Abstract
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.
Highlights
Head and neck cancer accounts for over 500,000 new cases and nearly 300,000 deaths annually worldwide as of 2012 [1, 2]
Status of immune checkpoint inhibitor (ICI) Clinical Trials for First-Line Treatment. Immune checkpoint inhibitors such as nivolumab, pembrolizumab, and durvalumab are currently being investigated in the first-line recurrent or metastatic (R/M) SCCHN setting for fit patients, with the EXTREME regimen chosen as a comparator arm in several recently opened phase 3 trials (Table 3)
The EXTREME regimen remains the evidence-based standard of care for first-line treatment of patients with R/M SCCHN, ICIs have shown promising overall survival (OS) results as monotherapies with tolerable toxicities and improvements in patient-reported outcomes in patients with R/M SCCHN in the second, later-line, and platinum-refractory setting
Summary
Head and neck cancer accounts for over 500,000 new cases and nearly 300,000 deaths annually worldwide as of 2012 [1, 2]. ORRs to commonly used therapies (including methotrexate, docetaxel, paclitaxel, and cetuximab as monotherapies) drop off to well under 20% and median survival in phase 3 trials has been reproducibly reported at ≈5–6 months [7, 12,13,14,15,16] This grim outlook for second-line treatment is being reshaped by the introduction of immune checkpoint inhibitors (ICIs); results of recent trials will be reviewed here. It has been proposed that stimulation of ADCC is an underlying mechanism for cetuximab’s clinically meaningful activity and the comparatively notable response rates with first- and second-line treatment in patients with R/M SCCHN, which set it apart from other mAb EGFR inhibitors (e.g., panitumumab) [33].
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