The GORTEC 2015-01 PermbroRad phase II study is the first randomised study that tested pembrolizumab/radiotherapy versus cetuximab/radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for receiving high-dose cisplatin. There was no difference in loco-regional control at 15 months between concurrent pembrolizumab/radiotherapy versus cetuximab/radiotherapy and there was no difference in overall survival (OS) or progression-free survival (PFS) between the two arms at 2 year follow-up. However, there were significantly more grade ≥ 3 adverse events with cetuximab/radiotherapy, essentially due to skin and mucosal reactions. The findings from the GORTEC 2015-01 PermbroRad study are published by Prof. Jean Bourhis of the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland and colleagues on 27 October 2022 in the Annals of Oncology.
The authors wrote in the background that a majority of squamous cell carcinoma of head and neck are locally advanced and commonly treated with concomitant chemoradiotherapy. Cisplatin-based chemoradiotherapy is a well established standard of care in non-operated patients, but carrying substantial toxicity when compared to radiotherapy alone. However, a large proportion of patients are not suitable for receiving high-dose cisplatin-based chemotherapy either due to age, general and/or medical condition(s).
An alternative standard of care has been established, combining radiotherapy and cetuximab based on the results of a phase III study which showed improved efficacy with relatively good toxicity profile. Both standard of care chemoradiotherapy and cetuximab/radiotherapy are associated with poor outcome in patients with stage T4 and/or ≥N2 and/or HPV negative tumours. So, there is a strong medical need for developing new treatments to improve outcomes in these patients.
At the time when the GORTEC 2015-01 PermbroRad study was initiated, anti-PD1 inhibitor, pembrolizumab was shown to be active in recurrent/metastatic squamous cell carcinoma of head and neck. This was later confirmed by large scale randomised studies which subsequently showed both for nivolumab (CHECKMATE-141) and pembrolizumab (KEYNOTE-048) that PD1 inhibition is a new standard of care in first- and second-line treatment for recurrent/metastatic squamous cell carcinoma of head and neck. In addition, there is also a strong pre-clinical rational for combining PD1 targeting with radiotherapy.
The goal of the GORTEC 2015-01 PermbroRad study was to evaluate the potential benefit of PD1 inhibition in locally advanced squamous cell carcinoma of head and neck, when used earlier than in a recurrent/metastatic context. The study team hypothesis was that the combination of pembrolizumab with radiotherapy would be well tolerated, given the favourable toxicity profile of the drug and that could improve the outcome of patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin/radiotherapy, as compared to the standard of care cetuximab/radiotherapy.
Patients with non-operated stage III-IV squamous cell carcinoma of oral cavity, oropharynx, hypopharynx and larynx unfit for receiving high-dose cisplatin were enrolled in this study. Patients received once-daily radiotherapy up to 69.96 Gy in 33 fractions with weekly cetuximab (cetuximab/radiotherapy arm) or 200 mg Q3W pembrolizumab during radiotherapy (pembrolizumab/radiotherapy arm). The primary endpoint was loco-regional control rate 15 months after radiotherapy. To detect a difference between arms of 60% to 80% in 15-month loco-regional control, inclusion of 66 patients per arm was required to achieve a power of at least 0.85 at 2-sided significance level of 0.20.
Between May 2016 and October 2017, 133 patients were randomised, 66 to cetuximab/radiotherapy and 67 to pembrolizumab/radiotherapy. Two patients (one in each arm) were not included in the analysis due a consent withdrawal and a progression before treatment start. The median age was 65 years (interquartile range 60-70), 92% were smokers, 60% had squamous cell carcinoma of oropharynx (46% with p16 positive tumour) and 75% had stage IV disease. Median follow-up was 25 months in both arms.
15-month loco-regional control rates were 59% with cetuximab/radiotherapy and 60% with pembrolizumab/radiotherapy, odds-ratio 1.05 (95% confidence interval [CI] 0.43-2.59; p = 0.91). There was no significant difference between arms in terms of PFS with hazard ratio (HR) 0.85 (95% CI 0.55-1.32; p = 0.47) and OS, HR 0.83 (95% CI 0.49-1.40; p = 0.49). The authors commented that a longer follow-up would be useful for drawing definitive conclusion, since a potential delayed benefit of PD1 inhibition on OS cannot be excluded.
Toxicity was lower in pembrolizumab/radiotherapy arm than in cetuximab/radiotherapy arm, 74% versus 92% patients with at least one grade ≥3 adverse events (p = 0.006), mainly due to mucositis, radiodermatitis and rash.
The authors commented that although the study was not designed as a non-inferiority study, the observed results indirectly suggests that concurrent 3 cycles of pembrolizumab is likely as active as cetuximab when combined with radiotherapy. However, the therapeutic ratio might be slightly improved with pembrolizumab since a significant reduction of the overall number of grade ≥ 3 adverse events was seen with pembrolizumab in comparison to cetuximab, especially with less dermatitis, mucositis and rash. This reduction of toxicity may be important to consider in this particular population of patients who are old, or have co-morbidities that preclude the use of high-dose cisplatin.
This work was supported with a non-restricted grant by MSD France which was not involved in the analysis and interpretation of the results. This study is an investigator-sponsored study run by the French head and neck oncology and radiotherapy group (GORTEC).
Tao Y, Biau J, Sun XS, et al. Pembrolizumab versus cetuximab, concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PermbroRad): a multicenter, randomized, phase 2 trial. Annals of Oncology; Published online 27 October 2022. DOI: https://doi.org/10.1016/j.annonc.2022.10.006