Timing matters: concurrent vs. sequential immunotherapy in combination with chemoradiation in head and neck cancer

Head and neck cancer (HNC) is the sixth most common form of cancer globally, with 90% of HNC comprised of head and neck squamous cell carcinoma (HNSCC) (1). Notably, over 60% of patients with HNSCC present with advanced or metastatic disease at diagnosis with a relatively poor prognosis (2). The advent of immunotherapy has been a significant breakthrough in the field of oncology; however, the optimal timing of immunotherapy relative to other standard of care (SOC) treatments, such as chemoradiation therapy (CRT), remains unknown.

Pembrolizumab and nivolumab, monoclonal antibodies (mAbs) targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway, have been accepted as SOC for recurrent/metastatic (R/M) HNSCC for nearly a decade. Nivolumab and pembrolizumab were approved in the platinum-resistant setting in 2016, and more recently in 2019, pembrolizumab alone or with chemotherapy became the SOC first-line therapy for R/M HNSCC (2,3).

Given the success in the R/M setting, immunotherapy combinations with SOC therapy, including surgical resection, and/or radiation with or without chemotherapy, have been trialed in locally advanced HNSCC. As these mAbs function by manipulating the patient’s immune system to recognize and target malignant cells, a healthy or functional immune system is imperative (2). Importantly, CRT has the potential to affect not only cancer cells but may also cause off-target effects on surrounding and peripheral circulating cells, including immune cells. Radiation therapy (RT) has been shown to modulate the tumor immune microenvironment, including upregulation of major histocompatibility complex class I (MHC-I) and its transcriptional regulators, as well as upregulation of PD-L1 in in vivo murine models (4,5). Chemotherapy has also been shown to modulate the immune response by increasing PD-L1 expression (6,7). However, while RT to the primary tumor may have beneficial immune effects, multiple studies have shown that radiation of the draining lymph nodes (DLNs) has detrimental effects. The upregulation of conventional type I dendritic cells and type I interferon signaling, both necessary for responding to immune checkpoint inhibition, is lost with lymphoablation (8). Additionally, nodal irradiation decreases antigen-specific T cells and epitope spreading (9). The overall effects of DLN irradiation include increases in local, distant, and metastatic tumor growth, as well as worsened overall survival (OS) (8,9). Thus, the timing of immunotherapy relative to CRT may be important.

There have been several studies investigating the combination of immunotherapy with CRT in the treatment of HNSCC; however, the results of these studies have been mixed. The JAVELIN Head and Neck 100 study, published in 2021, is one of the first randomized phase III trials to test the addition of an anti-PD-1/PD-L1 antibody concurrently with definitive CRT for patients with locally advanced HNSCC not undergoing surgical resection (10). In this study, patients with locoregionally advanced HNSCC were randomized to avelumab or placebo initiated a week prior to cisplatin-radiotherapy, and then delivered concurrently with CRT, and as maintenance therapy for 1 year after CRT (10). At the first interim analysis, the trial crossed the futility boundary and was halted as the avelumab arm was not associated with improvement in the primary endpoint of progression-free survival [PFS; stratified hazard ratio (HR) =1.21; 95% confidence interval (CI): 0.93–1.57; one-sided log-rank P=0.92]. In addition, OS was reported in a secondary analysis and was not improved with avelumab (stratified HR =1.31; 95% CI: 0.93–1.85; one-sided log-rank P=0.94) (10). A similar study, KEYNOTE-412, published in 2024, also showed no significant difference in the primary endpoint of event-free survival (EFS) with the addition of pembrolizumab to CRT. Median EFS was not reached (95% CI: 44.7 months–not reached) in the pembrolizumab group and was 46.6 months (95% CI: 27.5–not reached) in the placebo group [HR =0.83; 95% CI: 0.68–1.03; log-rank P=0.043 (significance threshold, P≤0.024)] (11). However, there was a trend to improvement in EFS with the addition of pembrolizumab to CRT upon further follow-up presented at the American Society of Clinical Oncology (ASCO) meeting in 2025, as EFS was longer with pembrolizumab vs. placebo (HR =0.79; 95% CI: 0.65–0.96) (12).

PD-1 inhibitors have also been investigated in patients with surgically resectable locally advanced HNSCC. Two phase II studies investigating neoadjuvant and adjuvant pembrolizumab in patients with locally advanced HNSCC undergoing surgical resection showed improvement in disease-free survival (DFS) and locoregional control compared to historical controls (13,14). Although both studies included neoadjuvant pembrolizumab, Wise-Draper et al.’s study included concurrent adjuvant pembrolizumab and only showed an improvement in DFS in the intermediate pathological risk group receiving RT and pembrolizumab, but not in the high-risk pathological risk group receiving CRT and pembrolizumab compared to historical controls (13). In Uppaluri et al., only high-risk patients were included and received sequential adjuvant pembrolizumab administered after CRT was completed, and showed an improvement in 1-year relapse rate in the high-risk pathology group receiving sequential adjuvant pembrolizumab compared to historical controls (14). The KEYNOTE-689 trial, published in 2025, which was based on the prior early phase II studies, is an international, open-label, randomized phase III clinical trial that enrolled patients with newly diagnosed, non-metastatic, resectable stage III or IVA HNSCC. In this study, patients were randomized to receive either SOC alone, consisting of surgery followed by adjuvant RT with or without cisplatin, or SOC with neoadjuvant and adjuvant pembrolizumab. The pembrolizumab arm received two cycles of neoadjuvant pembrolizumab before surgery, followed by three cycles of adjuvant pembrolizumab concurrent with RT or CRT, depending on pathological risk assessment, and 12 additional cycles of pembrolizumab maintenance. The primary endpoint was EFS, which was 59.8% in the pembrolizumab group vs. 45.9% in the control group after 36 months (HR for progression, recurrence, or death =0.66; 95% CI: 0.49–0.88; two-sided P=0.004) (15). As a result of KEYNOTE-689, the addition of neoadjuvant and concurrent pembrolizumab with CRT was FDA-approved in 2025 as a new SOC in patients with resectable locally advanced HNSCC (16). NIVOPOSTOP was also conducted at a similar time as KEYNOTE-689 and included comparable patients. However, patients did not receive neoadjuvant immune checkpoint inhibitor (nivolumab) and only pathologically high-risk patients were enrolled after surgical resection to receive concurrent nivolumab with CRT. Similar to KEYNOTE-689, there was a benefit in DFS (HR =0.76; 95% CI: 0.60–0.98; stratified log-rank test P=0.034) (17).

Given the concern of concurrent immunotherapy, especially when the tumor is intact during definitive CRT, and impact on immune cell bystanders, Zandberg et al. investigated in a phase II clinical trial, concurrent vs. sequential pembrolizumab in combination with definitive CRT in patients with locally advanced HNSCC. In this study, 80 patients with locally advanced HNSCC were randomized to receive either concurrent pembrolizumab starting 1 week before CRT (including cisplatin and radiation 70 Gy) or sequential pembrolizumab starting 2 weeks after completion of CRT. Both arms received 8 total doses of pembrolizumab. At the conclusion of the study, both arms met the trivariate primary endpoint (1-year locoregional failure <60%, PFS ≥60%, and dose-limiting toxicity rate ≤20%), but in their pick-the-winner design, the sequential arm met criteria for further study. The sequential arm demonstrated superior 1-year PFS (84% vs. 71%) and favorable 4-year outcomes including locoregional control (96% vs. 64%; HR =0.11; 95% CI: 0.01–0.89; P=0.012), PFS (69% vs. 49%; HR =0.55; 95% CI: 0.25–1.22; P=0.132), and OS (83% vs. 71%; HR =0.51; 95% CI: 0.19–1.37; P=0.17) (3). However, larger studies are required to confirm that sequential pembrolizumab is superior to concurrent pembrolizumab during definitive CRT.

Given the disappointing results with the addition of concurrent immunotherapy with CRT in the absence of surgical intervention, it is intriguing that sequential treatment appeared to be superior in Zandberg et al. (3,10,11). However, there are key differences in the studies that are compared in Table 1. KEYNOTE-412 is now trending to improvement in survival with long-term follow-up, and it is important to note that avelumab used in JAVELIN Head and Neck 100 targets PD-L1 vs. PD-1, which could account for differences (10,12). Comparing early surgical studies with neoadjuvant pembrolizumab, there also seemed to be a benefit to sequential treatment in the pathological high-risk group (14). However, it is important to note that patients in the “intermediate/low risk” group in the Wise-Draper study may have been downstaged from neoadjuvant pembrolizumab; therefore, the comparison to historical groups may be complicated. In addition, KEYNOTE-689 and NIVOPOSTOP both demonstrated improved survival with concurrent PD-1 inhibitor treatment (15,17). Interestingly, unlike NIVOPOSTOP, in KEYNOTE-689, there was a reduction in distant metastasis-free survival (DMFS) with an estimated DMFS rate at 36 months of 59.1% for those receiving pembrolizumab vs. 49.0% in the placebo group, suggesting potential priming of the immune system by neoadjuvant pembrolizumab with the tumor intact (18). In addition, adjuvant immunotherapy may be more effective in targeting cancer cells after the bulk of the tumor burden had been removed, thus promoting the efficacy of concurrent immunotherapy in both KEYNOTE-689 and NIVOPOSTOP (15,17). It remains unclear if the concurrent CRT given in Zandberg et al. had significant negative effects on the immune system as adjacent lymph nodes are often targeted by RT and systemic effects of chemotherapy can damage the immune system, which could result in a lower efficacy of concurrent immunotherapy compared to sequential, especially given that significant tumor volumes were not surgically removed before treatment (8-10). Regarding human papillomavirus (HPV) status, the surgical trials discussed either investigated patients who were HPV-negative or included similar but small numbers of HPV-positive patients in both arms of the trials, whereas in the definitive trials, HPV was more common. Stratification by HPV in the definitive trials did not appear to affect survival outcomes. However, additional studies are necessary to determine if HPV status influences timing of immunotherapy and RT after surgical resection. In addition, the trials discussed above often included patients unselected for PD-L1 status, and efficacy results were consistent among PD-L1 groups. Interestingly, in KEYNOTE-689, >95% of patients had a PD-L1 combined positive score (CPS) ≥1, and therefore, it remains unclear of the efficacy of those with PD-L1 CPS 0 given the limited population (15). While these aforementioned studies provide a good context for informed decision-making in the treatment of patients, and that sequential immunotherapy after RT may be beneficial, further studies are warranted to address the timing of immunotherapy relative to RT and surgical resection as well as the effects of immunotherapy on the tumor immune microenvironment and regional lymph nodes before, during, and after CRT and surgical removal.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Cancer Research. The article has undergone external peer review.

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2616/coif). T.M.W.D. receives clinical trial funding from Astra Zeneca/Medimmune, Merck & Co., BMS, GSK, and Janssen; and board and/or consulting fees from Merck & Co, Caris Life Sciences, Adlai Nortye, Replimmune, ASCO, J&J, Adaptimmune, Genmab, Coherus; and travel fees from Merck & Co. The other authors have no conflicts of interest to declare.

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