: aiming at EXTREME precision

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