EORTC Clinical Trial in PerspectivePerspectives on window of opportunity trials in head and neck cancer: lessons from the EORTC 90111-24111-NOCI-HNCG study
Introduction
The process of drug development is arduous. Many promising anticancer agents are investigated first in the metastatic setting before being contemplated in the early-stage disease using the traditional phase I, II and II model that was developed in the 1960s for cytotoxic chemotherapy. While this method remains common, it is not without limitations, particularly when it comes to measuring the response of newer targeted therapies using the Response Evaluation Criteria in Solid Tumours (RECIST), which may not provide the full picture about a drug's activity. The evaluation of molecular end-points can be complicated within a traditional trial approach because of the difficulty in obtaining tumour tissue before and after drug administration. Other factors, such as exposure to previous therapies, can also confound results [1].
Window of opportunity studies were developed in an attempt to bypass these issues. With this trial design, novel agents are assessed presurgically for target modulation and pharmacokinetics before the commencement of standard therapy. The primary end-point must be well defined and evaluable by imaging or by the molecular response criteria, such as predictive markers. This approach differs from neoadjuvant trials where the agent under investigation is commonly given preoperatively with cytotoxic chemotherapy or hormonal therapy for a longer period and where the primary end-point is often pathologic or clinical response. The ultimate aim is that window of opportunity trials can expedite the drug development process by improving the understanding of the agent in question [1], [2].
The recently published EORTC 90111-24111-NOCI-HNCG window of opportunity study, (henceforth EORTC 90111), was the first to demonstrate the impressive activity of afatinib in selected treatment-naive patients with squamous cell carcinoma of the head and neck (SCCHN) [3]. The goal was to identify new and predictive biomarkers among treatment-naive patients in the curative setting. The trial also collected biological samples systematically with the aim of obtaining early data on pharmacodynamic parameters and for translational research purposes.
In this open-label, randomised, multicentre, phase II trial, patients were randomised in a 5:1 ratio to afatinib for 14 days (day 15 until day 1) before surgery (day 0) or to no treatment [3]. Tumour biopsies, 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography (18-FDG PET) and magnetic resonance imaging (MRI) were performed at diagnosis and just before surgery. Thirty patients were randomised and assigned to afatinib (N = 25; arm A) or to no treatment (N = 5; arm B). The study met its primary end-point as 70% (95% confidence interval [CI]: 47%–87%) of the patients in arm A achieved a partial metabolic 18-FDG PET response. Twenty-two percent of the patients (95% CI: 8–44%) also had a partial response according to RECIST, v1.1, after only 2 weeks of treatment. The cluster3-hypoxia gene signature and TP53 status were identified as potential predictive biomarkers warranting further investigation.
While window of opportunity studies have advantages, they do, however, have potential pitfalls that may lead to a misinterpretation of results. These aspects have not been sufficiently discussed in previous window of opportunity trials in SCCHN [3], [4], [5], [6] because they focussed mainly on the activity and translational research of the drug under investigation. We present here the key learnings from the EORTC 90111 study that may be applicable to future trials in SCCHN.
Section snippets
Patient and biomarker selection
The profile of patients with SCCHN is challenging for window studies. Alcohol- and tobacco-induced head and neck cancer patients tend to be non-compliant and generally come from a low socio-economic environment. Study recruitment can be hindered because of the complex research process requiring at least two biopsies and two 18-FDG PET or computed tomography (CT) scans, as well as MRI scans.
Diagnosis, workup and study treatment need to be arranged in a short timeframe, necessitating perfect
New window of opportunity studies for SCCHN
Window studies in SCCHN may have future application in the assessment of chemotherapeutic or new target therapy combinations or for patients with operable recurrent or metastatic disease. However, adapting the protocol for patients eligible for salvage surgery may prove difficult because the operability criteria depend on the skills of the surgical team. Furthermore, operability could be hampered if tumour progression occurs before surgery, and this would have a major outcome on survival rates.
Conclusion
The EORTC Head and Neck Cancer Group conducted a challenging window of opportunity study with afatinib that yielded new biomarkers worth exploring in the curative setting, as well as new insights on how to better conduct such a trial design. The critical learning points from EORTC 90111-24111-NOCI-HNCG include the need for optimal communication between patients and the research team, multidisciplinary teamwork and integrated quality assurance for surgery, imaging and pathology. These factors
Conflict of interest statement
None declared.
Acknowledgements
The authors wish to thank Aileen Eiszele for editing and writing assistance.
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