Hematology/Oncology Division, Scripps Clinic, La Jolla, CA 92037, USA.
© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
This article aims to review the role of immunotherapy in tumors of the head and neck, focusing primarily on US Food and Drug Administration (FDA) approved checkpoint inhibitors in squamous cell histology. The data showing superiority of checkpoint inhibitors over cytotoxic chemotherapy that led to FDA approval of two agents (Keytruda® Merck and Opdivo® Bristol-Myers-Squibb) in the recurrent and metastatic setting will be reviewed in detail, as well as summaries of ongoing trials for checkpoint inhibitor and combination therapies in both the curative and metastatic settings. Upcoming positive data regarding immunotherapy use and other innovative immune based therapies in rare histologies such as nasopharyngeal carcinoma and salivary gland tumors will also be reviewed. Additionally, data regarding management of immunotherapy side effects will be discussed and a brief review of recently published guidelines will be provided. Lastly, we will address risks to special patient populations that need further study.
Head and neck cancer, immunotherapy, checkpoint inhibitor, pembrolizumab, nivolumab
Head and neck cancers are a heterogeneous and diverse group of tumors with unique challenges related to the anatomic location of tumors, complex and often rare histologies, and potential loss of function and disfigurement caused by treatment. Historically, systemic therapies have been mainly limited to advanced stages where they can be used in combination with radiation for definitive treatment and in the palliative setting for non-curable recurrent and metastatic disease. Cisplatin with concurrent radiation has developed as an effective technique to preserve organ function in advanced but potentially curable tumors[1,2]. Debate continues as to the role of neoadjuvant chemotherapy in locally advanced head and neck squamous cell tumors (LA-HNSCC); individual trials have shown benefit but large meta-analyses show no overall survival benefit[1,3,4]. Cytotoxic therapy plays a large role in palliation in the recurrent and metastatic setting, where options including multi-drug regimens may be toxic with modest benefit or single agent therapy with small benefit[5-7]. Overall survival for recurrent and metastatic head and neck squamous cell carcinoma (RM HNSCC) remains generally poor at less than 1 year with current cytotoxic therapeutic options[5-7]. The most commonly used first line chemotherapeutic regimen of cisplatin or carboplatin/5-FU/Cetuximab (Eribitux®, Eli Lilly) had a reported overall survival (OS) benefit of 10.1 months when the data was first published in 2008, and is the only one to have a level 1 recommendation from the National Comprehensive Cancer Network (NCCN)[6,8]. Cetuximab as a single agent use in second line has a 13% response rate and 7.5 month OS.
In the last several years, a new class of systemic therapies have been developed that harness the body’s immune responses in fighting tumors. Classified broadly as immunotherapy, this is a heterogeneous group of therapies that target specific immune pathways to amplify the body’s natural tumor fighting abilities. Vaccine therapies are also in development, and have been approved in other malignancies such as melanoma. Another vaccine target is Epstein-Barr Virus (EBV) related malignancies, such as nasopharyngeal carcinoma. These are under development with ongoing trials looking at efficacy and safety.
One of the most successful groups of therapies to emerge is a class of drugs that target the programmed death-1/programmed death ligand-1 (PD-1 and PD-L1) pathway, as well as a co-regulatory pathway mediated through cytotoxic T-lymphocyte-associated protein 4 (CTLA 4). This pathway has been named the “checkpoint pathway” with agents acting on these proteins generally referred to as checkpoint inhibitors. Ipilumumab (Yervoy®, Bristol-Myers Squibb) is the first US Food and Drug Administration (FDA) approved CTLA-4 inhibitor which came to the market in 2011 for treatment of melanoma; the first PD-1 inhibitor, pembrolizumab (Keytruda®, Merck) was approved for melanoma in September 2014, and nivolumab (Opdivo®, Bristol-Myers Squibb) gained its first approval in December 2014, also in melanoma. Since then, these agents have gained approval in multiple tumor types and multiple settings, including head and neck squamous cell carcinoma.
This article will review the indications for checkpoint inhibitors in head and neck tumors, examining the data and discussing adverse events and their management, as well as review data on upcoming therapies.
Pembrolizumab (Keytruda®) is a monoclonal IgG4 isotype antibody that binds to the programmed death-1 (PD-1) receptor on T-cells, preventing them from binding programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2) ligands expressed on tumor cells. The first study done with pembrolizumab in recurrent or metastatic HNSCC is the phase I KEYNOTE 012, a multi-cohort trial looking at multiple tumor types, including HNSCC. It was conducted as a two-part safety and efficacy trial, with the primary outcome in both phases being safety and overall response rate (ORR). In the first phase (1a), 60 patients all with high PD-L1 expression (> 1%) were enrolled; 23 were human papillomavirus (HPV) positive, 37 HPV negative. Pembrolizumab was dosed at 10 mg/kg every 2 weeks. 17% of patients had grade 3 or 4 adverse events, and the ORR was 18%, further broken down as 25% in HPV positive and 14% in HPV negative patients.
In the second phase expansion cohort (1b), 132 patients were enrolled, this time regardless of PD-L1 expression. Fifty-seven percent of these patients had received at least 2 prior lines of therapy. Primary outcomes were again safety and ORR; secondary outcomes were evaluated in this portion of the trial and included progression free survival (PFS), OS, and relationship of outcome to PD-L1 expression. In this cohort, the dose of pembrolizumab was changed to 200 mg every 3 weeks. ORR was again 18% and grade 3 or 4 adverse events dropped to 9%. PFS was 2 months, and OS was 8 months. In HPV positive patients, the ORR was 32%.
This led to a phase II study in HNSCC with pembrolizumab, KEYNOTE 055. In this single arm study, patients were enrolled who had previously failed platinum and cetuximab therapy. A total of 171 patients were enrolled regardless of PD-L1 status and treated with the set dose of 200 mg every 3 weeks. The primary endpoints were safety and ORR. Twenty-two percent of these patients were HPV positive, and though not required for enrollment, 82% had > 1% PD-L1 positivity. Seventy-five percent of patients had received at least 2 prior lines of therapy. ORR was 16%, and grade 3 or 4 adverse events were 15%. The PFS was 2.1 months and OS 8 months.
Based on this data, the FDA granted accelerated approval to pembrolizumab on 5 August 2016. This approval is contingent upon completing a phase III study, which is the KEYNOTE 040 trial presented at the European Society for Medical Oncology (ESMO) annual meeting in September 2017; the data has not yet been formally published as of this writing. In this prospective study, 495 platinum-treated patients were randomized 1:1 to pembrolizumab 200 mg every 3 weeks or standard therapy with docetaxel, methotrexate, or cetuximab. The primary endpoint was median OS in the intent to treat population; secondary endpoints included median PFS, ORR, PFS and OS in patients withPD-L1 combined positive score ≥ 1% (slightly different to the previously used definition of PD-L1 expression). A pre-specified efficacy boundary for OS in the intention to treat (ITT) population was set at one-sided P = 0.0175. The overall survival in pembrolizumab treated patients was 8.4 vs. 7.1 months in the standard therapy group, hazard ratio (HR) 0.81 (CI 0.66-0.99, P = 0.0204); this did not meet the pre-specified OS benefit, but did provide 19% reduction in the risk of death. PFS was 2.1 and 2.3 months respectively. Incidence of grade 3 or greater adverse events was 13.4% in the pembrolizumab group and 36.3% in the standard therapy group. Although the pre-specified statistical benefit was not met, the data is consistent with the phase 1 and 2 results, as is the toxicity profile.
PD-L1 status was again re-examined in this study, looking at two separate cut-offs not well described in the abstract: PD-L1 based on tumor proportion score, with the cut off being either greater than or less than 50%, and PD-L1 combined positive score ≥ 1%. There did appear to be some predictive benefit to these varying markers of expression, with PD-L1-TPS ≥ 50% suggesting an OS benefit of 11.6 vs. 7.9 months. It is unknown if this data will ultimately alter the FDA labeling for pembrolizumab in HNSCC to include PD-L1 expression testing similar to non-small cell lung cancer.
Nivolumab (Opdivo®) acts via a similar mechanism to pembrolizumab: it is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response. It received FDA approval for advanced HNSCC in November 2016 based on the randomized phase III CHECKMATE 141 trial. The trial randomized 361 patients in a 2:1 fashion to nivolumab 3 mg/kg or investigator’s choice of methotrexate, docetaxel, or cetuximab. Primary endpoint in this trial was overall survival, with secondary endpoints including PFS, ORR, safety, and quality of life. Fifty-five percent of patients had at least two lines of prior systemic therapy. P16 expression was not available for every patient who participated, but in the nivolumab group 26% of 113 patients tested were positive; in the standard therapy group 24% of 65 patients were positive. Median OS was 7.5 months in nivolumab group vs. 5.1 months in the standard group (P = 0.01, HR 0.70). Interestingly, PFS was non-significant between the two groups, with nivolumab PFS being 2 months and standard therapy 2.3 months (HR 0.70, P = 0.32). ORR for nivolumab was 13.3% vs. 5.8% in standard therapy. However, looking at the median PFS and median OS curves, there is a late separation consistent with more durable responses to nivolumab therapy. Toxicity in these patients (grade 3 or higher) was 13.1% vs. 35.1%.
PD-L1 expression was not required for the CHECKMATE 141 trial, but a pre-specified analysis looked at the degree of expression to determine if there was any clear correlation. PD-L1 expression could be evaluated in 260 of the 361 patients; significant expression (considered ≥ 1%) was found in 57.3% of these patients. P16 status was also evaluated, independently and in conjunction with PD-L1 expression. For patients with significant PD-L1 expression, the hazard ratio for death was 0.55 (95% CI; 0.36 to 0.83); in PD-L1 negative patients, it was 0.89 (95% CI; 0.54 to 1.45, P = 0.17). Patients with PD-L1 of ≥ 5% and ≥ 10% were also evaluated and had similar hazard ratios to those with PD-L1 ≥ 1%.
Similarly, a post hoc analysis of P16 status was done. One hundred and seventy-eight patients were positive; and overall survival was evaluated with regards to this status. Patients were found to respond to nivolumab regardless of P16 positivity. In P16 positive patients, median OS was 9.1 months for nivolumab vs. 4.4 months for standard therapy. In P16 negative patients, median OS was 7.5 vs. 5.8 months (HR 0.73, P = 0.55). This confirmed what has been previously demonstrated; that patients who are P16 tend to do better, but this is not necessarily a predictive biomarker for response to treatment.
Lastly, the investigators stratified patients by both PD-L1 expression and P16 expression. All the hazard ratios were < 1 but none were statistically significant based on the number of patients. Both PD-L1 expression and P16 expression are associated with better outcomes confirming their prognostic value, however even PD-L1 low and P16 negative patients had partial and complete responses to therapy, indicating these were not predictive biomarkers in this study.
Taken together, these trials with pembrolizumab and nivolumab demonstrate that checkpoint inhibitor therapy in the second line setting has improved overall survival at 7.5-8.4 months than 5.7-7.1 months with cytotoxic therapy, with manageable toxicity profiles. These response rates may be higher with prolonged OS for patients with high PD-L1 expression and HPV positive tumors [Table 1].
Summary of the key trial data leading to Food and Drug Administration approval or ongoing phase II/III trials
|Study||Therapy||Phase||Number of patients||ORR||PFS||OS|
|KEYNOTE-055||Pembrolizumab||II||171||16%||2.1 months||8 months|
|KEYNOTE-040||Pembrolizumab||III||495||14.6%||2.1 months||8.4 months|
|CHECKMATE-141||Nivolumab||III||361||13.3%||2 months||7.5 months|
Other checkpoint inhibitors are being actively studied in RM HNSCC. Phase II durvalumab (Infinzi®, AstraZeneca) data from the HAWK trial was presented at ESMO in 2017, with similar results in terms of response rate and safety to pembrolizumab and nivolumab. Durvalumab is a monoclonal antibody inhibiting PD-L1, and in this study patients had progressed through first line platinum therapy and required 25% PD-L1 expression. One hundred and twelve patients were recruited, and ORR was 13.5% with HPV positive tumors showing ORR of 26.5% and HPV- tumors showing ORR of 7.9%. Median PFS was 2.3 months; median OS data was not mature. Interestingly, this is one of the first trials to show differential response to therapy based on PD-L1 expression. Based on this data, durvalumab is in phase III studies as single agent therapy for patients who progress after platinum therapy.
Atezolizumab (Tecentriq® Genentech), another monoclonal anti-PD-L1 antibody, is also under study for RM HNSCC with phase 1a safety results announced at ESMO as well. In a safety analysis of 32 patients, 9% had grade 3 or greater adverse events, and ORR was promising at 22%. Phase II and III studies are ongoing.
Table 1 summarizes some of the key immunotherapy trial data to date that have led to FDA approval or ongoing phase II/III trials. Table 2 summarizes several active trials that are recruiting or have finished accrual and are awaiting results. This list is a cross-section of various studies, but is not a complete representation due to the large number of ongoing trials. Many are evaluating agents already approved for HNSCC or other tumors in the neoadjuvant or adjuvant setting, or in combination with other agents, either cytotoxic or other immunotherapy agents.
Selection of trials in head and neck squamous cell carcinoma active as of 29 March 2018
|Atezolizumab||III||A study of atezolizumab (anti-PD-L1 antibody) as adjuvant therapy after definitive local therapy in patients with high risk locally advanced squamous cell carcinoma of the head and neck||Adjuvant||NCT03452137|
|Atezolizumab, nivolumab, pembrolizomab||II||Priming immunotherapy with advanced disease with radiation||Relapsed||NCT03313804|
|Avelumab||III||Randomized trial of avelumab-cetuximab-radiotherapy vs. standard of care (SoC) in LA-HNSCC (REACH)||Curative||NCT02999087|
|Avelumab||III||Study to compare avelumab in combination with SoC chemoradiotherapy (CRT) vs. SoC CRT for definitive treatment in patients with locally advanced head and neck squamous cell tumors (LA-HNSCC) (javelin head and neck 100)||Curative||NCT02952586|
|Avelumab||II||A study of avelumab in combination with other cancer immunotherapies in advanced malignancies (javelin medley)||Advanced/ metastatic||NCT02554812|
|Durvalumab||II||Carboplatin, nab-paclitaxel, durvalumab before surgery and adjuvant therapy in HNSCC||Curative||NCT03174275|
|Durvalumab||II||Durvalumab before surgery in treating patients with oral cavity or oropharynx cancer||Curative||NCT02827838|
|Durvalumab, Tremelimumab||I/II||A trial of durvalumab and tremelimumab in combination with stereotactic body radiation (SBRT) in patients with metastatic cancer (ABBIMUNE)||Advanced/|
|Ipilumumab||I||Immunotherapy study of evofosfamide in combination with ipilumumab||Advanced/|
|Nivolumab||I||Safety testing of adding nivolumab to chemotherapy in patients with intermediate and high-risk local-regionally advanced head and neck cancer (EAGLE)||Locally advanced||NCT02764593|
|Nivolumab, Pembrolizumab||II||Reirradiation with pembrolizumab in locoregional inoperable recurrence or second primary squamous cell cancer CA of the head and neck||Recurrent/|
|Nivolumab||II||Nivolumab, carboplatin, and paclitaxel in treating patients with stage III-IV head and neck squamous cell carcinoma that can be removed by surgery||Neoadjuvant||NCT03342911|
|Nivolumab||III||Nivolumab or nivolumab plus cisplatin, in combination with radiotherapy in patients with cisplatin-ineligible or eligible locally advanced squamous cell head and neck cancer||Locally advanced||NCT03349710|
|Nivolumab, Ipilimumab||III||Study of nivolumab in combination with ipilimumab compared to the standard of care (extreme study regimen) as first line treatment in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (CHECKMATE 651)||Recurrent/|
|Pembrolizumab||II||Immunotherapy with MK-3475 in surgically resectable HNSCC||Neoadjuvant||NCT02296684|
|Pembrolizumab||III||Study of pembrolizumab (MK-3475) or placebo with chemoradiation in participants with locally advanced head and neck squamous cell carcinoma (MK-3475/KEYNOTE-412)||Curative||NCT03040999|
|Pembrolizumab||II||Efficacy study of pembrolizumab in relapsed, locally recurrent squamous cell cancer of the head and neck||Relapsed||NCT02769520|
|Pembrolizumab||III||A study of pembrolizumab (MK-3475) for first line treatment of recurrent or metastatic squamous cell cancer of the head and neck (MK-3475-048/KEYNOTE-048)||Recurrent/|
|Tremelimumab, MEDI4736||III||Study of MEDI4736 monotherapy and in combination with tremelimuab vs. SoC therapy in patients with head and neck cancer||Recurrent/|
|Tremelimumab, MEDI4736||III||Phase III open label study of MEDI 4376 with/without tremelimumab vs. SoC in recurrent/metastatic head and neck cancer||Recurrent/|
Immunotherapy is being actively explored in non-squamous histology tumors of the head and neck. Both nasopharyngeal carcinoma and salivary gland carcinomas express PD-L1, and this has been independently associated with worse disease free survival in these tumor types[20,21]. There are published early phase I and II results as well as ongoing trials looking at various targets, both with checkpoint inhibitors and vaccine therapy. The preliminary results and ongoing trials are summarized in Table 3.
Trials for nasopharyngeal carcinoma and salivary gland tumors with immunotherapies
|Histology||Trial name/NCT||Therapy||Phase||No. patients||Results|
|NPC||KEYNOTE 028||Pembrolizumab||IB||27||PFS 6.5 months, 26% partial response, 52% stable disease|
|NPC||NCT02339558||Nivolumab||II||40||PR 19%, SD 33%, median overall survival (MOS) not reached|
|NPC||KEYNOTE 122 |
|NPC||NCT02605967||PDR001 (anti-PD-1 agent)||II||114||Recruiting|
|NPC||NCT01800071, NCT01094405||MVA EBNA1/LMP2||I/II||22 and 25||Completed; recruiting|
|Salivary gland||KEYNOTE 028||Pembrolizumab||IB||26||ORR 12%, m duration of response (DOR) 4 months|
|Salivary gland||NCT03172624, NCT03146650||Ipilimumab, nivolumab||II, II||64, 63||Recruiting|
|Salivary gland||KEYNOTE 158 (NCT02628067)||Pembrolizumab||II||N/A||Recruiting|
|Salivary gland||NCT03360890||Pembrolizumab, docetaxel||II||46||Recruiting|
PD-L1 expression testing is not currently required for either FDA approved therapy, nivolumab or pembrolizumab in HNSCC, unlike some other tumor types. As reviewed previously, expression was included in the phase II and III trials with both agents but did not show a clear correlation between activity and response rates. There are several possible theories as to why this may be the case; some of it may be rooted in the assays used for testing themselves. There are at least 4 commercially available immunohistochemistry (IHC) assays, each used with a different checkpoint inhibitor to evaluate PD-L1 expression. Dako 22C3 (Agilent) was used in the KEYNOTE trials with pembrolizumab; Dako 28-8 (also IHC based) used in the CHECKMATE trials with nivolumab. Roche produces the other two available assays; Ventana SP142 is used with atezolizumab, and Ventana SP263 with durvalumab. Comparisons of these assays by testing the same specimen have yielded statistically significant differences in results; this may be related to the different cutoff values for positivity (> 1% vs. 50%)[25,26]. Most importantly, there does not appear to be a predictive correlation in many tumor types, head and neck tumors included, as patients with negative results can respond to therapy. One possible reason for this could be related to a co-regulatory pathway called programmed cell death ligand 2 (PDL2): data published in June 2017 looked at PDL2 expression in patients with HNSCC. Even in patients who were PD-L1 negative, PDL2 positivity correlated with a statistically significant response to pembrolizumab therapy. Response rates were highest in patients who expressed both receptors. PD-L1 expression in tumor cells vs. tumor infiltrating lymphocytes (TILs) is also felt to be an important factor in interpreting response rates of tumors. Active research is ongoing looking at the prognostic implications, the role in predicting response to cytotoxic therapy, and the role in predicting response to checkpoint inhibitor therapy.
The immune related adverse events (irAEs) of immunotherapies are important due to their unique presentation and management compared to cytotoxic therapies. Due to the mechanism of “unleashing” the immune system via up-regulation of T-cell activity, most toxicities are immune mediated and treated with steroids and immune modulators. The unique mechanism of action of these drugs also raises concerns about their use in certain patient populations as well, who may be at increased risk for adverse events. In general toxicity rates are lower with immunotherapy in RM HNSCC; in most of the published trials, grade 3-4 adverse events range from 9%-18%[12-15,17] by comparison, the standard therapy arm in CHECKMATE 141 had a grade 3-4 reaction rate of 35%, more consistent with what is seen in clinical practice with traditional therapies.
The most common adverse events are usually mild and include fatigue, nausea, rash, and decreased appetite. Inflammatory processes such as colitis and pneumonitis are amongst the more common serious reactions; rarely, hepatitis, cardiomyopathy, autoimmune cytopenias, and nephritis have been reported. Endocrinopathies are also a recognized adverse event from these therapies, with hypothyroid the most common, necessitating routine monitoring. Hyponatremia, hypophysitis, hyperglycemia, and even new development of type 1 diabetes have all been reported with varying severities with the various checkpoint inhibitors.
Management of these reactions varies according to symptom and severity. Both the American Society for Clinical Oncology (ASCO) and the Society for Immunotherapy of Cancer (SITC) have created consensus practice guidelines to guide treatment, and have similar recommendations[28,29]. Grade 1 reactions can often be managed symptomatically with supportive care; for grade 2, therapy should be held and prednisone or equivalent started at 0.5-1 mg/kg, with either dose escalation or rapid taper depending on the patient’s response. Therapy can be resumed when the reaction is ≤ grade 1 and the patient is off steroids. Grade 3 and 4 reactions necessitate stopping therapy and starting prednisone or equivalent at 1-2 mg/kg; once the patient responds, a slow taper can be done over 4-6 weeks, with appropriate GI and infectious prophylaxis depending on duration of steroid treatment. Generally, therapy can be resumed after resolution of symptoms to ≤ grade 1, except for grade 4 reactions where immunotherapy should be permanently discontinued. In patients with severe colitis that does not respond to steroids alone, the addition of infliximab, an anti-TNFa antibody, has improved symptoms and can be weaned off steroids faster.
Endocrinopathies require management related to the specific derangement; holding immunotherapy is not recommended unless the reaction is grade 3 or greater. The most common endocrinopathy that patients develop is hypothyroidism necessitating replacement therapy, though hyperthyroidism and thyroiditis can occur. If hypophysitis develops, patients should be screened for all possible complications including hypogonadism, hypothyroidism, and hypoadrenergic complications. In hyperglycemia, insulin therapy is generally preferred as these patients can develop type I diabetes and diabetic ketoacidosis; if these have been ruled out, oral hyperglycemic therapy can be considered. Referral to endocrinology for co-management is important in these patients to minimize long term impacts of these toxicities, and in some situations patients can be optimized and allowed to continue on immunotherapy if they are responding well, even if the reaction was initially grade 4.
Certain patient populations appear to be at increased risk for adverse events with the use of checkpoint inhibitors. Others may require further study of the impact these therapies could have. Immunotherapy adverse reactions mimic autoimmune phenomena, raising the question of how patients with pre-existing autoimmune diseases may respond. There is retrospective data examining patients with these conditions who go on to receive immunotherapy, especially with ipilumumab and melanoma. In these studies, exacerbations of autoimmune diseases occurred in 38%-75% of patients; most were managed with corticosteroids or immunosuppressive therapy and very few fatalities occurred[31-33]. Patients on immunosuppressive therapy prior to treatment appeared to have lower rate of flare/adverse events, as did patients with neurologic or gastrointestinal diseases as compared to arthritic or skin related autoimmune diseases. Similarly, post organ-transplant patients on immunosuppressive therapy are at increased risk of certain malignancies, especially cutaneous. These patients are mostly excluded from clinical trials so little prospective data exists. Retrospective case reports and analyses indicate that there is increased risk for organ rejection[34,35]. This risk varies with organ type and agent: renal transplants and PD-1 agents appear to have the highest risks. Lastly, patients with inherited mutations that increase the risk for head and neck cancers, such as Li Fraumeni Syndrome and Fanconi Anemia, may benefit from checkpoint inhibitor therapy, though there is no prospective or retrospective data identifying these patients and their response rates or adverse event profiles.
Head and neck tumors are a historically difficult group of tumors to treat due to variability in histology, location, and modest responses to systemic therapy. Response rates to systemic therapies are low, especially in recurrent and metastatic tumors, and overall survival remains dismal. Checkpoint inhibitors such as pembrolizumab and nivolumab provide an alternative to cytotoxic therapies in squamous cell tumors, with adequate response rates and a modest overall survival benefit, and overall better tolerability in terms of toxicities. Their use does require special attention to the unique irAEs that can occur. Other checkpoint inhibitors including durvalumab, avelumab, atezolizumab, tremelimumab, and ipilumumab are actively being explored in clinical trials. In addition, there are ongoing trials looking to move these agents into the curative setting and combine them with more traditional therapy options to gain more cumulative survival benefit. This is an interesting and exciting time for this field with potential advances that will hopefully significantly improve patient outcomes.
Concept and design, data analysis: Costantini C, Quenelle N
Data acquisition, manuscript preparation: Quenelle N
Critical revision, finalizing of the manuscript: Costantini CAvailability of data and materials
Not applicable.Financial support and sponsorship
None.Conflicts of interest
Both authors declared that there are no conflicts of interest.Ethical approval and consent to participate
Not applicable.Consent for publication
© The Author(s) 2018.
1. Pignon JP, Bourhis J, Domenge C, Designé L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-analysis of chemotherapy on head and neck cancer. Lancet 2000;355:949-55.DOI
2. Pignon JP, le Maître A, Maillard E, Bourhis J; MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomized trials and 17,346 patients. Radiother Oncol 2009;92:4-14.DOIPubMed
3. Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, Tjulandin S, Shin DM, Cullen K, Ervin TJ, Murphy BA, Raez LE, Cohen RB, Spaulding M, Tishler RB, Roth B, Viroglio Rdel C, Venkatesan V, Romanov I, Agarwala S, Harter KW, Dugan M, Cmelak A, Markoe AM, Read PW, Steinbrenner L, Colevas AD, Norris CM Jr, Haddad RI; TAX 324 Study Group. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705-15.DOIPubMed
4. Hitt R, López-Pousa A, Martínez-Trufero J, Escrig V, Carles J, Rizo A, Isla D, Vega ME, Martí JL, Lobo F, Pastor P, Valentí V, Belón J, Sánchez MA, Chaib C, Pallarés C, Antón A, Cervantes A, Paz-Ares L, Cortés-Funes H. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemotherapy in locally advanced head and neck cancer. J Clin Oncol 2005;23:8636-45.DOIPubMed
5. Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, Kish JA, McClure S, VonFeldt E, Williamson SK. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 1992;10:1245-51.DOIPubMed
6. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116-27.DOIPubMed
7. Wiegand S, Zimmermann A, Wilhelm T, Werner JA. Survival after distant metastasis in head and neck cancer. Anticancer Res 2015;35:5499-502.PubMed
8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): head and neck cancers. Available from: https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. [Last accessed on 24 Aug 2018].
9. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, Knecht R, Amellal N, Schueler A, Baselga J. Open label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007;25:2171-7.DOIPubMed
10. Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol 2015;33:2780-8.DOIPubMed
11. US Food and Drug Administration. Highlights of prescribing information: Keytruda. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125514s004s006lbl.pdf. [Last accessed on 24 Aug 2018].
12. Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, Heath K, McClanahan T, Lunceford J, Gause C, Cheng JD, Chow LQ. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of head and necl (KEYNOTE-012): an open-label, multicenter, phase 1b trial. Lancet Oncol 2016;17:956-65.DOI
13. Chow LQM, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, Berger R, Eder JP, Burtness B, Lee SH, Keam B, Kang H, Muro K, Weiss J, Geva R, Lin CC, Chung HC, Meister A, Dolled-Filhart M, Pathiraja K, Cheng JD, Seiwert TY. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol 2016;34:3838-45.DOIPubMed
14. Bauml J, Seiwert TY, Pfister DG, Worden F, Liu SV, Gilbert J, Saba NF, Weiss J, Wirth L, Sukari A, Kang H, Gibson MK, Massarelli E, Powell S, Meister A, Shu X, Cheng JD, Haddad R. Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study. J Clin Oncol 2017;35:1542-9.DOIPubMedPMC
15. Abstract LBA45_PR 'pembrolizumab (pembro) vs standard of care (SOC) for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): phase 3 KEYNOTE-040 trial'. Ann Oncol 2017; doi: 10.1093/annonc/mdx440.040.DOI
16. Food and Drug Administration. Highlights of prescribing information: nivolumab. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125554s055lbl.pdf. [Last accessed on 24 Aug 2018].
17. Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016;375:1856-67.DOIPubMedPMC
18. Zandberg D, Algazi A, Jimeno A, Good JS, Fayette J, Bouganim N, Ready N, Clement PM, Goswmi T, Jarkowski A, Armstrong JM, Asubonteng K, Melillo G, Mesia R. Durvalumab for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): preliminary results from a single-arm, phase 2 study. Ann Oncol 2017;28:372.DOI
19. Bahleda R, Braiteh FS, Balmanoukian AS, Brana I, Hodi FS, Garbo L, Liu B, Molinero L, O'Hear C, Shen X, Colevas AD. Long-term safety and clinical outcomes of atezolizumab in head and neck cancer: phase 1a trial results. Ann Oncol 2017;28:373.DOI
20. Mukaigawa T, Hayashi R, Hashimoto K, Ugumori T, Hato N, Fujii S. Programmed death ligand-1 expression is associated with poor disease free survival in salivary gland carcinomas. J Surg Oncol 2016;114:36-43.DOIPubMed
21. Zhang J, Fang W, Qin T, Yang Y, Hong S, Liang W, Ma Y, Zhao H, Huang Y, Xue C, Huang P, Hu Z, Zhao Y, Zhang L. Co-expression of PD-1 and PD-L1 predicts poor outcome in nasopharyngeal carcinoma. Med Oncol 2015;32:86.DOIPubMed
22. Hsu C, Lee SH, Ejadi S, Even C, Cohen RB, Le Tourneau C, Mehnert JM, Algazi A, van Brummelen EMJ, Saraf S, Thanigaimani P, Cheng JD, Hansen AR. Safety and antitumor activity of pembrolizumab in patients with programmed death-ligand-1-positive nasopharyngeal carcinoma: results of the KEYNOTE-028 study. J Clin Oncol 2017;35:4050-56.DOIPubMed
23. Ma BB, Goh BC, Lim WT, Lo KW, Hui EP, Riess JW, Agulnik M, Chang AY, Kish JA, Lim DW, Adkins DR, Cullen KJ, Gitlitz BJ, Foster NR, Pettinger AM, McKinzie S, To KF, Costello B, Streicher H, Chan AT. Abstract CT076: multicenter phase II study of nivolumab in previously treated patients with recurrent and metastatic non-keratinizing nasopharyngeal carcinoma - mayo clinic phase 2 consortium P2C-MN026, NCI9742, NCT02339558. Cancer Res 2018; doi: 10.1158/1538-7445.AM2017-CT076.DOI
24. Cohen RB, Delord JP, Doi T, Piha-Paul SA, Liu SV, Gilbert J, Algazi AP, Damian S, Hong RL, Le Tourneau C, Day D, Varga A, Elez E, Wallmark J, Saraf S, Thanigaimani P, Cheng J, Keam B. Pembrolizumab for the treatment of advanced salivary gland carcinoma: findings of the phase 1b KEYNOTE-028 study. Am J Clin Oncol 2018; doi: 10.1097/COC.0000000000000429.DOI
25. Diggs LP, Hsueh EC. Utility of PD-L1 immunohistochemistry assay for predicting PD-1/PD-L1 inhibitor response. Biomark Res 2017;5:12.DOIPubMedPMC
26. Rimm DL, Han G, Taube JM, Yi ES, Bridge JA, Flieder DB, Homer R, West WW, Wu H, Roden AC, Fujimoto J, Yu H, Anders R, Kowalewski A, Rivard C, Rehman J, Batenchuk C, Burns V, Hirsch FR, Wistuba II. A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer. JAMA Oncol 2017;3:1051-8.DOIPubMedPMC
27. Yearley JH, Gibson C, Yu N, Moon C, Murphy E, Juco J, Lunceford J, Cheng J, Chow LQM, Seiwert TY, Handa M, Tomassini JE, McClanahan T. PD-L2 expression in human tumors: relevance to anti-PD-1 therapy in cancer. Clin Cancer Res 2017;23:3158-67.DOIPubMed
28. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, Chau I, Ernstoff MS, Gardner JM, Ginex P, Hallmeyer S, Holter Chakrabarty J, Leighl NB, Mammen JS, McDermott DF, Naing A, Nastoupil LJ, Phillips T, Porter LD, Puzanov I, Reichner CA, Santomasso BD, Seigel C, Spira A, Suarez-Almazor ME, Wang Y, Weber JS, Wolchok JD, Thompson JA; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Practice Guideline. J Clin Oncol 2018;36:1714-68.DOIPubMed
29. Puzanov I, Diab A, Abdallah K, Bingham CO, III, Brogdon Dadu CR, Hamad L, Kim S, Lacouture ME, LeBoeuf NR, Lenihan D, Onofrei C, Shannon V, Sharma R, Silk AW, Skondra D, Suarez-Almazor ME, Wang Y, Wiley K, Kaufman HL, Ernstoff MS, corresponding author and on behalf of the Society for Immunotherapy of Cancer Toxicity Management Working Group. Managing toxicities associated with immune checkpoint inhibitors: concensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017;5:95.DOIPubMedPMC
30. Minor DR, Chin K, Kashani-Sabet M. Infliximab in the treatment of anti-CTLA4 antibody (ipilumumab) induced immune-related colitis. Cancer Biother Radiopharm 2009;24:321-5.DOIPubMed
31. Menzies AM, Johnson DB, Ramanujam S, Atkinson VG, Wong ANM, Park JJ, McQuade JL, Shoushtari AN, Tsai KK, Eroglu Z, Klein O, Hassel JC, Sosman JA, Guminski A, Sullivan RJ, Ribas A, Carlino MS, Davies MA, Sandhu SK, Long GV. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol 2017;28:368-76.PubMed
32. Gutzmer R, Koop A, Meier F, Hassel JC, Terheyden P, Zimmer L, Heinzerling L, Ugurel S, Pföhler C, Gesierich A, Livingstone E, Satzger I, Kähler KC; German Dermatooncology Group (DeCOG). Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity. Eur J Cancer 2017;75:24-32.DOIPubMed
33. Abdel-Wahab N, Shah M, Lopez-Olivo MA, Suarez-Almazor ME. Use of immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoimmune disease: a systematic review. Ann Intern Med 2018;168:121-30.DOIPubMed
34. Kittai AS, Oldham H, Cetnar J, Taylor M. Immune checkpoint inhibitors in organ transplant patients. J Immunother 2017;40:277-81.DOI
35. Chae YK, Galvez C, Anker JF, Iams WT, Bhave M. Cancer immunotherapy in a neglected population: the current use and future of T-cell-mediated checkpoint inhibitors in organ transplant patients. Cancer Treat Rev 2018;63:116-21.DOIPubMed
Simone Anfossi et al., Cancer Drug Resistance, 2020
Development of a Functional Assessment of Chronic Illness Therapy item library and primary symptom list for the assessment of patient-reported adverse events associated with immune checkpoint modulators
Kimberly A. Webster et al., Journal of Cancer Metastasis and Treatment, 2020
Yuhao Wang et al., Cancer Drug Resistance, 2019
Jesus Rodriguez-Pascual et al., Cancer Drug Resistance, 2019
Yuanhong Sun et al., Journal of Cancer Metastasis and Treatment, 2019
Molly E. Heft Neal et al., Journal of Cancer Metastasis and Treatment, 2019
Shigehiro Yagishita et al., Journal of Cancer Metastasis and Treatment, 2019
Claudia Tulotta et al., Journal of Cancer Metastasis and Treatment, 2019
Thibault Gauduchon et al., Journal of Cancer Metastasis and Treatment, 2019
Leonardo G. da Fonseca et al., Hepatoma Research, 2019