Brunner, Cornelia

Doescher, Johannes

Hoffmann, Thomas K.

Laban, Simon

Schuler, Patrick J.

English

OPUS Augsburg

          Immunotherapy for head and neck cancers:an update and future perspectivesJohannes Doescher*,1, Simon Laban1, Patrick J Schuler1, Cornelia Brunner1 & Thomas KHoffmann11Department of Otorhinolaryngology, Head & Neck Surgery, University of Ulm, Frauensteige 12, 89075 Ulm, Germany*Author for correspondence: johannes.doescher@googlemail.com“cancer therapy approaches are changing as immunotherapeutic agents make their way intocurative treatment regimen and artificial intelligence is utilized in finding the optimal therapy foreach individual patient.”                                                                                                                                                             For a long time, there have been no innovative therapies available for head and neck squamous cell carcinoma(HNSCC). This changed with the emerging immunotherapeutic approaches of PD-1 and PD-L1 blockade and themultitude of clinical trials, which are recruiting at the moment. The following article aims to give an overview aboutrecent immunotherapeutic study results for the treatment of HNSCC and interesting running studies. Furthermore,the role of potential biomarkers is elucidated, and finally a look ahead into the future regarding machine learningis discussed.PD-1/PD-L1 axisBased on the success of basic immunology and the increasing insights of tumor escape mechanisms during the pastdecade, new promising therapeutic agents were developed with the goal to restore immunity against cancer cells.These new therapeutics include checkpoint inhibitors, like blockers of the PD-1/PD-L1 interaction. At ESMO2018, results of the Keynote-048 study were presented, showing a significant survival advantage for patients withrecurrent and/or metastatic (R/M) HNSCC and a positive PD-L1 expression (combined positive score [CPS]score ≥20 and also ≥1) treated with pembrolizumab versus standard of care (SOC) first-line therapy (cisplatin,5-FU and cetuximab = EXTREME). The CPS score is calculated by counting all PD-L1 positive cells (tumor andimmune) in relation to living tumor cells multiplied by 100 (see ‘Biomarkers’ section below). Opposed to the loweroverall response rate (ORR) of patients treated with pembrolizumab alone (23.3 vs 36.1% for EXTREME) standsthe favorable safety profile compared with the EXTREME regimen. Only 16.7% of the patients experienced agrade 3–5 toxicity compared with 69% in the EXTREME arm. Therefore, the authors propose a pembrolizumabmonotherapy as new first-line standard for R/M HNSCC with a CPS ≥ 1. Patients with low or negative PD-L1 expression can be treated with a combination of cisplatin, 5-FU and pembrolizumab as even in this studygroup the overall survival was not diminished as compared with EXTREME at the same safety profile and ORR(35.6 vs 36.3%) [1]. When looking at the duration of response (DOR) another conclusion could be made. In thetotal population, DOR for pembrolizumab alone was 20.9%, for pembrolizumab and chemotherapy 6.7% andfor EXTREME 4.3%. This shows that adding pembrolizumab to chemotherapy raises the DOR not as muchas pembrolizumab alone. Additionally, the progression-free survival could not be significantly prolonged evenin the CPS ≥ 20 cohort. Therefore, the real advantage of pembrolizumab may lie in the durable response andpembrolizumab alone could also be beneficial for PD-L1-negative patients.The importance of these results also lies in the implementation of a possible biomarker for response prediction,which is desperately needed regarding the high costs of immunotherapeutic agents and the limited ORR [2,3].Currently, most studies address possible combination therapies. To this end, immunotherapeutic agents, whichare effective in palliative settings, are combined with SOC approaches or with other immunotherapeutic drugs.                                             561                                            For reprint orders, please contact: reprints@futuremedicine.com                                                 One strategy persuaded within the SCORES study is the combination of durvalumab (anti-PD-L1) with so-called antisense oligonucleotides. In a previous Phase II study, an ORR of 9.2% (3.46–19.02%) for durvalumabmonotherapy was observed with a limited toxicity profile in patients with PD-L1 low or negative R/M HNSCC [4].To further increase the response rate, the combination of durvalumab and a STAT3 inhibitor and a CXCR2inhibitor is being explored. These inhibitors are antisense oligonucleotids which are constructed to inhibit proteinexpression at the mRNA level. First results of the study show a promising ORR of 23% for the combinationof durvalumab and danvatirsen (anti-Stat3) regardless of PD-L1 expression after first-line failure. Additionally,mechanistic observations of danvatirsen monotherapy revealed an increase of gene expression signatures associatedwith response to anti-PD-1 inhibitors and a decrease of immunosuppressive gene expression [5].Another combination comprises pembrolizumab and the intratumoral injection of SD-101, a synthetic olignu-cleotide, which has an agonistic effect on the Toll-like receptor 9 (TLR9) and so enhances antigen presentationby dendritic cells. In a Phase Ib/II study, 26 patients with R/M HNSCC were included. Patients with previousanti-PD-1/PD-L1 treatment were excluded. First results describe a good tolerability and an ORR of 30.4%, whichis almost double when looking at the ORR of pembrolizumab monotherapy in a similar setting in Keynote-040(14.6%) [6,7].The next step, which is currently under investigation, integrates anti-PD-1 drugs in curative treatment plans. Thefirst Phase III trial to mention is Keynote-412 (NCT03040999), which is approaching the final enrollment goal of780 patients. It is a two-armed, randomized, triple-blind design with concomitant administration of pembrolizumabversus placebo in a primary chemoradiotherapy scheme for advanced head and neck carcinoma. The primary endpoint is event-free survival and stratification follows radiotherapy regimen, p16 status and disease stage [8]. Asimilar study (Javelin) is recruiting patients for investigating the anti-PD-L1 antibody avelumab (NCT02952586).Additionally, there is a multitude of investigator-initiated trials (IIT) evaluating all sorts of combinations withanti-PD-1/PD-L1 and SOC. In case of surgical treatment, checkpoint inhibitors are given in a neoadjuvant as wellas an adjuvant setting. The IMSTAR HN trial (IIT, EudraCT 2016-004758-13) is currently recruiting patientswith locally advanced HNSCC. The three-armed design allows for randomization in either neoadjuvant nivolumab,followed by surgery, adjuvant SOC and nivolumab or nivolumab and ipilimumab versus surgery and adjuvant SOCalone.Other immune checkpoint targetsMonalizumab is a blocking antibody for the checkpoint receptor NKG2A, which is expressed on natural killer cellsand CD8+ T cells and is responsible for inhibiting the function of these cells by binding to its ligand, HLA-E.On human tumors, HLA-E is strongly expressed on HNSCC, which represents a suitable target for this kind ofimmunotherapy. Moreover, a combination of monalizumab and other checkpoint inhibitors as well as cetuximabwas seen to increase effectiveness of the treatment in preclinical models [9]. This led to a Phase II study for R/MHNSCC. Patients received 10 mg/kg monalizumab biweekly and cetuximab in standard dosing weekly. The ORRwas 27.5% with a median overall survival of 10.3 months. One patient even had a complete response, whereas25% had a partial response and 55% resulted in stable disease. The combination was well tolerated without anymultiplication of cetuximab-related adverse events. Of special value is the pretreatment of the patients in this study,because almost half had received anti-PD-1 treatment beforehand [10].OX-40 is a costimulatory receptor on B and T cells and its activation can lead to autoimmunity but also to abetter immune response toward cancer cells [11]. However, there are only very few studies recruiting patients at themoment. In a neoadjuvant approach, before surgery, an anti-OX-40 antibody (MEDI6469) was tested in a PhaseIb study and first results were presented at ASCO 2018 [12]. Patients received the drug by infusion on day 1, days3–4 and days 5–6 and underwent surgery either 2 days, 1 or 2 weeks after the last dose of anti-OX-40. The highestactivation of T cells could be found after 2 weeks from the last dose. The administration was well tolerated with nograde 3 or 4 adverse events. No pathological response could be observed. Therefore, the same authors are recruitingfor a similar study with another anti-OX-40 antibody (MEDI0562). In this study, all patients received surgery after2 weeks from the last anti-OX-40 infusion but in two different administration plans (NCT03336606). Results areexpected no earlier as 2022.Another costimulatory receptor is CD137 or 4-1BB, which is mainly found on activated CD8+ T cells.Despite its downregulation in HNSCC patients [13], synergistic effects of anti-CD137 antibody and cisplatin-basedchemoradiotherapy in a HNSCC mouse model have been observed [14]. These data and promising results of aPhase I study with a combination of the 4-1BB agonist utomilumab and pembrolizumab with an ORR of 26.1%562                                                                                     including a partial response of a HNSCC patient lead to the design of a Phase II study for incurable HPV+oropharyngeal squamous cell carcinoma (NCT03258008) [15]. In this study, utomilumab is combined with asubcutaneous injection of ISA101b, an E6/E7 vaccine with promising results in a combination with nivolumabfor HPV+ cancers of all locations (ORR: 33%) [16].BiomarkersThe search for suitable biomarkers has been one of the central issues in the research community and a variety ofapproaches have been published. For anti-PD-1 and anti PD-L1 treatment, the analysis of PD-L1 expression is theonly approach which has made it into the routine diagnostic. For pembrolizumab, the determination of PD-L1expression is compulsory before clinical application. For the determination of PD-L1 expression, two algorithmshave been suggested so far: the CPS calculates all PD-L1 positive cells relatively to living tumor cells. The tumorpositive score is easier to assess and describes the percentage of all viable tumor cells with positive PD-L1 membranestaining. The CPS, however, is more precise as it includes patients with low PD-L1 expression on tumor cellsbut a relevant expression on antigen-presenting cells. PD-L1 expression on this immune cell subset was found tobe the major predictor of anti-PD1/PD-L1 therapy in a mouse model and human study of ovarian cancer andmelanoma [17]. However, the used antibodies are different to the ones used in the large clinical trials and a recentcomparison of different PD-L1 antibodies and evaluation algorithms shows huge differences. Four, in clinicalstudies commonly used, immunohistochemistry antibodies were tested: VENTANA PD-L1 (SP263), VENTANAPD-L1 (SP142), PD-L1 IHC pharmDx 22C3 (Agilent) and PD-L1 IHC pharmDx 28-8 (Agilent). All stainingswere evaluated using tumor cell, immune cell and CPS scoring methods. The authors found great differences inidentifying PD-L1 positive patients when using other evaluation algorithms as the corresponding method for eachassay and conclude that these assays should not be interchanged. Additionally, one should be careful in interpretingeffectiveness measurements for one or the other anti-PD-1/PD-L1 treatment when patient groups are stratified bya specific PD-L1 assay and its corresponding scoring algorithm [18]. This might be very challenging for pathologistsas they have to invest in a new staining system, if the antibody is restricted to a particular one, and learn to use thedifferent algorithms depending on the suggested anti-PD1/PD-L1 drug for the patient. Therefore, harmonizingprojects for PD-L1 testing are desirable.In the future, the impact of machine learning or artificial intelligence will not be neglectable. There are alreadyalgorithms under development that help to immunoprofile tumors by analyzing known parameters, but also bydiscovering new prognostic and predictive parameters [19]. In this context, the project BD2Decide for a personalizedhead and neck cancer decision support has to be mentioned. The aim is to establish big data models in a jointventure of 12 European institutions [20]. These developments show that cancer therapy approaches are changing asimmunotherapeutic agents make their way into curative treatment regimen and artificial intelligence is utilized infinding the optimal therapy for each individual patient.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or finan-cial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria,stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Conflict of interestS Laban advisory board for Astra-Zeneca (AZ), Merck Sharp & Dohme (MSD); S Laban and PJ Schuler speaking fees from Bristol-Myers Squibb (BMS), Merck Serono, MSD; PJ Schuler advisory board for BMS; TK Hoffmann advisory board for BMS, MSD andMerck.References1. Burtness B, Harrington KJ, Greil R et al. KEYNOTE-048: Phase III study of first-line pembrolizumab (P) for recurrent/metastatic headand neck squamous cell carcinoma (R/M HNSCC). Ann. Oncol. 29(Suppl 8), (2018).2. Hirschmann A, Lupatsch JEE, Schwenkglenks M et al. Cost-effectiveness of nivolumab in the treatment of head and neck cancer. OralOncol. 87(October), 104–110 (2018).3. Hoffmann TK, Schuler PJ, Laban S et al. Response evaluation in head and neck oncology: definition and prediction. ORL J.Otorhinolaryngol. Relat. Spec. 79(1–2), 14–23 (2017).                                        563                                                 4. Siu LL, Even C, Meśıa R et al. Safety and efficacy of durvalumab with or without tremelimumab in patients with PD-L1–low/negativerecurrent or metastatic HNSCC. JAMA Oncol. 5(2), 195–203 (2018).5. Cohen EEW, Harrington KJ, Hong DS et al. A Phase Ib/II study (SCORES) of durvalumab (D) plus danvatirsen (DAN; AZD9150) orAZD5069 (CX2i) in advanced solid malignancies and recurrent/metastatic head and neck squamous cell carcinoma (RM-HNSCC):updated results. Ann. Oncol. 29(suppl 8), (2018).6. Cohen EEW, Soulières D, Le Tourneau C et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatichead-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, Phase IIIstudy. Lancet 393(10167), 156–167 (2018).7. Cohen EEW, Algazi A, Laux D et al. Phase Ib/II, open label, multicenter study of intratumoral SD-101 in combination withpembrolizumab in anti-PD-1 treatment naı̈ve patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).Ann. Oncol. 29(Suppl 8), (2018).8. Machiels J-P, Licitra L, Tao YG et al. KEYNOTE-412: Phase III study of pembrolizumab plus chemoradiation vs chemoradiation alonefor locally advanced head and neck squamous cell carcinoma (HNSCC). Ann. Oncol. 29(Suppl 8), (2018).9. André P, Denis C, Soulas C et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing bothT and NK cells. Cell. 175(7), 1731–1743.e13 (2018).10. Fayette J, Lefebvre G, Posner MR et al. Results of a Phase II study evaluating monalizumab in combination with cetuximab in previouslytreated recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Ann. Oncol. 29(Suppl 8), (2018).11. Croft M, So T, Duan W, Soroosh P. The significance of OX40 and OX40L to T cell biology and immune disease. Immunol.Rev. 229(1), 173–191 (2009).12. Bell RB, Duhen R, Leidner RS et al. Neoadjuvant anti-OX40 (MEDI6469) prior to surgery in head and neck squamous cell carcinoma.J. Clin. Oncol. 36(15 Suppl), 6011 (2018).13. Baruah P, Lee M, Odutoye T et al. Decreased levels of alternative co-stimulatory receptors OX40 and 4-1BB characterise T cells fromhead and neck cancer patients. Immunobiology 217(7), 669–675 (2012).14. Lucido CT, Vermeer PD, Wieking BG, Vermeer DW, Lee JH. CD137 enhancement of HPV positive head and neck squamous cellcarcinoma tumor clearance. Vaccines (Basel) 2(4), 841–853 (2014).15. Tolcher AW, Sznol M, Hu-Lieskovan S et al. Phase Ib study of utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in combinationwith pembrolizumab (MK-3475) in patients with advanced solid tumors. Clin. Cancer Res. 23(18), 5349–5357 (2017).16. Massarelli E, William W, Johnson F et al. Combining immune checkpoint blockade and tumor-specific vaccine for patients withincurable human papillomavirus 16-related cancer: a Phase 2 clinical trial. JAMA Oncol. 77030(1), 1–8 (2018).17. Lin H, Wei S, Hurt EM et al. Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression. J.Clin. Invest. 128(2), 805–815 (2018).18. Scott M, Wildsmith S, Ratcliffe M et al. Comparison of patient populations identified by different PD-L1 assays in head and necksquamous cell carcinoma (HNSCC). Ann. Oncol. 29(suppl 8), (2018).19. Koelzer VH, Sirinukunwattana K, Rittscher J, Mertz KD. Precision immunoprofiling by image analysis and artificial intelligence.Virchows Arch. 1–12 (2018).20. BD2Decide (2018). www.bd2decide.eu/content/home564                                           

Immunotherapy for head and neck cancers: an update and future perspectives

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Immunotherapy for head and neck cancers: an update and future perspectives

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