Abstract
Background
The approved induction chemotherapy regimen with docetaxel, cisplatin, and 5-fluorouracil is associated with a high risk of severe toxicity, which may compromise the feasibility of subsequent chemoradiation. Safer and more effective induction strategies are needed for patients with unresectable locally advanced head and neck squamous cell carcinoma (HNSCC).
Methods
We aimed to evaluate the feasibility, efficacy, and safety of induction immunochemotherapy followed by (chemo)radiation in patients with unresectable locally advanced HNSCC. In this prospective, multicenter, non-randomized phase II trial, patients with PD-L1–positive (Combined Positive Score ≥1) locally advanced squamous cell carcinoma of the oropharynx, larynx, or hypopharynx and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 received three 21-day cycles of pembrolizumab, cisplatin, and 5-fluorouracil, followed by chemoradiotherapy or radiotherapy in the absence of disease progression.
Results
Among 120 enrolled patients, 116 were evaluable for response. The objective response rate after induction therapy was 62.9%, including 16.4% complete responses. After a median follow-up of 26 months, the 2-year PFS and OS rates were 53.0% and 65.1%, respectively. Grade 3–4 adverse events occurred in 30.8% of patients, with neutropenia reported in 23.3% and febrile neutropenia in 1.7%. Immune-related events were infrequent and mild (skin rash: 1.7%; hypothyroidism: 0.8%). No treatment-related deaths occurred.
Conclusions
Induction immunochemotherapy with pembrolizumab, cisplatin, and fluorouracil demonstrated encouraging efficacy, manageable toxicity, and high transition and completion rates of chemoradiation. These findings should be considered hypothesis-generating rather than practice-changing and require confirmation in a randomized trial.
Plain Language Summary
This study tested whether giving immunotherapy together with chemotherapy before radiation therapy can help patients with advanced head and neck cancer. One hundred twenty patients received three treatment cycles with pembrolizumab plus cisplatin and fluorouracil. Most patients responded well and almost all were able to continue to curative radiation treatment. Serious side effects were manageable, and no treatment-related deaths occurred. These results suggest that starting treatment with immunotherapy plus chemotherapy may improve outcomes and prepare patients better for radiation therapy.
Keywords
Highlights
- Induction immunochemotherapy shows encouraging progression-free survival in patients with unresectable locally advanced squamous-cell carcinoma of the oropharynx, hypopharynx and larynx - Pembrolizumab plus cisplatin and fluorouracil is a feasible and well-tolerated regimen - Delivery of induction immunochemotherapy enables high rates of subsequent chemoradiation completion
Introduction
Chemoradiation therapy (CRT) is the standard of care for locally advanced head and neck squamous cell carcinoma (HNSCC).1,2 The role of induction therapy remains controversial. According to MACH-NC meta-analysis there was no overall survival benefit in the induction chemotherapy group.3 Despite the lack of evidence of survival benefit of induction therapy, some patients with high tumor burden could have advantages from this approach in tumor shrinkage and improving organ function prior to radiation therapy (RT) or concurrent chemoradiation.
The standard induction chemotherapy regimen includes docetaxel, cisplatin and a continuous 5-fluorouracil infusion (the known TPF regimen) with high toxicity being the major issue of this combination. In previous studies, up to 17% of patients were unable to proceed to CRT after starting the TPF regimen, the most common grade 3–4 toxicities were neutropenia and febrile neutropenia. Treatment-related mortality reached up to 5%.4
In Keynote - 048 trial pembrolizumab improved overall survival compared to cetuximab with chemotherapy in first-line treatment of recurrent or metastatic HNSCC in the population with combined positive score (CPS) of 1 or more.5 Given the limitations of induction chemotherapy, there is an increasing interest in integrating immunotherapy into earlier disease stages. We initiated a prospective, multicenter, non-randomized study to evaluate the efficacy and tolerability of induction immunochemotherapy with pembrolizumab, platinum, and 5-fluorouracil in patients with locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, or larynx. Here we present the first efficacy and safety results, including the risk of treatment discontinuation before subsequent radical CRT.
Methods
Patients
Inclusion Criteria
The study included patients aged ≥18 years with histologically confirmed squamous cell carcinoma of the oropharynx (p16+: T0–3N3, T4N0–3; p16–: T3–4aN0–1, T1–4aN2–3), hypopharynx (T2–3N0–3, T1N1-3, T4aN0–3), or larynx (stage III–IVa: T1–2N2–3, T3N2–3, T4aN0–3) according to the TNM 8th edition. Patients had no prior systemic chemotherapy, radiation therapy or major surgery for HNSCC, except diagnostic biopsy. Additional eligibility criteria included PD-L1 CPS ≥1 using the Dako 22C3 assay, and ECOG performance status 0–2. This selection criterion was based on evidence from the KEYNOTE-048 trial demonstrating improved outcomes with pembrolizumab-based therapy in PD-L1–expressing tumors. The PD-L1 CPS assessment and p16 immunohistochemistry were performed in local laboratories. Adequate organ function was required, defined as: neutrophils ≥1500/mm3, platelets ≥100,000/mm3, hemoglobin ≥90 g/L, bilirubin ≤2× the upper limit of normal (ULN), ALT and AST ≤3× ULN, and estimated glomerular filtration rate (GFR) >55 mL/min/1.73 m2 for cisplatin or >45 mL/min for carboplatin (CKD-EPI formula). All patients provided written informed consent.
Exclusion Criteria
Patients were excluded if they had cancer of the oral cavity or nasopharynx, distant metastases, clinically significant cardiovascular disease (recent myocardial infarction, uncontrolled arrhythmias, or New York Heart Association (NYHA) class III–IV heart failure), significant autoimmune disease requiring systemic therapy, or prior immune checkpoint inhibitor therapy.
Patients were consecutively enrolled at all participating centers according to predefined eligibility criteria.
Data Confidentiality
All patient data were fully de-identified prior to analysis. No information that could directly or indirectly identify individual participants was included in this study.
Study Design and Treatment Procedures
This prospective, multicenter, nonrandomized phase II study was conducted at three oncology hospitals in Moscow.
Baseline evaluation included contrast-enhanced computed tomography (CT) of the head, neck and chest; flexible laryngoscopy; ultrasound of cervical lymph nodes and abdomen; and biopsy of the primary tumor and lymph nodes suspected of metastasis.
All eligible patients received three cycles of induction immunochemotherapy consisting of pembrolizumab 200 mg intravenously (IV) on Day 1, cisplatin 100 mg per square meter of body-surface area (mg/m2) IV on Day 1 (or carboplatin at an area under the curve of 5 if cisplatin was contraindicated), and 5-fluorouracil 1000 mg/m2/day on Days 1–4. Treatment cycles were repeated every 21 days. The initial protocol specified cisplatin 75 mg/m2, but following preliminary safety evaluation, the dose was amended to 100 mg/m2 every 3 weeks. The intervention was delivered by qualified medical oncologists (for induction immunochemotherapy administration), specialized chemotherapy nurses, and radiation oncologists with support from medical physicists and radiotherapy technicians for chemoradiation planning and delivery. The use of granulocyte colony-stimulating factor (G-CSF) was not prespecified as primary prophylaxis, but could be considered as secondary prophylaxis in the event of febrile neutropenia or treatment delay.
The intervention was delivered individually to each participant. There was no group-based or cluster-based allocation; all eligible patients received the induction regimen on a per-subject basis followed by individually tailored chemoradiation.
No Adherence-Promoting Incentives were Used
After three cycles, all patients underwent follow-up evaluation, including contrast-enhanced CT of the head, neck, and chest; ultrasound of the cervical lymph nodes and abdominal organs; and flexible laryngoscopy to assess treatment efficacy. Patients without disease progression after three cycles of induction therapy proceeded to a course of CRT with platinum-based radiosensitizer or radiation therapy depending on performance status and renal function. Patients with disease progression were managed according to institutional standards, which could include CRT, surgery or palliative systemic therapy.
Reporting Guidelines
The reporting of this study conforms to the TREND statement for the reporting of non-randomized evaluations of behavioral and public health interventions.6
End Points and Assessments
The primary endpoint was progression-free survival (PFS), defined as the time from the first dose of induction therapy to radiographic disease progression per RECIST v1.1 or death from any cause, whichever occurred first. PFS was selected as the primary endpoint because it provides an early measure of disease control following multimodality treatment and is less influenced by subsequent therapies than overall survival. Overall survival (OS) was defined as the time from the first dose of induction therapy to death from any cause. Objective response rate (ORR) was the proportion of patients with confirmed complete or partial response as best overall response per RECIST v1.1. The intent-to-treat (ITT) population was used for efficacy analyses; the safety population included all patients who received ≥1 dose of study treatment.
The median progression-free survival based on historical data was 11 months.7 The planned sample size (N=120) provided 80% power at a one-sided α=0.025 to detect an improvement in median PFS from 11 months (historical control) to 20 months, corresponding to a hazard ratio (HR) of 0.60, assuming uniform accrual over 24 months and a minimum follow-up of 6 months. The calculation was based on the log-rank test using standard asymptotic methods (Schoenfeld approximation). Two-sided p-values <0.05 were considered statistically significant for secondary/exploratory analyses. Time-to-event data were described with the use of Kaplan–Meier curves.
Adverse events were assessed after each cycle and graded according to CTCAE v.5 (Common Terminology Criteria for Adverse Events, version 5). Renal function was monitored throughout the study, with GFR calculated using the CKD-EPI formula (Chronic Kidney Disease Epidemiology Collaboration equation).8
Statistical analyses were performed using Stata/SE 17.0 (StataCorp LLC, College Station, TX, USA).
Institutional Review Board Statement and Ethical Approval
The study was approved by the Institutional Review Board of Sechenov University, Ministry of Health of the Russian Federation, and by the Local Ethics Committee of the S.S. Yudin City Clinical Hospital, Moscow Healthcare Department. The study was conducted in accordance with the Declaration of Helsinki and ICH-GCP guidelines (Ethics Committee approval No. 29, April 1, 2022). The study was conducted in accordance with the Declaration of Helsinki of 1975, as revised in 2024.
All patients provided written informed consent. The trial was registered at ClinicalTrials.gov (registered after accrual start: date of registration 2022-09-21; Identifier: NCT05551767).
Results
Between April 2022 and August 2024, a total of 134 patients were screened; and 121 met the eligibility criteria, 1 declined participation prior to treatment initiation, and 120 patients were enrolled and received the study intervention. (Figure 1). Baseline characteristics are summarized in Table 1. The median age was 59 years (range, 35–75), and 105 patients (87.5%) were male. The primary tumor site was the oropharynx in 87 patients (72.5%), the hypopharynx in 21 (17.5%), and the larynx in 12 (10.0%). The majority of patients presented with advanced disease, with 93 patients (77.5%) having stage T3–T4 tumors and 79 (65.8%) having N2–N3 nodal involvement. CONSORT flow diagram of patient enrollment and allocation in the study Characteristics of the Patients
At baseline, 108 patients (90%) had good performance status (ECOG 0-1), with the remaining 12 patients (10%) showing moderate impairment (ECOG 2). The PD-L1 CPS was 1–19 in 87 patients (72.5%) and ≥20 in 33 (27.5%). Among patients with oropharyngeal cancer, 34 (39%) were p16-positive. Nineteen patients (15.8%) had weight loss of more than 10% within the 6 months before treatment, 10 patients (8.3%) had undergone tracheostomy, and 3 patients (2.5%) required placement of a gastric tube before induction therapy.
Efficacy of Induction Immunochemotherapy
Response was evaluated in 116 out of 120 enrolled patients. Following 3 treatment cycles, complete response was achieved in 19 patients (16.4%) and partial response in 54 patients (46.6%), as per RECIST 1.1 criteria. The overall response rate was 62.9%. The median depth of tumor response was -55%, ranging from -100% (indicating complete radiological response) to +65% (indicating disease progression) (Figure 2). Disease progression during induction chemotherapy was observed in 4 patients (3.4%) (Table 2). Waterfall Plot of Treatment Response Depth (percentage change in the sum of target lesion diameters from baseline radiographic assessment during induction immunochemotherapy) Efficacy Outcomes of Induction Immunochemotherapy
Subsequent Chemoradiation
Analysis of Chemoradiation Therapy Implementation After Induction Immunochemotherapy
The median follow-up duration was 26 months (range: 2.5–36+ months). The two-year progression-free survival (PFS) was 53%. Estimated median progression-free survival (PFS) was 31 months. The two-year overall survival (OS) was 65.1% (Figure 3). Progression-free (a) and overall survival (b)
Safety
Adverse Events During Induction Therapy (Safety Population, n=120)
Grade 3–4 adverse events occurred in 51 patients (42.5%). The most common of them were anemia (42.5%), neutropenia (24.2%), and nephrotoxicity (9.1%). Stomatitis (3.3%), nausea (2.5%), vomiting (0.8%), and febrile neutropenia (1.7%) were less frequent. Elevations in liver enzymes (4.2%) and bilirubin (1.7%) were infrequent. No grade 3–4 thrombocytopenia, diarrhea, or neurotoxicity was reported. No treatment-related deaths occurred. There was mild immune-related toxicity: 2 (1.7%) patients had skin rash and 1 (0.8%) – hypothyroidism.
Discussion
In patients with locally advanced head and neck squamous-cell carcinoma, the absence of distant metastases allows to conduct curative-intent therapy. Standard management typically includes surgery or chemoradiation, both of which carry substantial risks of severe, and even fatal adverse events. High-dose cisplatin administered every three weeks remains the standard systemic agent in combination with radiation therapy, supported by the MACH-NC meta-analysis showing improved survival with CRT compared with radiation therapy alone.3 The role of induction chemotherapy, however, remains uncertain, with results from MACH-NC limited by heterogeneity in trial designs and regimens. The majority of studies assessed the efficacy of various chemotherapy regimens as induction therapy.4,9-12 The randomized study by Ghi and colleagues demonstrated that induction docetaxel, cisplatin, and fluorouracil (TPF) followed by CRT improved overall survival compared with CRT alone, highlighting the potential of treatment intensification strategies. 13
An optimal induction regimen should achieve tumor shrinkage, improve clinical status and increase the likelihood of completing radiation therapy, while minimizing early disease progression. Among cytotoxic combinations, TPF has shown the greatest activity but was associated with substantial toxicity.
The combination of pembrolizumab with platinum and fluorouracil (PF) is established as first-line therapy for recurrent or metastatic disease. In this multicenter phase II study, we evaluated its use as induction therapy in unresectable stage III–IVa cancers of the oropharynx, hypopharynx, and larynx. Three cycles of induction immunochemotherapy produced promising activity, with an overall response rate of 62% including 16.4% complete responses. These outcomes are broadly comparable to those observed with TPF in the TAX 323 trial (68% response rate, 8.5% complete responses) and TAX 324 trial (72% response rate, 17% complete responses).7,12 The low rate of progression during induction and the high frequency of clinical improvement allowed the prevailing majority of patients to proceed with radiation therapy, resulting in encouraging progression-free survival, with a median exceeding two years. For context, TAX 323 reported a median progression-free survival of 11 months after induction TPF. 12
Comparisons with previously published historical cohorts mentioned above are descriptive and exploratory in nature and should be interpreted with caution. Differences in patient populations, treatment protocols, staging procedures, and efficacy assessment across studies limit the validity of direct comparisons and preclude firm conclusions regarding treatment superiority.
Recent efforts to integrate immunotherapy into treatment algorithms for locally advanced HNSCC have shown conflicting results. The phase III KEYNOTE-412 trial tested pembrolizumab concurrently with CRT but the strategy did not improve overall survival. 14 Nevertheless, other studies have suggested potential value of immunotherapy in the induction setting in various tumor types. In non–small cell lung cancer, neoadjuvant immunochemotherapy has become standard for stage II–IIIB disease after demonstrating efficacy. 15 Several early-phase HNSCC studies are also evaluating induction immunochemotherapy, including regimens with camrelizumab combined with chemotherapy, with encouraging preliminary results. 16 Two early-phase trials (NCT03114280, NCT02997332) are evaluating durvalumab or pembrolizumab added to the TPF regimen. An ongoing phase II study is assessing induction therapy with carboplatin, paclitaxel and nivolumab in locally advanced HNSCC (NCT03342911).
This study has some limitations. It was a non-randomized trial and overall survival analysis remains immature. An important limitation of this study is the absence of a concurrent control arm, which represents a structural issue of the study design. As a single-arm phase II trial, the study was primarily intended to explore the feasibility and potential activity of the investigated treatment strategy rather than to provide definitive comparative efficacy data.
Cisplatin-based CRT was underrepresented: only 11.7% of patients received high-dose cisplatin, 6.8% received weekly cisplatin, and 81.6% were treated with carboplatin-based CRT. This heterogeneity represents a potential confounding factor that may have influenced both efficacy and toxicity outcomes and limits the ability to isolate the specific contribution of induction immunochemotherapy to the observed results. Meanwhile the optimal concurrent systemic therapy following induction chemotherapy has not been clearly established. In clinical trials and real-world practice, weekly carboplatin is commonly used as an alternative radiosensitizer, particularly in patients who already received cisplatin in induction phase of treatment. For example, the known TAX 324 trial incorporated weekly carboplatin at an area under the curve of 1.5 as an intravenous infusion during a 1-hour period for a maximum of seven weekly doses during the course of radiation therapy after induction TPF. 12
Our findings provide evidence that incorporating immunotherapy into induction treatment is feasible and may enhance the effectiveness of subsequent chemoradiation in patients with locally advanced head and neck squamous cell carcinoma. Induction immunochemotherapy with pembrolizumab, cisplatin and fluorouracil was associated with high response rate, acceptable safety, and a high rate of transition to CRT. Almost all patients were able to proceed with curative-intent therapy, and a significant proportion of them tolerated the planned radiation dose to target sites.
Given the single-arm design and limited sample size, the findings of this study should be interpreted with caution. Although the results are encouraging, they should be considered hypothesis-generating rather than practice-changing. Confirmation in prospective randomized controlled trials will be required to determine the true clinical benefit of induction immunochemotherapy in this patient population.
Conclusion
This multicenter phase II study shows that induction therapy with pembrolizumab combined with cisplatin and fluorouracil is a feasible, well-tolerated regimen that is associated with encouraging progression-free survival in patients with unresectable locally advanced squamous-cell carcinoma of the oropharynx, hypopharynx and larynx. The regimen has a favorable safety profile, enabling high rates of subsequent chemoradiation completion. Given the non-randomized design of the study and heterogeneity of radiosensitizing cytostatics during chemoradiation these findings are hypothesis-generating and require confirmation in a randomized trial aimed to identify the patient subgroups most likely to benefit from induction immunochemotherapy.
Footnotes
Acknowledgements
The authors wish to express their gratitude to the patients and their families who took part in this trial. We also acknowledge the financial support provided by the Moscow Center For Healthcare Innovations. Furthermore, we are indebted to Academician I.V. Reshetov for his help in facilitating this study.
ORCID iDs
Ethical Considerations
The study was approved by the Local Ethics Committee (Institutional Review Board equivalent) of the State Budgetary Healthcare Institution of Moscow “City Clinical Oncology Hospital No. 1 of the Moscow Department of Health” (Ethics Committee approval No. 29, April 1, 2022).
Consent to Participate
Written informed consent was obtained from all participants prior to their inclusion in the study.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was funded by Moscow Center For Healthcare Innovations (grant agreement No. 2112-10/22).
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement
Data supporting the findings of this study are available from the corresponding author upon reasonable request.
Registration
ClinicalTrials.gov Identifier: NCT05551767.