Observational, prospective, phase 4 study in patients with first‐line recurrent and/or metastatic squamous cell carcinoma of the head and neck treated with cetuximab and platinum‐based therapy: DIRECT

Abstract Background Cetuximab plus platinum‐based therapy (PBT) followed by cetuximab maintenance until progression (EXTREME) is a guideline‐recommended first‐line treatment option in recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). DIRECT (Dose Intensity RElative to CeTuximab) was the first phase 4 observational study evaluating EXTREME administration in the real‐world setting. Aims The primary aim of this study was to assess the relative dose intensity of cetuximab in patients with R/M SCCHN treated with first‐line cetuximab according to the EXTREME regimen. Methods and results Patients were ≥18 years old and eligible to receive cetuximab/PBT. Primary endpoint was cetuximab relative dose intensity (RDI). Of prospectively enrolled patients (n = 157), 119 received ≥1 cycle of EXTREME. Practices differing from the EXTREME trial were 5‐fluorouracil omission (14%), maintenance cetuximab given every other week (54%), prior cetuximab, disease‐free interval <6 months. 64% of patients reached cetuximab RDI ≥80%; mean cetuximab RDI was 88%. 46% of patients received maintenance cetuximab (mean RDI, 91%). Median progression‐free survival and overall survival were 4.5 and 9.4 months. No new/unexpected safety findings were observed. Conclusions The DIRECT study showed that first‐line cetuximab plus PBT was a feasible, beneficial first‐line treatment regimen in patients with R/M SCCHN in the real‐world setting.


| INTRODUCTION
Recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) has a poor prognosis. 1 Cetuximab plus platinumbased chemotherapy followed by cetuximab maintenance (EXTREME) was the first regimen to yield significant survival benefits over chemotherapy alone in the first-line treatment of R/M SCCHN. [2][3][4][5] This regimen, which is currently an established first-line treatment option for patients with R/M SCCHN, is composed of ≤6 cycles of a platinumbased chemotherapy (cisplatin/carboplatin +5-fluorouracil  with the anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab, followed by maintenance cetuximab therapy until progressive disease (PD). 2 The EXTREME regimen resulted in a median overall survival (OS) improvement of nearly 3 months over chemotherapy alone (10.1 vs. 7.4 months), and an overall response rate of 36% versus 20% in the chemotherapy-alone arm. 2 Maintenance therapy is a standard component of the EXTREME regimen, and international guidelines recommend continuing cetuximab treatment until disease progression for patients with at least stable disease after combination treatment with chemotherapy. 2,5,6 The treatment landscape for patients with R/M SCCHN is rapidly evolving as multi- The phase 4 DIRECT trial is the first observational, prospective study to characterize physicians' treatment practices and patient adherence with the EXTREME regimen in the first-line R/M SCCHN setting. 8 This study enrolled largely unselected patients, thereby reflecting the real-world population observed in clinical practice.
Patients could be treated with the EXTREME regimen as described in the pivotal study or, at the physicians' discretion, with an adapted version of the EXTREME regimen to address individual patients' conditions. Thus, the findings of this observational study shed light on how the EXTREME regimen is applied in the real-world setting.

| Trial design and patients
DIRECT (EMR 62202-556) was a phase 4, observational, longitudinal, multicenter, noncomparative study to assess the relative dose intensity (RDI) of cetuximab in patients with R/M SCCHN undergoing firstline treatment with the EXTREME regimen across France. The trial spanned 21 months, which included a 6-month recruitment period and a maximum follow-up period of 12 months. Patients were accrued prospectively (before beginning cetuximab treatment). Any individual ≥18 years of age with histologically proven R/M SCCHN and eligibility to receive the EXTREME regimen could participate in this study.
Those who required an adaptive EXTREME regimen (e.g., patients with cardiovascular disorders [a contraindication to 5-FU]) could also participate at physicians' discretion. Exclusion criteria consisted of concomitant participation in an interventional trial, known allergic reaction to one of the treatment components, and factors that impinged on the patient's ability to maintain adherence throughout the study. Also excluded were patients treated with cetuximab according to the scheme of the EXTREME study who had received <1 complete cycle of chemotherapy in combination with cetuximab, patients with nasopharyngeal carcinoma, and patients with a contraindication in accordance with the respective label, except for that of 5-FU. Finally, it is worth noting that patients were recruited before any anti-programmed death-(ligand) 1 (PD-[L]1) therapies were available for the R/M SCCHN population.
In accordance with European regulations, French observational studies do not require review or approval from an institutional review board or institutional ethics committee. Nevertheless, these studies are not exempt from scientific opinion or ethical and legal authorization.

| Treatment
Treatment was conducted per physician's choice and largely per label specifications for cetuximab and according to the EXTREME protocol.
The EXTREME label consists of cetuximab (loading dose of 400 mg/ m 2 as a 2-h intravenous [IV] infusion and then 250 mg/m 2 as a 1-h IV infusion per week) + cisplatin (100 mg/m 2 on day 1) or carboplatin (area under the curve of 5 mg/ml/min as a 1-h IV infusion on day 1) + 5-FU (1000 mg/m 2 /day for 4 days) every 3 weeks for a maximum of six cycles, with the intention to continue cetuximab until PD. The only adaptations were to omit 5-FU due to preexisting cardiovascular disorders, to administer cetuximab every 2 weeks in the maintenance phase (at a dose of 500 mg/m 2 ), and to enroll patients with prior cetuximab treatment in the locally advanced (LA) setting. An exception to the physician's discretion was to exclude patients who had received a taxane as part of the first-line regimen.

| Outcome assessment
The primary objective of this study was to describe the use of the EXTREME regimen in a real-world clinical setting. The selected method of measurement was the cetuximab RDI (defined as the ratio of actual cumulative dose received by patients to the planned dose), and the primary study endpoint was the percentage of patients with a cetuximab (or chemotherapy) RDI of ≥80%. Mean RDI is an indicator of whether patients can successfully complete the recommended regimen in the real world. 9 A key secondary objective was the assessment of cetuximab (and, when applicable, chemotherapy) RDI by treatment phase (combination and maintenance). Additional secondary objectives included determination of the incidence of skin reactions related to cetuximab (and cetuximab RDI) based on the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03, analysis of the impact that management of skin reactions may have on 2 of 9 cetuximab RDI, and determining reasons why patients may discontinue or interrupt treatment and thus achieve a lower RDI. A complementary statistical analysis was also performed to determine survival outcomes at 12 months, including progression-free survival (PFS) and OS. Finally, patients were followed up until treatment discontinuation or for a maximum of 12 months after their first visit. Per an amendment to the protocol, the status of all patients who discontinued the study within <1 year of the inclusion visit was retrospectively recorded as 1 year.

| Statistics
On the basis of the EXTREME study results (84% of patients had a cetuximab RDI of ≥80%), 2 it was estimated that, of 150 enrolled patients, 135 would be evaluable for a cetuximab RDI of ≥80%. The full analysis sample was defined as all patients who received ≥1 dose of cetuximab in addition to the loading dose. The statistical safety analysis consisted of all patients who received ≥1 dose of cetuximab (i.e., the loading dose). Patient status was evaluated at 12 months; PFS and OS analyses were performed using Kaplan-Meier curves.
Exploratory subgroup analyses were performed using univariate statistical tests (χ 2 , Fisher exact, t or Wilcoxon, log-rank). If indicated, multivariate analysis was performed using Cox regression. Statistical analysis was performed using SAS software (SAS Institute, Cary, NC). Detailed information regarding prior treatments is presented in Table 1.

| Patient population
Of the 157 patients, 139 patients entered the study with recurrent disease (locoregional only, n = 76; recurrent with metastasis, n = 63), 17 patients had metastasis upon initial diagnosis, and one patient's status upon enrollment was missing (

| Treatment exposure
In DIRECT, among the 157 patients who received the cetuximab loading dose, 140 also received ≥1 additional dose of cetuximab, and 17 patients discontinued treatment following the loading dose. The chemotherapy regimens received and the number of patients who received each regimen are described in Table 2. A total of 39.0% of patients began with a carboplatin-based regimen; 61.0% received cisplatin-based treatment. Nineteen patients (13.5%) switched from cisplatin-to carboplatin-based therapy, and two patients (1.4%) switched from carboplatin-to cisplatin-based treatment ( Table 2) During the combination phase, the mean cetuximab RDI remained high (87.6% ± 16.9%), and 64.3% of patients had a cetuximab RDI of ≥80%. The mean RDI with chemotherapy was 79.1% for cisplatin, 81.9% for carboplatin, and 82.7% for 5-FU (Table 3).
Seventy-two patients (45.9%) received ≥1 dose of cetuximab in the maintenance setting, and the median duration of maintenance therapy was 14.2 weeks. In this cohort, the mean cetuximab RDI was 91.4% ± 15.7% (Table 3) and ≥80% in 57 (85.1%) of the 67 patients for whom RDI data were available. A total of 45.8% of patients (n = 33) who received maintenance therapy were treated with weekly cetuximab, and 54.2% (n = 39) received cetuximab every 2 weeks.

| Safety of treatment with cetuximab
Among the 157 patients, the total incidence of skin reactions of any grade during treatment was 70.7%, and the most common dermatologic AE was papulopustular eruption/acne-like rash, which occurred in 91 patients (58.0%), followed by xerosis or dry skin in 49 patients (31.2%) ( Table 4). Additionally, the incidence rate of infusion-related reactions was 1.9%.

| Efficacy
Median follow-up was 8 months (range, 0-29 months). The 12-month PFS rate was 11.3% (95% CI, 6.9%-17.0%), and the 12-month OS rate      The primary objective of the DIRECT study was to measure RDI in the real-world setting as an indicator of the feasibility and tolerability of treatment with cetuximab-and platinum-based chemotherapy followed by cetuximab maintenance therapy until PD (EXTREME regimen). PFS and OS were also assessed. Although the DIRECT study is not directly comparable to the EXTREME study, the proportion of patients who received maintenance therapy and the recorded median the EXTREME regimen in the first line. 10,11 Cetuximab RDI measurements suggest good adherence in combination with platinum-based chemotherapy in the real world, although the proportion of patients with an RDI ≥80% was lower in the present study than in EXTREME (64% vs. 84%). 2

| CONCLUSION
The DIRECT study provided real-world support for use of the EXTREME regimen in everyday clinical practice. The DIRECT study's outcomes (PFS, OS, safety profile) were similar to those observed in the cetuximab-containing arm of EXTREME, although a distinct and more inclusive patient population was enrolled, including patients with DFI <6 months since the last platinum treatment, patients with prior cetuximab treatment, and patients with contraindications to 5-FU. Nearly 50% of patients in DIRECT were able to complete the combination phase and thus continued to receive maintenance therapy. Additionally, the DIRECT study identified a low rate of treatment interruptions and dose reductions, the majority of which occurred in the combination therapy phase. In conclusion, the DIRECT study demonstrated that first-line cetuximab plus platinum-based chemotherapy, including cetuximab maintenance therapy, was a feasible and beneficial treatment regimen in patients with R/M SCCHN in the everyday clinical setting.

ETHICAL STATEMENT
In accordance with European regulations, French observational studies do not require review or approval from an institutional review board or institutional ethics committee. Nevertheless, these studies are not exempt from scientific opinion or ethical and legal authorization. Written informed consent was obtained from all study participants.

DATA AVAILABILITY STATEMENT
Any requests for data by qualified scientific and medical researchers for legitimate research purposes will be subject to Merck's Data Sharing Policy. All requests should be submitted in writing to Merck's data sharing portal (https://www.merckgroup.com/en/ research/our-approach-to-research-and-development/healthcare/ clinical-trials/commitment-responsible-data-sharing.html). When Merck has a co-research, co-development, or co-marketing or copromotion agreement, or when the product has been out-licensed, the responsibility for disclosure might be dependent on the agreement between parties. Under these circumstances, Merck will endeavor to gain agreement to share data in response to requests.

ROLE OF FUNDING SOURCE
Merck Santé SAS, Lyon, France, an affiliate of Merck KGaA, Darmstadt, Germany, fully funded the study and designed the protocol and amendments in discussion and agreement with the coordinating investigators. Data were interpreted by Merck KGaA and the coordinating investigators. The final decision to submit for publication was made by the coordinating investigators.