Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412

Head and neck cancer, the sixth most common cancer worldwide [1], is diagnosed in approximately 706,000 new patients annually and accounts for 358,000 deaths every year [2]. Among these patients, 60% have locally or regionally advanced disease at the time of diagnosis [3]. Head and neck squamous cell carcinoma (HNSCC) constitutes more than 90% of head and neck cancers and most commonly affects the oral cavity, oropharynx, hypopharynx and larynx [1]. The global incidence of HNSCC varies based on environmental and genetic risk factors and on persistent infection with the oncogenic human papillomavirus (HPV), primarily HPV-16 [1,4,5]. Overall incidence is influenced by tobacco use and alcohol consumption in patients with HPV-negative disease and HPV-driven oropharyngeal cancer [1]. In fact, HPV-driven HNSCC has led to a >25% increase in HNSCC incidence in USA during the past decade [1]; it is anticipated that the incidence will continue to rise.

Treatment for newly diagnosed HNSCC is determined by an experienced multidisciplinary team after an assessment based on the location of the primary tumor, the stage of the disease, and the expected functional outcomes [3]. For patients with early-stage disease, single-modality treatment with surgery or radiation is generally recommended. For patients with locally advanced (LA) HNSCC, the standard of care is chemoradiation therapy (CRT) or surgery followed by radiation, with or without chemotherapy [6]. The 5-year overall survival (OS) rate for patients with HPV-negative stage III/IV HNSCC remains low at 40–50%, but patients with HPV-associated oropharyngeal cancer have a better prognosis [4,7]. The prognosis for patients with stage 3 (T4 or N3, TNM Classification of Malignant Tumours, 8th edition) HPV-associated HNSCC is similar to that for patients with HPV-negative HNSCC (5-year OS is ~50%) [7,8].

Evidence is mounting that radiation can act as an immunologic stimulus, potentially counteracting the immunosuppressive tumor microenvironment and providing a strong rationale for the combination of radiation and immunotherapeutic agents [9]. PD-1 is an immune checkpoint receptor known to play a role in tumor immune evasion, and its ligand, PD-L1, is also highly expressed in HNSCC tumors on the tumor cells and on the components of the tumor microenvironment [10–12]. The anti-PD-1 agents pembrolizumab and nivolumab have been approved by the US FDA as monotherapy for the treatment of patients with recurrent and/or metastatic (R/M) HNSCC with disease progression on or after platinum-containing chemotherapy [13,14]. Pembrolizumab has also recently been approved for first-line treatment of patients with R/M HNSCC, as monotherapy for those patients whose tumors express PD-L1 (combined positive score ≥1) and in combination with platinum and fluorouracil regardless of PD-L1 expression [13]. While the safety of these agents in patients with LA HNSCC has been established in early-phase studies, more data are needed to demonstrate superior efficacy to CRT in this patient population.

Recently, results were reported from a preplanned interim analysis of the Phase III JAVELIN Head and Neck 100 study of the combination of the anti-PD-L1 agent avelumab and CRT versus CRT alone in previously untreated LA HNSCC. The JAVELIN Head and Neck 100 study was terminated based on the recommendation of the independent data monitoring committee showing that avelumab plus CRT versus CRT alone is unlikely to show significant improvement in the primary end point of progression-free survival [15]. Given that pembrolizumab is an anti-PD-1 agent, whereas avelumab is an anti-PD-L1 agent and the efficacy of pembrolizumab has been established in patients with R/M HNSCC, the results of the JAVELIN Head and Neck 100 study are not expected to influence the conduct of KEYNOTE-412 (ClinicalTrials.gov: NCT03040999).

KEYNOTE-412 trial

KEYNOTE-412 (NCT03040999) is a randomized, double-blind, Phase III study evaluating the efficacy and safety of pembrolizumab or placebo given concomitantly with CRT followed by maintenance pembrolizumab therapy or placebo in patients with LA HNSCC.

Background & rationale

Pembrolizumab is a potent and highly selective humanized monoclonal antibody of the immunoglobulin G4-κ isotype designed to block the interaction between PD-1 and its ligands, PD-L1 and PD-L2 [13]. Pembrolizumab has demonstrated robust antitumor activity and a favorable safety profile in multiple tumor types and is currently approved in more than 80 countries for one or more advanced malignancies, including previously untreated R/M HNSCC or R/M HNSCC with disease progression on or after platinum-containing chemotherapy [13]. The durability of response and tolerability of pembrolizumab monotherapy in patients with R/M HNSCC has been demonstrated in early-phase trials, including the Phase Ib KEYNOTE-012 study with long-term follow-up [16], and in patients previously treated with platinum and cetuximab in the Phase II KEYNOTE-055 study [17]. The Phase III KEYNOTE-040 study evaluated pembrolizumab monotherapy in patients whose HNSCC progressed after platinum therapy [18], whereas the Phase III KEYNOTE-048 study evaluated pembrolizumab, alone or in combination with chemotherapy, in patients who did not previously receive systemic therapy for R/M disease [19].

In the Phase III KEYNOTE-040 study (NCT02252042), 495 patients with HNSCC that progressed during or after platinum-containing treatment for R/M disease or whose disease recurred or progressed within 3–6 months of previous platinum-containing therapy for LA disease were randomly assigned to receive pembrolizumab monotherapy or investigator's choice of standard of care (SOC; methotrexate, docetaxel, or cetuximab) [18]. After a median follow-up of 7.5 months in the pembrolizumab arm and 7.1 months in the SOC arm, a clinically meaningful increase in median OS was observed in patients receiving pembrolizumab compared with SOC (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.65–0.98; nominal p = 0.0161). Treatment-related adverse events (AEs) were reported in 63% of patients treated with pembrolizumab compared with 84% of patients treated with SOC. Overall, the pembrolizumab safety profile was better than that of SOC and consistent with the safety profile of pembrolizumab in previous studies; no new toxicities were observed [18].

The KEYNOTE-048 study (NCT02358031) enrolled 882 patients who had not previously received systemic therapy for R/M HNSCC and who were randomly assigned to receive pembrolizumab monotherapy, pembrolizumab plus chemotherapy (cisplatin or carboplatin plus 5-FU), or cetuximab plus chemotherapy (the EXTREME regimen) [19]. At the final analysis, OS with pembrolizumab monotherapy was found to be noninferior to the EXTREME regimen in the total population (HR: 0.83; 95% CI: 0.70–0.99). OS with pembrolizumab monotherapy was superior to EXTREME in patients with tumor PD-L1 combined positive score (CPS) of ≥20 (HR: 0.58; 95% CI: 0.44–0.78) and in patients with tumor PD-L1 CPS of ≥1 (HR: 0.74; 95% CI: 0.61–0.90). Pembrolizumab plus chemotherapy significantly improved OS compared with EXTREME in the total population (HR: 0.72; 95% CI: 0.60–0.87). OS with pembrolizumab plus chemotherapy was superior to EXTREME in patients with tumor PD-L1 CPS of ≥20 (HR: 0.60; 95% CI: 0.45–0.82) and in patients with tumor PD-L1 CPS of ≥1 (HR: 0.65; 95% CI: 0.53–0.80). Responses were durable and the safety profile was favorable in both pembrolizumab arms [19]. Results from both of these large Phase III trials support pembrolizumab as monotherapy and as part of combination therapy in the treatment of relapsed or metastatic disease.

Additionally, a single-arm, open-label, Phase Ib trial investigated the safety and tolerability of pembrolizumab in combination with standard cisplatin-based, definitive CRT in patients with stage III–IVB HNSCC (NCT02586207). Patients were treated with pembrolizumab at a fixed dose of 200 mg intravenously approximately 7 days before the initiation of CRT and every 3 weeks during CRT (two concomitant doses) with five additional doses following CRT. CRT consisted of weekly cisplatin 40 mg/m² intravenously for six doses (240 mg/m² maximum) given concurrently with radiation at a dose of 2 Gy once daily for 35 fractions (total 70 Gy). Co-primary end points included safety and complete response rate at treatment end. A safety analysis was performed in 27 patients with oropharyngeal, hypopharyngeal, and laryngeal LA HNSCC of any HPV status; 21 patients completed all planned doses of pembrolizumab, 27 completed the full radiation dose, and 23 received the target dose of cisplatin. Six patients discontinued treatment because of immune-related AEs (n = 3; grade 2 peripheral motor neuropathy; grade 3 aspartate aminotransferase elevation; grade 1 Lhermitte-like syndrome) or for protocol reasons (n = 3; early neck dissection [n = 2]; prolonged hospitalization [n = 1]); one patient died of concurrent illness unrelated to treatment [20]. Combination therapy was deemed safe and did not significantly limit radiation or chemotherapy dosing. The study is ongoing with 34 HPV-positive and 23 HPV-negative patients enrolled in the expansion cohorts to evaluate antitumor activity [20]. Results from a recent analysis of the efficacy and safety in the HPV-positive expansion cohort showed that most patients (79%) had disease of intermediate risk. Approximately 85% of patients (29/34) experienced complete response based on imaging and/or surgery and 97.1% (95% CI: 80.9–99.6) demonstrated progression-free survival at 1 year. Additional observations revealed no impact on CRT delivery and no new safety signals [21].

Support for the hypothesis of pembrolizumab treatment for LA HNSCC is demonstrated by the antitumor activity of pembrolizumab monotherapy for R/M HNSCC, in conjunction with the initial safety results of pembrolizumab plus CRT in patients with LA disease. The addition of pembrolizumab to standard CRT may also address the need for an effective treatment option for patients with LA HNSCC, with the potential to translate into superior effectiveness and improved patient outcomes.

Study design & treatment

KEYNOTE-412 (NCT03040999) is a randomized, double-blind, placebo-controlled, Phase III study of intravenous (iv.) infusion of pembrolizumab 200 mg or placebo every 3 weeks (Q3W) in combination with CRT and as maintenance therapy for a total of 17 doses (Figure 1). This dosing schedule and duration was selected in order to evaluate the efficacy of pembrolizumab given in combination with curative intent therapy with the primary end point of event-free survival (see the Study End points section). In addition, 1 year of adjuvant pembrolizumab has been shown to be effective in improving outcomes and providing clinically meaningful benefit to patients with melanoma. In the KEYNOTE-054 study, 1 year of adjuvant pembrolizumab treatment versus placebo resulted in significantly longer recurrence-free survival in patients with high-risk stage III melanoma [22].

This study occurred at 151 sites in 21 countries. Cisplatin 100 mg/m² IV Q3W will be given concurrently with radiotherapy in both study arms. The radiotherapy regimen consisted of accelerated fractionation (AFX) or standard fractionation (SFX). For patients treated with AFX RT, 70 Gy was administered in a total of 35 fractions over 6 weeks at a frequency of six fractions per week. SFX 70 Gy will be administered for a total of 35 fractions over 7 weeks at a frequency of five fractions per week. Treatment will continue until centrally confirmed disease progression, unacceptable toxicity, intercurrent illness that prevents further administration of treatment, investigator's decision to withdraw the patient, nonadherence to treatment or trial procedures, administrative reasons requiring cessation of treatment, or the patient has received 17 administrations of pembrolizumab/placebo (~1 year).

The trial is split into three treatment phases. The first phase includes the pembrolizumab/placebo priming dose, followed by CRT in combination with two additional pembrolizumab/placebo doses given every 3 weeks (duration, 8 weeks). The second phase includes pembrolizumab/placebo maintenance dosing (14 doses) during post-CRT follow-up (total treatment duration, ∼1 year). The third phase includes posttreatment follow-up.

Eligible patients were randomly assigned 1:1 to pembrolizumab or placebo using an interactive voice/integrated web response system. Randomization was stratified according to radiotherapy regimen (AFX vs SFX), tumor site, p16 status (oropharynx – p16 positive vs oropharynx – p16 negative or larynx/hypopharynx/oral cavity HNSCC), and tumor stage (III vs IV). Treatment assignments are masked to patients, investigators and sponsor personnel.

Eligibility criteria

Eligibility criteria are described in Table 1. In brief, inclusion criteria include patients aged ≥18 years with a pathologically proven new diagnosis of LA HNSCC who were eligible for definitive CRT and were not considered for primary surgery based on investigator decision. Patients with oropharyngeal p16-positive disease were required to have T4 (N0–N3), M0 or N3 (T1–T4), M0 tumors. Patients with oropharyngeal p16-negative disease were required to have any T3–T4 (N0–N3), M0 or any N2a–3 (T1–T4), M0 tumors. Patients with larynx/hypopharynx/oral cavity disease, independent of p16, will be required to have any T3–4 (N0–N3), M0 or any N2a–3 (T1–T4), M0 tumors. Tumors were staged according to the 7th edition of the American Joint Committee on Cancer (AJCC) staging manual for patients enrolled before 1 January 2018, and according to the 8th edition of the AJCC staging manual for patients enrolled on or after that date [8,23].

Planned sample size, study period & statistical analysis

Target accrual for this trial was approximately 780 patients. The study started in April 2017, and enrollment completed in May 2019. The estimated study completion date is June 2023.

All randomly assigned patients will be included in the efficacy analysis and will be analyzed by randomized treatment group. All randomly assigned patients who received at least one dose of study drug will be assessed in the safety analysis and will be analyzed by treatment received. The treatment effect will be evaluated using a stratified log-rank test. Hazard ratios will be estimated using a stratified Cox regression model. Event rates over time will be estimated using the Kaplan–Meier method. Interim analyses for efficacy and safety are planned, and results will be reviewed by an external data monitoring committee; this committee will also review safety data periodically throughout the study.

Study end points

The primary end point of the trial is event-free survival (EFS) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). EFS is defined as the time from the date of randomization to the date of first record of progression per RECIST v1.1 by blinded independent central review ([a] locoregional progression or recurrence or [b] distant metastasis), salvage surgery at the primary tumor site when invasive cancer is present, neck dissection performed >20 weeks after completion of CRT when invasive cancer is present, or death from any cause. The key secondary end point is OS, which is defined as the time from randomization to death from any cause. Other secondary end points include safety and patient-reported outcomes (PROs); PROs are assessed using the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) core 30 items (C30) and head and neck module (H&N35) as well as the EuroQoL-5D (EQ-5D). Exploratory end points include potential predictive biomarkers and immune dynamics in the subgroup of patients with oropharyngeal p16-negative or larynx/hypopharynx/oral cavity HNSCC and the overall population.

Study procedures

At the discretion of the investigator, computed tomography (CT) or magnetic resonance imaging (MRI) will be used to assess tumor response and disease progression; the same method of assessment will be used for each patient. All patients underwent clinical and radiologic (CT or MRI and fluorodeoxyglucose positron emission tomography [FDG-PET] or FDG-PET/CT) assessment within 6 weeks of randomization. Follow-up imaging was acquired at week 12 after CRT and will be repeated every 3 months for 3 years after randomization and then every 6 months for years 4 and 5. At 12 weeks after CRT, an FDG-PET or FDG-PET/CT scan was acquired as part of neck management.

Safety and tolerability will be assessed by clinical review of all relevant parameters, including AEs, laboratory tests, and vital signs. AEs will be graded and recorded throughout the trial and follow-up period using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Patients will be monitored throughout the study and for 30 days after the end of treatment (90 days for serious AEs). Treatment-related toxicity will also be recorded up to 5 years after the end of treatment.

PRO assessments (EORTC QLQ-C30, EORTC-H&N35 and EQ-5D) will be administered electronically, beginning with a baseline assessment at cycle 1 until year 5; assessments will be administered before drug administration, AE evaluation, and disease status. Tumor PD-L1 expression will be assessed by central evaluation. PD-L1 will be measured using CPS, which is calculated by the number of PD-L1–positive cells (tumor cells, lymphocytes and macrophages) divided by the total number of tumor cells, multiplied by 100. Exploratory biomarker investigation may include genetic, RNA, and proteomics analyses of blood and tumor samples.

Conclusion

Despite the currently available treatment options for patients with LA HNSCC, there is a need for better therapies in the curative setting for this patient population. With observed benefit in patients with R/M HNSCC, the immune checkpoint inhibitor pembrolizumab warrants further investigation in LA HNSCC. The Phase Ib study investigating the safety and tolerability of pembrolizumab in combination with CRT in patients with LA HNSCC suggests that this approach may be safe and to date has had no evidence of new safety concerns. Herein we described the methodology for the ongoing Phase III KEYNOTE-412 (NCT03040999) study investigating the safety and efficacy of pembrolizumab versus placebo combined with concurrent CRT and as maintenance therapy for LA HNSCC. Results from the KEYNOTE-412 (NCT03040999) study will elucidate the role of the combination of CRT with pembrolizumab in patients with LA HNSCC, a patient population for whom the 5-year survival rates remain poor at 40–50% [4,7]. In addition, biomarker data from this study may assist in determining factors that influence the efficacy of immunotherapy and in selecting patient subpopulations most likely to benefit from treatment with pembrolizumab.