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Immunotherapy for Head and Neck Cancer

Oncology
Otorhinolaryngology

Authors

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Maryann Zhao
Author
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Ravindra Uppaluri MD, PhD
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Introduction

Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer in the world with an incidence of 890,000 new cases and 450,000 deaths per year, which is roughly 4.5% of all cancer diagnoses and 4.6% of all cancer deaths, respectively.[1] HNSCC originates from mucosal epithelium of the oral cavity, pharynx and larynx, and is the most common malignancy of the head and neck region with increasing incidence worldwide. It is now acknowledged to have two etiologies– those associated with oncogenic HPV strains localized in the tonsil and base of tongue regions and those associated with carcinogen exposures, such as smoking and alcohol consumption.[2] HPV-positive disease is generally associated with a better prognosis and ultimately may be eradicated with effective vaccination campaigns.
Patients often present with locally advanced disease and, in the United States, approximately 15% present with metastatic disease.[3] Surgery is the standard of care treatment modality for the oral cavity subsite cancers. Definitive chemoradiation therapy (CRT) is considered in patients with pharyngeal and laryngeal or unresectable disease. Despite improvements in survival rates for HNSCC patients, the 5-year survival for patients with locally advanced HPV-unrelated HNSCC is 40-50%, with many patients developing recurrent or metastatic disease.[4,5] Until the approval of immunotherapies, first line treatment for recurrent or metastatic disease was platinum-based chemotherapy combined with cetuximab, an epidermal-growth-factor-receptor (EGFR) specific monoclonal antibody.[6] Second line therapy consisted of cetuximab, methotrexate and a taxane. The median overall survival (OS) for recurrent or metastatic disease is 10-13 months.[5]
Immunotherapy has revolutionized the treatment of cancers with immune checkpoint blockade (ICB) representing the most widely employed avenue of activating therapeutic antitumor immunity. Therapies blocking the programmed death 1 (PD-1) pathway, such pembrolizumab and nivolumab, have led to durable, long-term survival in various tumor settings, including metastatic melanoma, advanced renal cell carcinoma, and non–small cell lung cancer.[7,8]
Since 2016, ICB has been explored for recurrent and metastatic HNSCC and the US Food and Drug Administration approved two anti-programmed cell death protein (PD-1) monoclonal antibodies for recurrent and metastatic HNSCC in patients who were platinum therapy refractory. Further trials in 2019 led the FDA and European Commission to approve anti-PD1 therapy as first-line for unresectable recurrent or metastatic disease.[4] Despite the promise, only a proportion of patients benefit from the therapies with a response rate of 15-20%.[4] As the frontier for treatment of recurrent or metastatic HNSCC, immunotherapy needs to be better understood from patient selection to biomarker identification to integration with other treatment modalities. Here, we aim to provide an overview of the basic biological background of immune checkpoint blockade and clinical approach for integrating immunotherapy into treatment of patients with HNSCC.

Biology of Immune Checkpoint Blockade

Immunotherapies aim to strengthen the immune system’s intrinsic ability to eradicate cancer cells from the body through several different modalities, some of which include immune effector cells, oncolytic virus therapy and monoclonal antibodies (mAbs). In order to reactivate the immune response against the cancer, immune checkpoint inhibitors (ICIs, typically mAbs) target the “brakes” that temper natural immune responses and are hijacked by cancer cells. The final outcome where T cells kill tumors results first from a priming step and a second step at the T cell:tumor synapse with ICIs being able to target one or both of these steps. During T cell activation, which requires “dual signaling”, the T cell is primed by a tumor antigen presenting cell (APC) that [1] involves the T cell receptor recognizing the MHC-antigen complex on the APC, and [2] a process called co-stimulation where a molecule called B7 on the APC and CD28 on the T cell interact to promote T cell priming. This latter complex, which can be targeted by ICB, provides a co-stimulatory signal to the T cell to prime it to be ready to kill its target. Activated T cells however may become dysfunctional in the tumor microenvironment via expression of checkpoints, such as PD-L1 on tumor cells. Thus, ICIs can target these critical steps in the development of a cytotoxic T cell response to enhance tumor cell killing.
Across many cancer types, the FDA has approved ICB targeting three molecules: cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1) and its ligand PD-L1.[8] Although investigation into antibodies blocking several other molecules, such as LAG3 and TIM3, is ongoing, this review will focus on anti-PD-1 therapies as these have been approved for use in HNSCC. CTLA-4 therapy targets the priming phase of T cell activation and is approved in several malignancies. However, trials testing CTLA-4 blockade in HNSCC have failed to reach survival endpoints.[9] PD-1 is most highly expressed on exhausted T cells in addition to other activated immune cells, such as macrophages, dendritic cells and B cells.[10] When PD-1 interacts with its ligand PD-L1 and PD-L2, it results in T cell suppression and protects the body from autoimmune disease. The ligands are typically expressed on endothelial cells, antigen-presenting cells and activated lymphocytes. Their expression is inducible and upregulated in many solid and hematologic malignancies thus resulting in cancer immune evasion.[11,12]
Several different immune escape mechanisms are deployed by HNSCCs to evade immune attack, including antigen presentation machinery (APM) defects, checkpoint molecule expression and recruitment of inhibitory immune cells. HNSCC tumor cells genomically alter APM molecules such as the HLA to avoid T cell recognition.[13,14] They can also express immunosuppressive checkpoints, such as PD-L1 to promote T cell dysfunction. The PD-1/PD-L1 pathway has been noted to be at higher levels in HPV+ HNSCCs compared to HPV- HNSCCs with a greater number of PD-1 expressing cytotoxic T lymphocytes.[15] Another mechanism that is utilized is the dysregulation of cytokines in HNSCC. Overexpression of transforming growth factor-ß, a regulatory cytokine, can lead to the enhanced proliferation of head and neck epithelial cells and enhance inflammation.[16] IL-6 is associated with patterns of invasion and pathological nodal status.[17] Lastly, HNSCC recruits immunosuppressive cells such as T regulatory cells (Tregs), myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages, to the tumor microenvironment.[18]

Immune Checkpoint Blockade in HNSCC

Immunotherapy, specifically ICB targeting PD-1, has shown immense promise in improving the survival of HNSCC patients. Here we summarize the clinical trials that have led to the approval of ICB in HNSCC.
In 2016, two landmark trials, KEYNOTE-012 and CheckMate 141, assessed the efficacy of anti-PD-1 monoclonal antibodies pembrolizumab and nivolumab, respectively, in patients with recurrent or metastatic HNSCC. KEYNOTE-012, as a multicenter phase 1b trial, enrolled patients with recurrent or metastatic HNSCC in two cohorts: the first had 60 patients with PD-L1 positive tumors (tumor or stroma with ≥ 1% PD-L1 expression based on immunohistochemistry) treated with 10 mg/kg pembrolizumab every two weeks and the second treated 132 patients, regardless of their PD-L1 expression level, with 200 mg pembrolizumab every three weeks.[19] Results showed that the overall response (by central imaging review) was 18% (95% CI, 12-26).[20] CheckMate 141, a phase 3 trial, enrolled 361 HNSCC patients with recurrent disease who had progressed after platinum chemotherapy.[21] The patients were randomized to receive either nivolumab (3 mg/kg) or investigator’s choice of single-agent standard therapy (methotrexate, docetaxel or cetuximab). Patients on nivolumab treatment had an increased median overall survival (7.5 months vs. 5.1 months) compared to patients on chemotherapy. At two year follow up, the results continued to support that nivolumab increased survival regardless of PD-L1 expression level.[22] Based on the results of these two trials, the National Comprehensive Cancer Network (NCCN) officially listed pembrolizumab and nivolumab as standard therapy for second line recurrent or metastatic HNSCC without options for salvage surgery or radiation. [23]
In 2019, anti-PD-1 therapy was approved as first line therapy for recurrent or metastatic HNSCC. KEYNOTE-048, a phase 3 trial, enrolled 882 patients who were not eligible for local curative therapy and had not received systemic therapy. They randomized patients to receive pembrolizumab alone, pembrolizumab plus chemotherapy (cisplatin or carboplatin and 5-FU) or the EXTREME chemotherapy regimen (cetuximab plus cisplatin or carboplatin and 5-FU) in the first line setting. Pembrolizumab and chemotherapy improved overall survival in all patients compared to the EXTREME regime (13.0 months vs 10.7 months, HR 0.77 [95% CI, 0.63-0.93]).[24] Pembrolizumab alone also significantly prolonged OS for both patients with combined positive score (CPS) ≥ 20 and ≥ 1, and performed similarly to EXTREME irrespective of CPS but had a longer duration of response.[24] CPS quantifies PD-L1 expression on all cells on a biopsy slide (tumor, lymphocytes and macrophages), and divides this number by the total live tumor cells multiplied by 100. Collectively these results supported the recommendation for the use of pembrolizumab as first line therapy for recurrent or metastatic HNSCC patients who have not received platinum-based chemotherapy.

Utilization of Biomarkers in Patient Selection

Despite advances in treatment of HNSCC with immunotherapy, only a proportion of patients benefit from the therapies with a response rate of 15-20%.[21,24] There is a need to better understand biomarkers to predict prognosis in patients treated with immunotherapy. While there is no requirement for biomarker testing in patients that are treated with nivolumab or pembrolizumab, certain biomarkers have been investigated, including PD-L1. However, for first line recurrent HNSCC patients, a CPS score informs clinicians on whether to treat with pembrolizumab alone (CPS≥1) or pembrolizumab plus chemotherapy (CPS=0). Note that in KEYNOTE-048, 85% of patients had a CPS≥1.
Across various clinical trials, the predictive value of PD-L1 expression is variable and conflicting. To understand how expression levels are measured, it is necessary to define which antibody is used and if measurements are performed on tumor alone (TPS) or tumor and stroma (CPS), as previously described. CheckMate 141 found that the benefit of nivolumab on the risk of death in patients with PD-L1 positive tumors (≥ 1% expression) decreased over time at the two year follow up compared to PD-L1 negative tumors.[21,22]
In comparison, KEYNOTE-048 found that patients with PD-L1 CPS ≥ 20 and ≥ 1 had better OS when treated with pembrolizumab with or without chemotherapy compared to the chemotherapy alone.[24] PD-L1 immunohistochemical staining cannot always be used reliably to accurately predict response to ICB as HNSCC is known to have intra- and inter-tumor heterogeneity. It has been suggested that the combining PD-L1 expression in tumor cells with its expression on tumor infiltrating lymphocytes better predicts tumor response to ICB. Genomic and other biomarkers remain investigational and are not clinically used at this point.

Immune Related Adverse Events

Despite the tremendous benefits of ICB, immunotherapy has the known risk of patients developing immune related adverse events (irAE). irAE can impact nearly every organ system with effects ranging from a mild rash to severe colitis to myocarditis to autoimmune disease, such as type I diabetes.[8,25] Of note, anti-PD1 therapy is well tolerated compared to chemotherapy and even other immune checkpoint therapies, such as anti-CTLA4.[26,27] irAE were originally thought to occur exclusively early after initiation of immunotherapy, but there is growing evidence that the adverse events can occur even months to years post-immunotherapy.[28]
Safety assessments for both anti-PD1 therapies, pembrolizumab and nivolumab, showed favorable safety profiles. CheckMate 141 revealed that nivolumab had a reduced rate of grade 3 and 4 adverse events compared to the chemotherapy (13% vs. 35%) as measured by the National Cancer Institute Common Terminology for Adverse Events (version 4.0).[21]
While there were less gastrointestinal events, the nivolumab-treated group had increased rates of other irAEs such as rash and hypothyroidism than the chemotherapy group. Grade 3 and 4 adverse events occurred at a similar rate in KEYNOTE-012 for pembrolizumab treated patients (17%) and one fifth of these patients experienced irAE (pneumonitis, diabetes mellitus, colitis, liver injury).[19,20] In comparison, KEYNOTE-048 demonstrated that pembrolizumab alone had a lower Grade 3 or above all-cause adverse events than pembrolizumab plus chemotherapy or cetuximab plus chemotherapy although the rates of adverse events were higher in all groups (55%, 85% and 83%, respectively) compared to the previous studies that were mentioned.[24]
Pembrolizumab-treated patients were found to be at a greater risk for hypothyroidism as an adverse effect than the cetuximab plus chemotherapy group, which was consistent with previous studies. While pembrolizumab with chemotherapy was associated with a higher risk for hypothyroidism and cough, cetuximab with chemotherapy had increased rates of rash and acneiform dermatitis.[24] Given the risks of irAE, it is generally recommended to monitor patients for adverse events at least once a month with considerations to discontinue therapy depending on the grade.[4]
While most recommend the continuation of therapy for grade 1 events, many would suggest stopping the immunotherapy for grade 2 and above, and inpatient treatment for grade 3 events with the administration of corticosteroids, although these recommendations do not have universal consensus among the field.

Measurement of Response

Immunotherapy displays different kinetics from traditional therapies and thus poses a new challenge for measuring response. Unlike treatments with chemotherapy or targeted therapy, patients treated with immunotherapy may experience delayed radiographic evidence of response. There is debate over the best criteria to measure response given the unique kinetics and scenarios seen with immunotherapy. Clinical trials often use Response Evaluation Criteria in Solid Tumors (RECIST), which is an anatomically based imaging measurement for assessing changes in tumor size. However, this method does not account for certain phenomena that are specifically seen in immunotherapy, such as pseudo-progression and hyperprogression. Pseudo-progression describes an increase in lesion diameter initially due to inflammation or even tumor growth before observing shrinkage in tumor size.[29]
Hyperprogression on the other hand is when there is rapid tumor growth after the initiation of therapy, often greater than a minimum of two-fold increase in size.[30] Using the criteria from RECISTv1.1, the guidelines used for several HNSCC anti-PD1 trials, the increase in tumor size or new lesions would be accounted as progressive disease despite stabilization in disease after the flare. Therefore, improved metrics that account for the atypical behavior seen in immunotherapy were developed and are designated as immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).[31]
Under irRECIST, changes in tumor size due to initial flares before reduction in tumor size are reported as immune unconfirmed progressive disease, allowing for more accurate representation of patients’ responses. While modified criteria, such as irRECIST, have been approved, they have yet to be widely adopted as current immunotherapy clinical trials were designed using versions of RECIST. Once patients are determined to have a complete response, the typical recommendation is to continue ICB therapy for at least 2 years. For those in remission, an additional one or two years barring any toxicity or progression on immunotherapy is considered, although there is not complete consensus among the field.[4]

Summary

Recurrent and metastatic HNSCC is one of the most clinically challenging diseases to treat. Immune checkpoint blockade targeting PD-1 has revolutionized treatment for these patients with improvements in overall survival. Although there has been tremendous progress, there is still a need to better understand how to identify patients who will be responders to therapy through biomarkers or genomic signatures, assess patients’ response to immunotherapy and optimize the management of adverse events. Finally, additional approaches to improve the current immunotherapy response rates are a critical need.

Disclosure

R.U. serves on advisory boards for Merck, Regeneron and Daichi-Sankyo.

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