Emerging role of immune checkpoint inhibitors in recurrent and metastatic head and neck squamous cell carcinoma

Tumor microenvironment (TME)

HNSCC orchestrates a multifaceted immunoevasive phenotype through the deployment of sophisticated resistance strategies that collectively subvert host immune surveillance. It is able to establish a profoundly immunosuppressive microenvironment through

• The elaboration of soluble immunomodulatory mediators

• The preferential recruitment and clonal expansion of regulatory immune cell populations with suppressive functionality and

• The progressive attenuation of tumor-associated antigenic presentation.

The resultant immunosuppressive milieu represents a dynamic network of intricate molecular crosstalk between neoplastic cells and diverse immune effector populations, culminating in the systematic impairment of anti-neoplastic immune responses and the establishment of immune tolerance within the TME.^[3]

Immune checkpoint pathways

The upregulation of immune checkpoint receptors, most notably the programmed cell death protein-1 (PD-1) and its connected ligand programmed death-ligand 1 (PD-L1), constitutes a pivotal mechanism of immune evasion employed by HNSCC. These co-inhibitory signaling axes serve as physiological guardians against autoimmune pathogenesis under homeostatic conditions; however, malignant cells hijack these regulatory circuits to circumvent immunological detection and elimination. Through pharmacological blockade of these inhibitory checkpoints, immune checkpoint inhibitors (ICIs) facilitate the restoration of effector T-cell functionality and reinvigorate anti-tumor immune responses that have been rendered ineffective within the immunosuppressive TME.^[4,5]

Human papillomavirus (HPV) status and immune response

HPV status profoundly modulates the immunological architecture of HNSCC, with HPV-positive malignancies demonstrating markedly distinct immunophenotypic signatures relative to their HPV-negative counterparts. This viral etiology-dependent divergence manifests in differential immune cell infiltration patterns and cytokine expression profiles, which collectively influence therapeutic responsiveness to immune checkpoint inhibition. The delineation of HPV status thus represents a critical biomarker for therapeutic stratification and prognostic assessment in clinical decision-making paradigms.^[6]

Immune checkpoint pathway

Despite the intricate immune escape mechanisms of HNSCCs, a number of immune checkpoints have been identified as potential treatment targets. PD-1/PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), T-cell immunoglobulin mucin 3 (TIM-3), lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (TIGIT), V-domain immunoglobulin suppressor of T-cell activation (VISTA), and indoleamine 2,3-dioxygenase 1 (IDO1) are the main immune checkpoint pathways involved in HNSCC immunosuppression.^[7,8]

Vaccines

Therapeutic vaccines (viral and non-viral) and oncolytic viruses are promising immunotherapeutic strategies for HNSCC, especially in HPV-associated cases. Therapeutic vaccines target tumor-associated antigens, such as HPV oncoproteins, to stimulate both cellular and humoral immune responses. Oncolytic viruses selectively destroy cancer cells and enhance anti-tumor immunity by promoting tumor antigen presentation and triggering inflammation in the TME. Together, these approaches aim to boost the body’s immune response against cancer.^[9]

CAR T-cell therapy

CAR T-cell therapy in HNSCC is challenging due to factors such as immune suppression in the TME, antigen heterogeneity, and poor T-cell infiltration. To overcome these barriers, researchers are exploring tumor-associated antigens (e.g., epidermal growth factor receptor [EGFR], human epidermal growth factor receptor 2, B7-H3, and CD70) and developing advanced chimeric antigen receptor (CAR) T-cell strategies, including dual-targeting, armored CARs, clustered regularly interspaced short palindromic repeats modifications, and combination therapies with checkpoint inhibitors. These innovations aim to improve CAR T-cell efficacy and broaden its potential in treating HNSCC.^[10]

Standard treatment for advanced HNSCC before ICIs

Cytotoxic chemotherapy with platinum and 5FU has been the historical backbone of standard treatment of advanced HNSCC since the Southwest Oncology Group study published in 1992.^[11] The response rates were 30–35%, and median OS was 5–8 months. The next big update happened with the addition of cetuximab, an EGFR inhibitor to cytotoxic chemotherapy backbone in the EXTREME trial^[12] which led to improvements in median OS from 7.4 to 10.1 months (hazard ratio [HR]: 0.80, confidence interval [CI]: 0.64–0.99; P = 0.04), median progression-free survival (mPFS) from 3.3 to 5.6 months (HR: 0.54, P < 0.001), and overall response rate (ORR) 20% versus 36% P < 0.001. EXTREME was associated with high rates of grade 3 and above toxicity, which led to treatment discontinuation in about 20%.

ICIs in the second line

The introduction of immunotherapy has significantly advanced treatment of advanced HNSCC, which creates an immunosuppressive TME to evade the immune system. Targeting the immune system, particularly immune checkpoints, offers a promising therapeutic option. A key target is the PD1/PD-L1 pathway, which normally limits immune responses to prevent self-damage.

The first type of ICI to demonstrate efficacy was the PD-1 inhibitor pembrolizumab in advanced HNSCC patients with platinum-refractory disease, defined as progression of disease within 6 months of curative intent combined treatment of platinum and radiation or while on platinum-based systemic therapy in the first-line palliative setting.

Pembrolizumab received accelerated approval in this setting based on phase 1b KEYNOTE-012 trial data.^[13] KEYNOTE-040 was the first phase 3 randomized controlled trial (RCT) to compare pembrolizumab monotherapy with standard-of-care single-agent systemic treatment (methotrexate, docetaxel, or cetuximab) in platinum-refractory population.^[14] The trial demonstrated median OS benefit, 6.9 versus 8.4 months (HR : 0.80, CI : 0.65–0.98, P = 0.0161) with a much lower incidence of adverse events (13% vs. 36%).

Nivolumab was evaluated in CHECKMATE 141, a phase 3 RCT that compared nivolumab monotherapy with standard-of-care single-agent systemic treatment (methotrexate, docetaxel, or cetuximab) in a platinum-refractory population.^[15] This trial demonstrated a median OS benefit of 5.1 versus 7.5 months (HR: 0.70, CI: 0.51–0.96, P = 0.01), more than double the 1-year survival rate (16.6% vs. 36%), and lower grade 3/4 adverse events (35.1% vs. 13.1%).

ICIs, particularly pembrolizumab and nivolumab, have become the preferred second-line treatment in platinum-refractory HNSCC, offering improved survival and better tolerability over standard chemotherapy.

ICIs in first line

KEYNOTE-048 was the first phase 3 RCT that brought ICIs to the frontline setting with or without chemotherapy based on the PD-L1 status.^[16] In patients with recurrent/metastatic (R/M) HNSCC, the trial compared pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy with stratification for PD-L1 positivity; combined positive score (CPS) ≥20, CPS ≥1, and total population. The updated results with a median follow-up of 45.0 months (Interquartile range 41.0–49.2; n = 882) confirm the sustained survival benefit of pembrolizumab, both as monotherapy and in combination with chemotherapy, in the first-line treatment of R/M HNSCC. The OS was improved with pembrolizumab monotherapy in the PD-L1 CPS ≥20 (HR: 0.61, 95% CI: 0.46– 0.81) and CPS ≥1 (HR: 0.74, 95% CI: 0.61–0.89) populations and was non-inferior in the total population (HR: 0.81, 95% CI: 0.68–0.97). Pembrolizumab plus chemotherapy significantly improved OS in the CPS ≥20 (HR: 0.62, 95% CI: 0.46–0.84), CPS ≥1 (HR: 0.64, 95% CI: 0.53–0.78), and total (HR: 0.71, 95% CI: 0.59–0.85) populations. Progression-free survival 2 (PFS2) also favored pembrolizumab, with improvements seen in CPS ≥20 (HR: 0.64, 95% CI: 0.48–0.84) and CPS ≥1 (HR: 0.79, 95% CI: 0.66–0.95) populations, and with pembrolizumab-chemotherapy in CPS ≥20 (HR: 0.64, 95% CI: 0.48–0.86), CPS ≥1(HR: 0.66, 95% CI: 0.55–0.81), and the total population (HR: 0.73, 95% CI: 0.61–0.88). The ORRs of ICI used in first line for treatment of R/R HNSCC are given in Table 1. The ORR for second-course pembrolizumab was 27.3% (3 of 11). PFS2 was similar following pembrolizumab and longer following pembrolizumab-chemotherapy in patients who received next-line taxanes, while it was shorter after pembrolizumab and similar after pembrolizumab-chemotherapy for those receiving non-taxane regimens. Treatment-related grade ≥3 adverse events were reported in 17% of patients treated with pembrolizumab monotherapy, 72% in the pembrolizumabchemotherapy group, and 69% in the EXTREME group, reaffirming pembrolizumab’s favorable safety profile as monotherapy and acceptable tolerability in combination.^[17]

To reduce the challenges associated with 5FU, KEYNOTE-B10, a phase 4 trial, evaluated the efficacy of paclitaxel, carboplatin, and pembrolizumab versus the EXTREME regimen^[18] and demonstrated a median PFS of 5.6 months, median OS of 13.1 months, ORR of 48% (48 of 101), and manageable safety profile.

ICI combination therapy

Given the clinical efficacy demonstrated with ICIs as monotherapy, multiple combination immunotherapeutic strategies have been investigated. The concurrent blockade of CTLA-4 and PD-1 represents the most extensively studied regimen, with improved OS and durable responses observed across various malignancies. In HNSCC, CTLA-4 expression is upregulated relative to normal tissue, and preclinical models have shown that CTLA-4 inhibition reduces tumor burden. Mechanistically, CTLA-4 primarily attenuates early T-cell priming within secondary lymphoid organs, whereas PD-1 modulates effector T-cell activity in peripheral tissues, including within the TME. Given these distinct but complementary immunoregulatory roles, dual checkpoint inhibition targeting both CTLA-4 and PD-1 pathways may yield synergistic or additive antitumor effects.

The EAGLE trial compared durvalumab or durvalumab plus tremelimumab or standard of care therapy.^[19] There was no statistically significant improvement in survival. The KESTREL trial compared durvalumab or durvalumab plus tremelimumab or the EXTREME regimen^[20] and again there was no statistically significant improvement in survival. Finally, the CHECKMATE-651 trial compared nivolumab plus ipilimumab with the EXTREME regimen, and there was no statistically significant improvement in survival.^[21] A fact that was noticeable across all these trials was the higher than expected survival of the standard of care arm, most likely attributed to the subsequent use of immunotherapy on progression.

A combination of ICI and cetuximab has been tried in various settings. Sacco et al.^[22] conducted a phase 2 trial in second-line platinum-resistant or ineligible, relapsed/refractory setting with pembrolizumab and cetuximab and were able to demonstrate an ORR of 45%. Chung et al.,^[23] in another phase 2 trial, tried a combination of nivolumab and cetuximab in the same setting and demonstrated a 1-year PFS and OS of 19% and 44%, respectively. Neither trial reported higher-than-expected toxicity signals. A systematic review and meta-analysis by Zhang et al.^[24] combining cetuximab and ICIs showed that the combination was more effective in HPV-negative patients.

Similar to cetuximab, combinations of immunotherapy with tyrosine kinase inhibitors (TKIs) have also been explored. LEAP-010, a phase 3 RCT, evaluated pembrolizumab with or without lenvatinib in the first-line setting.^[25] The combination demonstrated improved mPFS 6.2 versus 2.8 months (HR: 0.64, CI: 5.1–7.2, P = 0.000104 and ORR 46.1% versus 25.4% but not mOS, 15 versus 17.9 months (HR: 1.15, CI: 0.91–1.45, P = 0.882). The grade ≥3 toxicity was also significantly higher in the lenvatinib arm, 61.4% versus 17.8%. Saba et al.,^[26] in a phase 2 study, evaluated pembrolizumab with cabozantinib and reported a mPFS of 12.8 months, a 2-year PFS of 32.6% (CI: 18.8–56.3%), a mOS of 27.7 months, and a 2-year OS of 54.7% (CI: 30.8–81.8%). Baseline p-MET overexpression led to higher ORR in the study population. Combination therapies of ICIs with cetuximab or TKIs are not approved at this point.

Newer ICIs

Newer ICI combinations are being explored in smaller phase 1 and phase 2 studies, and the results so far have been encouraging. In mouse models, concurrent administration of LAG-3 and PD-1 antibodies can theoretically reverse CD8+T lymphocyte exhaustion. This approach can restore T-cell immunity. This also led to a decrease in immunosuppressive cell populations such as Tregs and myeloid-derived suppressor cells (MDSCs).^[27] Inhibition of TIM-3 enhances T-cell proliferation and cytokine production, leading to increased immune activation. Preclinical studies indicate that dual blockade of TIM-3 and PD-1 has a synergistic effect, restoring T-cell function and amplifying anti-tumor immunity, making this combination a promising approach in cancer immunotherapy.^[28] According to recent research, TIGIT and PD-1 frequently co-express each other, indicating a close functional relationship. Dual blockade of TIGIT and PD-1 has effectively restored T-cell activity in preclinical models, demonstrating the therapeutic potential of this combination in the treatment of cancer.^[29] Particularly in cancers such as melanoma and non-small cell lung cancer, VISTA expression inhibits T-cell proliferation and cytokine production, which leads to immune evasion and resistance to PD-1 and CTLA-4 therapies. Dual inhibition of VISTA and PD-1 appears to improve T-cell-mediated anti-tumor responses, according to studies, which makes it a viable tactic to combat immune suppression.^[30] The published results of phase 1/2 studies are detailed in Table 2 below.

Resistance

Despite the clinical benefits of ICIs in R/M HNSCC, resistance remains a major challenge. Key resistance mechanisms include tumor molecular heterogeneity, particularly differences between HPV-positive and HPV-negative tumors. HPV-negative HNSCC often exhibits more immunosuppressive TMEs, enriched with tumor-associated macrophages (TAMs), MDSCs, Tregs, and cancer-associated fibroblasts (CAFs), which contribute to immune evasion and ICI resistance. CAFs play a pivotal role by promoting CD8+T-cell exclusion and supporting immunosuppressive macrophage differentiation. TAMs are major sources of PD-L1 and secrete pro-tumoral cytokines under hypoxic stress. Tregs and regulatory B cells further suppress antitumor immunity, and their presence correlates with poor outcomes.^[42]

T-cell exhaustion and senescence also impair ICI efficacy. Exhausted and senescent T cells, particularly in HPV-negative tumors, show impaired function despite persistent antigen exposure. In addition, metabolic dysfunction in the TME – marked by hypoxia, acidity, nutrient depletion, and abnormal lipid and amino acid metabolism – undermines effective T and NK cell responses. These factors collectively create an immunosuppressive niche that hinders ICI activity. Understanding and targeting these resistance mechanisms may improve the effectiveness of immunotherapy in HNSCC.^[43]

Toxicity

ICI use is associated with immune-related adverse events (irAEs) due to immune system overactivation. Common toxicities include fatigue, rash, pruritus, diarrhea, and endocrinopathies (e.g., hypothyroidism and adrenal insufficiency). Less frequently, severe irAEs such as pneumonitis, hepatitis, and colitis may occur. While most side effects are manageable with corticosteroids or immunosuppressants, early recognition and prompt intervention are essential to prevent morbidity. Compared to traditional chemotherapy, immunotherapy generally has a more favorable toxicity profile, but long-term immune-related effects warrant close monitoring.^[44]

A less noticed but significant burden on HNSCC patients is financial toxicity (FT) arising from high medical costs, treatment-related disability, and loss of income. Treatments such as surgery, chemoradiation, intensive care unit stays, and immunotherapy greatly increase expenses. Many patients face unemployment and reduced lifetime earnings, contributing to psychological distress and lower quality of life. The comprehensive score for FT and the financial index of toxicity are the only tools currently used to assess FT in HNSCC.^[45]

Personalizing immunotherapy and combinations

Artificial intelligence and multiomics technologies have helped to understand the TME of HNSCC to a point where molecular mechanisms underlying immunotherapy response is currently elucidated. This helps to predict and enhance efficacy, make personalized treatment plans, identify new biomarkers, conduct robust preclinical studies, and establish new immunotherapy targets.^[46] ICIs have also expanded beyond PD-L1 inhibition to target HPV (ISA101, PDS101, BNT113, CUE101, INO3112, and HB200), VISTA, IDO1, LAG3, TIM3, and TIGIT. Bispecific antibodies are being developed and studied to target EGFR and LGR5, EGFR, transforming growth factor-beta (TGFβ), PD-1, and CTLA4. In addition to older TKIs such as afatinib, erlotinib, gefitinib, and dacomitinib, which have shown clinical benefit in R/M HNSCC, newer multikinase inhibitors such as zanzalintinib, vandetanib, poziotinib, dovitinib, anlotinib, rogaratinib, pemigatinib, nintedanib, erdafitinib, pemigatinib, and futibatinib have shown efficacy in preclinical or phase 1 studies and are being explored on a larger scale.^[47,48]

Low-dose immunotherapy

To mitigate the risk of both irAEs and financial toxicities, low-dose ICI in combination with oral metronomic chemotherapy is successfully proven in phase 3 RCTs.^[49] A recently published systematic review was able to demonstrate the promise of this strategy and the need for further prospective randomized trials.^[50]