First‐line cetuximab + platinum‐based therapy for recurrent/metastatic head and neck squamous cell carcinoma: A real‐world observational study—ENCORE

Abstract Background ENCORE, an observational, prospective, open‐label study, investigated real‐world treatment practices and outcomes with cetuximab plus platinum‐based therapy (PBT) in first‐line (1L) recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Aims This multinational study aimed to investigate the long‐term use of cetuximab plus PBT for 1L R/M SCCHN in a clinical setting. In particular, this study aimed to explore clinical considerations such as the decision to prescribe cetuximab plus PBT in R/M SCCHN, the mode and duration of treatment, and patient outcomes. Methods and Results Previously untreated patients with R/M SCCHN whose planned treatment was cetuximab plus PBT were enrolled from 6 countries. Among 221 evaluable patients, planned treatments included cetuximab plus carboplatin (31.2%), cisplatin plus 5‐fluorouracil (31.7%), or carboplatin plus 5‐fluorouracil (23.1%); 3.2% included a taxane, and 45.2% did not include 5‐fluorouracil. Cetuximab treatment was planned for a fixed duration (≤24 weeks) in 15 patients (6.8%) and until disease progression in 206 (93.2%). Median progression‐free survival and overall survival were 6.5 and 10.8 months, respectively. Grade ≥3 adverse events occurred in 39.8% of patients. Serious adverse events occurred in 25.8% of patients; 5.4% were cetuximab‐related. Conclusion In patients with R/M SCCHN, first‐line cetuximab plus PBT was feasible and modifiable in a real‐world setting with similar toxicity and efficacy as in the pivotal phase III EXTREME trial. Clinical trial registration number: EMR 062202‐566.

death-ligand 1 (PD-L1) with a combined positive score of ≥1. 12 The NCCN guidelines ® recommend the EXTREME regimen as one of the 1L treatment options for patients with R/M SCCHN, regardless of PD-L1 status. 7 Cetuximab combined with pembrolizumab is also being explored for R/M SCHNN and clinical trials have shown promising preliminary results; a study in 33 patients who had not received any previous PD-1, PD-L1, or EGFR inhibition demonstrated an ORR of 45% for this combination. 13 Although recent clinical trials have provided insight into the use of cetuximab plus platinum-based therapy (PBT) in a controlled setting, little is known about its use in the real-world clinical setting by clinicians in Europe, particularly for those patients who are typically excluded from randomized controlled trials (e.g., patients who have an Eastern Cooperative Oncology Group performance status [ECOG PS] score of >2 or are elderly). Observational studies are therefore necessary to ensure that benefits observed in controlled clinical trials translate accordingly to patients in the real-world setting. ENCORE  Treatment involved cetuximab in combination with PBT for the 1L treatment of R/M SCCHN. All agents were given according to their locally approved labels, and planned treatment duration was according to normal clinical practice for each treating physician. The clinical decision to use cetuximab with PBT and the recording of patient baseline characteristics, planned treatment regimens, administration schedule, and efficacy/safety outcomes were at the sole discretion of the investigator. Patient follow-up was for 1 year after the first dose of cetuximab, or until death, whichever occurred first (some patients had longer follow-ups as the follow-up period was initially planned at 2 years and was reduced to 1 year after a protocol amendment; additionally, some patients began cetuximab treatment prior to enrollment). Patients were considered as receiving cetuximab maintenance therapy if any administration of cetuximab was given >7 days after the last administration of chemotherapy.
The primary objective was to assess treatment patterns for cetuximab, especially duration of use, for the treatment of 1L R/M SCCHN in combination with platinum-based chemotherapy across different regions worldwide. Key secondary objectives were to assess treatment outcomes, including the endpoints of best overall response (BOR), disease control rate (DCR), ORR, PFS and OS, and adverse events (AEs) related to cetuximab. Only serious adverse events (SAEs), non-serious AEs related to study treatment, and AEs leading to a delay or the permanent discontinuation of study treatment were to be recorded until the 30-day posttreatment safety follow-up assessment; AEs were graded according to the National Cancer Institute Common Terminology for Adverse Events v4.03.
Because this was a prospective observational study, several patients were enrolled who had started cetuximab treatment prior to enrollment; these patients were included in the analysis providing that consent had been given and that retrospective data were available. The full analysis set (FAS) therefore included all enrolled patients who received cetuximab; primary endpoints and safety were analyzed in the FAS. As some patients began cetuximab treatment prior to enrollment, the target analysis set (TAS) was created to allow for output generation of patients in the FAS. The TAS included all patients who received their first dose of cetuximab on or after the date of enrollment. Secondary efficacy endpoints were analyzed in both the FAS and TAS.

| Statistical analyses
Descriptive and exploratory statistical methods were used to analyze the study data; all statistical methods were of exploratory nature only.
BOR, ORR and DCR: these qualitative variables were summarized as a number and percentage for the FAS and TAS. The Cochran-Mantel-Haenszel test was used to test for differences in ORR and DCR between patients with planned cetuximab treatment until PD versus those with a planned fixed duration of cetuximab treatment. The corresponding odds ratios and 95% confidence intervals (CIs) for the odds ratios were determined. The association between ORR and planned duration of cetuximab treatment, respectively, and possible explanatory variables were analyzed using logistic regression methods.
PFS and OS: The Kaplan-Meier method was used to estimate median PFS and OS and the corresponding 95% CIs. A log-rank test was used to compare PFS and OS between patients who received cetuximab until PD and those who received cetuximab for a fixed duration. The hazard ratios for PFS and OS (including the 95% CIs) were determined to assess the effect of planned cetuximab treatment duration (not until PD vs. until PD). Cox proportional hazard methods were used to investigate the association between PFS and OS and possible explanatory variables.
Due to a protocol amendment, the planned follow-up time was reduced from 2 years to 1 year to allow for an earlier study end. However, the follow-up date for patients enrolled under the original plan of 2 years of follow-up was not censored; all evaluable data were used.  Table 1). The treatment goal was palliative, potentially curative, and symptomatic treatment in 141 patients (63.8%), 65 (29.4%), and 15 (6.8%), respectively, in the FAS.

| Treatments received
Cetuximab plus PBT regimens received in the overall population (FAS) are outlined in Table 2 Table 2). The mean total number of cetuximab administrations was 14.1 ± 12.91 with a cumulative cetuximab dose of 4032.9 ± 3653.64 mg/m 2 , and the mean relative dose intensity was 72.0 ± 30.62% (Supplementary Table 3).

| Efficacy outcomes
Efficacy outcomes for the FAS and TAS are presented in Table 3.
Median PFS was 6.5 months overall in the FAS (median PFS stratified by cetuximab duration was 6.

| Safety
In the safety analysis set (FAS; N =  The baseline characteristics of patients in the ENCORE study and the EXTREME trial were similar, although the median age was lower in the EXTREME trial (56 years) compared with the ENCORE study (64 years). 6 Also, most patients in the ENCORE study had an ECOG PS of 0 or 1, whereas ECOG PS was not specified in the EXTREME trial; instead, patients were eligible if they had a Karnofsky performance status of ≥70. 6 No new safety signals were observed with F I G U R E 2 Kaplan-Meier estimates of progression-free survival for patients whose planned cetuximab treatment was until progressive disease (PD) or for a fixed duration in the full analysis set (A) and target analysis set (B showed that cetuximab plus PBT was feasible in an unselected patient population and was adaptable to suit patient needs (e.g., almost half of the patients did not receive 5-FU).
The EXTREME regimen was recently evaluated in patients with R/M SCCHN who were ≥70 years old in the ELAN (ELderly head And Neck cancer) trials. 14 ELAN was a large prospective clinical program F I G U R E 3 Kaplan-Meier estimates of overall survival for patients whose planned cetuximab treatment was until progressive disease (PD) or for a fixed duration in the full analysis set (A) and target analysis set (B). CI, confidence interval; HR, hazard ratio.
designed to improve the management of elderly patients with SCCHN by using an adapted geriatric evaluation that is feasible for use in daily practice. In the ELAN FIT trial, 78 patients were treated with the EXTREME regimen with efficacy assessed by the ORR at 12 weeks and safety assessed by lack of grade ≥4 toxicity and no loss of independence. The 12-week ORR was 38% in fit elderly patients with SCCHN. Other efficacy outcomes included a median OS of 14.7 months (95% CI, 11.0-18.2 months) and a median PFS of 7.1 months (95% CI, 5.5-8.2 months); nearly a quarter (24%) of the patients experienced a grade ≥4 AE. Benefit was observed in elderly patients determined as fit by using the ELAN geriatric evaluation criteria. 14 The results of ENCORE compare favorably with these outcomes; thus, these data establish the utility of cetuximab plus PBT across a variety of patient populations.
There were limitations associated with the ENCORE study, which are typical of the observational study design. Some patients began cetuximab treatment before the date of enrollment, potentially leading to selection bias and study outcomes bias. Their outcomes may have a positive bias, particularly for time-to-event endpoints, because patients who were already on treatment without progression upon enrollment were more likely to be responders and have longer survival times than patients starting treatment at enrollment. The TAS was introduced for those patients in the FAS who had only started cetuximab after their enrollment. The difference between the results in the FAS and TAS allows an assessment of the effect of the selection bias.
Efficacy outcomes from the TAS may therefore be considered more reliable than those of the FAS. Furthermore, conducting the safety analysis on the TAS may be more representative of real-world clinical practice as any AEs occurring before study enrollment may not be captured in the FAS, potentially underestimating treatment toxicity.
Another limitation was that patients were enrolled from only 6 countries (Algeria, France, Italy, Portugal, Russia, and South Africa); therefore, a true global perspective of real-world practices for 1L R/M SCCHN treatment may not have been gained. The low number of patients whose treatment was planned for a fixed duration does not allow a valid conclusion regarding whether the planned treatment duration (until PD or for a fixed duration) had an impact on the treatment outcome; however, this analysis does show that treatment until PD is a well-accepted regimen, consistent with results from the EXTREME study. 6  Merck KGaA, Darmstadt, Germany has a co-research, co-development, or co-marketing or co-promotion agreement, or when the product has been out-licensed, the responsibility for disclosure might be dependent on the agreement between parties. Under these circumstances, the healthcare business of Merck KGaA, Darmstadt, Germany will endeavor to gain agreement to share data in response to requests.

ETHICS STATEMENT
All patients provided written informed consent prior to enrollment, and the protocol was approved by the local regulatory and ethics committee at each participating center. The study was conducted in accordance with the Declaration of Helsinki and the International Council on Harmonization Guidelines on Good Clinical Practice.