Pembrolizumab as a first line therapy in a patient with extensive Mucoepidermoid salivary gland carcinoma. A complete clinical, radiological and pathological response. A very specific case

Pembrolizumab as a first line therapy in a patient with extensive Mucoepidermoid salivary gland carcinoma. A complete clinical, radiological and pathological response. A very specific case | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Pembrolizumab as a first line therapy in a patient with extensive Mucoepidermoid salivary gland carcinoma. A complete clinical, radiological and pathological response. A very specific case Raed Farhat, Noam Asna, Yaniv Avraham, Ashraf Khater, Majd Asakla, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1433947/v2 This work is licensed under a CC BY 4.0 License Status: Under Review Version 2 posted 8 You are reading this latest preprint version Show more versions Abstract Background: Patients with advanced salivary gland malignancies (SGCs) have few therapy options. Although results from newly published trials suggest that checkpoint inhibition may be useful in a subgroup of patients, there are no clear criteria for PD-L1 score in SGCs. Chemotherapy benefits were observed to be limited, with a dismal prognosis in unresectable and high-grade SGC. Immunotherapies have demonstrated extraordinary efficacy in a variety of cancers, including non-small cell lung cancer and malignant melanoma. Anti-PD-1 antibody pembrolizumab has been shown to have potent anti-tumor action in a number of clinical trials. Case presentation: We report a unique case of advanced high grade mucoepidermoid carcinoma of the parotid salivary gland after Pembrolizumab treatment as a first line therapy. The tumor was downstaged as a result of the pembrolizumab treatment, allowing for a successful surgical excision with no facial nerve sacrifice and no major neoadjuvant treatment adverse effects, and the final specimen pathology was tumor-free. In these types of malignancies, a similar technique resulted in a complete response (CR) radiologically and pathologically has never been discussed before. Conclusions: In pretreated patients with high-grade salivary gland mucoepidermoid carcinoma, pembrolizumab showed good anticancer activity and provided a clinically, radiologically, and pathological response with a viable treatment choice. More research is needed to bring Pembrolizumab to the front-line of treatment. The time and duration of medication should be compared to the time required for surgery in these investigations. Pembrolizumab salivary gland cancers (SGCs): immunotherapy complete response (CR). Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Salivary gland carcinoma (SGC) is a rare disease that accounts for just 6% of all head and neck cancers 1 . Surgical excision with or without postoperative adjuvant radiation therapy is the curative treatment for most histological subtypes 2,3,4 . Mucoepidermoid carcinoma (MEC) is a malignant tumor that primarily arises from the salivary glands; In minor salivary gland malignancies, MEC most commonly is found 5 . In both children and adults, MEC is the most common malignant salivary gland tumor 6 . In extremely aggressive subtypes such salivary duct carcinomas, adjuvant treatment options such as chemotherapy or radiation had no discernible effect on survival 7 . Patients with unresectable primaries/recurrences or patients with distant metastasis 2 have no standard treatment or demonstrated efficacy. Chemotherapies such as cisplatin, doxorubicin, and cyclophosphamide have been documented to have modest benefit, with a poor prognosis 2,9,10 . Immunotherapies have demonstrated extraordinary efficacy in a variety of cancers, including non-small cell lung cancer and malignant melanoma. All of these treatments work in the same way, by guiding the body's own immune system to eliminate tumor cells 11,12 . Pembrolizumab is a monoclonal antibody this is absolutely humanized immunoglobulin G4/anti-PD-1. Pembrolizumab has proven sturdy antitumor pastime and a positive protection profile in a lot of tumor types, and it's far presently authorized in extra than 60 nations for 1 or extra superior malignancies, which includes recurrent or metastatic head and neck squamous carcinoma that advanced on or after platinum-primarily based totally chemotherapy withinside the United States 13,14,15 . With the inclusion of immunotherapy, either alone or in combination with chemotherapy, the newly released KEYNOTE-048 trial established a new standard in this situation 16 . This article reports a unique case of unresectable advanced high grade mucoepidermoid carcinoma of the salivary gland with complete response after Pembrolizumab treatment as a first line therapy. A similar strategy has never been tried in high grade salivary gland tumors, and complete radiological and pathological responses have never been reported before in this kind of tumors. This treatment resulted in downstaging of the tumor and led to its successful surgical resection. Case Presentation A 68-year-old male, diabetic with a forty pack-year smoking history presented with an enlarging left, slightly tender, rapidly progressive swelling of the left parotid gland during the previous 6 months before our first examination. The patient was referred to head and neck clinic, Department of Otolaryngology Head and Neck Surgery, Ziv Medical Center in Safed, in the north of Israel. Physical examination showed a firm, immobile, slightly tender, 3 × 3 cm left parotid mass with overlying skin change (Fig. 1) , with multiple hard, immobile lymph nodes, 3 * 2 cm, at level II,III,V of the left neck, the remainder of the head and neck examination was unremarkable. Flexible nasendoscopy findings of the nasopharynx, oropharynx, and larynx were unremarkable. Fine needle aspiration (FNA) of the left parotid mass was consistent with positive malignant cells for high grade mucoepidermoid carcinoma with mitosis. Contrast-enhanced magnetic resonance imaging (MRI) revealed a lobulated, irregular mass, 37*39*47 mm located in the posteroinferior segment of the superficial and deep lobe in the left parotid gland, with areas of extensive central necrosis, septation, and peripheral wall enhancement contiguous with the anterior portion of external auditory canal and SCM muscle with subcutaneous tissue and skin involvement, several nodules in the left infraparotid area and level II were calcified (Fig. 2). The 18F-FDG PET/CT revealed hypermetabolic activity within the mass in the left parotid gland with involvement of the skin, SCM muscle and several nodules in the left infraparotid area and level II,III in the left neck (Fig. 3). The final diagnosis was clinical stage IV (T4aN2bM0). The patient was considered as high-grade MECs which progressed rapidly and caused pain, soft tissue invasion; these MECs are associated with poor overall survival, which approaches 40–50% at 5 years, and with an increased risk for locoregional and distant failures 17,18,19 . The recommended therapy for high-grade MECs includes surgical resection with selective neck dissection followed by adjuvant radiotherapy 20 . In our case, the high morbidity and mortality associated with the need of extensive surgical resection with free flap reconstruction and the massive loss of tissue with possible facial nerve sacrifice, in addition to increased risk for locoregional and distant failures led us to think about neoadjuvant treatment. Pembrolizumab monotherapy was generally well tolerated in advanced Salivary Gland Carcinoma (SGC), with a safety profile that reflects previous experience of pembrolizumab in patients with advanced cancers 21 . Treatment plan was made by a multidisciplinary team and after multiple discussions with the goal of maximizing survival with preservation of form and function. Our patient received pembrolizumab intravenously at 200 mg every 2 weeks, with a good compliance. From September 2021 to November 2021, he underwent 2 cycles of pembrolizumab with no side effects. The MRI scan after 3 cycles revealed a significant decrease in the tumor or even its disappearance and on follow-up, the patient had attained a complete remission in the clinic examination (Fig. 4,5). Restaging with 18FDG PET-CT at 6 weeks after completion of immunologic treatment demonstrated a full resolution of the parotid gland metabolic activity. In the left neck, the nodal status had generally improved with no signs of hypermetabolic activity. High metabolic uptake was not seen elsewhere. (Fig. 6 ). As a precaution, left parotidectomy and unilateral neck dissection levels I,II,III,IV were recommended for locoregional control and because of remaining morphological masses on ct. (Fig. 7). All the 18FDG PET-CT scans performed are summarized in (Fig. 8 ). Final pathological results showed no evidence of carcinoma neither in the parotid gland nor in the neck lymph nodes and had free margins . The patient has continued to be supervised with CT scans and serum tumor marker measurements every 3 or 4 months and is still in complete remission at this time. Discussion This is the first report that describes complete resolution of high grade malignant salivary gland mucoepidermoid carcinoma with Pembrolizumab as a “first line” therapy treatment. Cohen et al 21 published the results of the phase Ib KEYNOTE-28 study, which used a single-agent pembrolizumab 10 mg/kg once every two weeks in 38 PDL1-expressing recurrent-metastatic salivary gland carcinomas. The majority of the included subjects had adenocarcinomas, and there was no evidence of progression prior to participation in this trial. Three of the 38 individuals enrolled had a Partial Response (PR), with an overall response rate of 12% and a median response duration of three months. There were no replies indicating complete remission. There is no gold standard for the treatment of advanced SGC, and present medicines are often ineffective. Small studies, many of which were completed before present analytical concepts (e.g., RECIST) 22 , are available to support the use of classical cytotoxic chemotherapy. Small phase I and II clinical trials, again with heterogeneous histologies and variances in design and eligibility for such treatment, make up the prospective experience with antiPD1 checkpoint inhibitors in salivary gland carcinomas. Although pembrolizumab has a primary site agnostic approval from the US Food and Drug Administration for mismatch repair–deficient cancers, it is crucial to highlight that this was based on a nine-patient cohort of non-colorectal cancer patients with no salivary gland malignancies23,24. In SGCs, the role of tumor mutation burden (TMB) is unknown. The KEYNOTE-158 trial's TMB subgroup analysis resulted to the approval of pembrolizumab as an agnostic therapy for patients with TMB > 10 mut/Mb. Three patients with salivary histology and elevated TMB were treated, with one of them achieving a partial response 23 . Although the current data from salivary gland malignancies trials are limited, our result in using Pembrolizumab as a first line agent in advanced high grade mucoepidermoid carcinoma suggests that this treatment remains a promising cancer therapy . More study is needed to assess Pembrolizumab's efficacy in front-line and maintenance settings, as well as trials of combinations with chemotherapy, radiation, or other immune checkpoints. Conclusion In conclusion, Pembrolizumab has demonstrated a promising antitumor activity in pre-treated patients with high grade salivary gland mucoepidermoid carcinoma, and offered a clinically, radiological and pathological response with a meaningful therapeutic option. Further studies that move the treatment of Pembrolizumab to front-line, maintenance settings and combinations with other treatment methods are necessary. These studies should include the time and duration of the pharmacotherapy in relation to the needed time of surgery. Side effects of the drugs should also be followed as well as patient compliance. Declarations Author contribution: Conceptualization: Raed Farhat, Shlomo Merchavy Data curation: Raed Farhat, Nidal Elkhatib. Formal analysis: Raed Farhat, Ashraf Khater,Majd Asakla,Alaa Safia. Investigation: Raed Farhat , Shlomo Merchavy Supervision: Shlomo Merchavy, Noam Asna. Validation: Shlomo Merchavy, Yaniv Avraham Visualization: Raed Farhat , Shlomo Merchavy Writing-original draft: Raed Farhat Writing-review & editing: Raed Farhat, Shlomo Merchavy Type of Manuscript: Case Report . Acknowledgments: we would like to thank the entire department of Otolaryngology head and neck surgery and Oncology Department for their help and support. Conflicts of interest statement and funding: None References Carvalho AL, Nishimoto IN, Califano JA, Kowalski LP. Trends in incidence and prognosis for head and neck cancer in the United States: a sitespecific analysis of the SEER database. Int J Cancer. (2005) 114:806–16. doi: 10.1002/ijc.20740 Mukaigawa, T. et al. Programmed death ligand-1 expression is associated with poor disease free survival in salivary gland carcinomas. J Surg Oncol 114, 36–43, https://doi.org/10.1002/jso.24266 (2016). Garden, A. S. et al. Postoperative radiotherapy for malignant tumors of the parotid gland. Int J Radiat Oncol Biol Phys 37, 79–85 (1997). Terhaard, C. H. et al. The role of radiotherapy in the treatment of malignant salivary gland tumors. Int J Radiat Oncol Biol Phys 61, 103–111, https://doi.org/10.1016/j.ijrobp.2004.03.018 (2005). Strutz J and Mann WJ: Praxis der HNO-Heilkunde. Thieme, Stuttgart, p. 579, 2009. Goode RK and El-Naggar AK: Mucoepidermoid carcinoma (Head and Neck). In: Barnes L, Eveson JW, Reichart P and Sidransky D (eds.): Pathology and genetics of Head and Neck Tumours. World Health Organization Classification of Tumours. IARC Press, Lyon, pp. 219-222, 2005. Osborn, V. et al. Characterization, treatment and outcomes of salivary ductal carcinoma using the National Cancer Database. Oral Oncol 71, 41–46, https://doi.org/10.1016/j.oraloncology.2017.05.005 (2017). Sridharan, V. et al. 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PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control 21, 231–237 (2014). Merck Sharp & Dohme Corp. Keytrudas (Pembrolizumab) injection, for Intravenous Use. Whitehouse Station, NJ: Merck Sharp & Dohme Corp., 2017. Chow LQM, Haddad R, Gupta S, et al. 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. 2016,34:3838–3845. Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an openlabel, multicentre, phase 1b trial. Lancet Oncol. 2016,17:956–965. Burtness, B., Harrington, K.J., Greil, R., Soulières, D., Tahara, M., de Castro, G., Psyrri, A., Basté, N., Neupane, P., Bratland, A., et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or meta-static squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study. Lancet 2019, 394, 1915–1928. [CrossRef] McHughCH, RobertsDB, El-NaggarAK, et al: Prognostic factors in mucoepidermoid carcinoma of the salivary glands. Cancer 118:3928-3936, 2012. ChenAM, LauVH, FarwellDG, et al: Mucoepidermoid carcinoma of the parotid gland treated by surgery and postoperative radiation therapy: Clinicopathologic correlates of outcome. Laryngoscope 123:3049-3055, 2013. BrandweinMS, IvanovK, WallaceDI, et al: Mucoepidermoid carcinoma: A clinicopathologic study of 80 patients with special reference to histological grading. Am J Surg Pathol 25:835-845, 2001Crossref,Medline,Google Scholar National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf (Accessed on January 04, 2021). Cohen, R., Delord, J., Doi, T., Piha-Paul, S., Liu, S., Gilbert, J., Algazi, A., Damian, S., Hong, R., Le Tourneau, C., Day, D., Varga, A., Elez, E., Wallmark, J., Saraf, S., Thanigaimani, P., Cheng, J. and Keam, B., 2021. Pembrolizumab for the Treatment of Advanced Salivary Gland Carcinoma . Laurie SA, Licitra L. Systemic therapy in the palliative management of advanced salivary gland cancers. J Clin Oncol. 2006,24: 2673–2678. Marabelle A, Fakih M, Lopez J, et al: Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: Prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 21:1353-1365, 2020 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 2 posted Editorial decision: Major revision 31 Mar, 2022 Editor assigned by journal 28 Mar, 2022 Reviews received at journal 28 Mar, 2022 Reviewers agreed at journal 28 Mar, 2022 Reviewers invited by journal 28 Mar, 2022 Editor invited by journal 28 Mar, 2022 Submission checks completed at journal 28 Mar, 2022 First submitted to journal 25 Mar, 2022 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1433947","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[{"code":1,"date":"2022-03-11 18:11:24","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research 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A complete clinical, radiological and pathological response. A very specific case","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSalivary gland carcinoma (SGC) is a rare disease that accounts for just 6% of all head and neck cancers\u003csup\u003e1\u003c/sup\u003e. Surgical excision with or without postoperative adjuvant radiation therapy is the curative treatment for most histological subtypes\u003csup\u003e2,3,4\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMucoepidermoid carcinoma (MEC) is a malignant tumor that primarily arises from the salivary glands; In minor salivary gland malignancies, MEC most commonly is found\u003csup\u003e5\u003c/sup\u003e. In both children and adults, MEC is the most common malignant salivary gland tumor\u003csup\u003e6\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn extremely aggressive subtypes such salivary duct carcinomas, adjuvant treatment options such as chemotherapy or radiation had no discernible effect on survival\u003csup\u003e7\u003c/sup\u003e. Patients with unresectable primaries/recurrences or patients with distant metastasis\u003csup\u003e2\u003c/sup\u003e have no standard treatment or demonstrated efficacy. Chemotherapies such as cisplatin, doxorubicin, and cyclophosphamide have been documented to have modest benefit, with a poor prognosis\u003csup\u003e2,9,10\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eImmunotherapies have demonstrated extraordinary efficacy in a variety of cancers, including non-small cell lung cancer and malignant melanoma. All of these treatments work in the same way, by guiding the body's own immune system to eliminate tumor cells\u003csup\u003e11,12\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePembrolizumab is a monoclonal antibody this is absolutely humanized immunoglobulin G4/anti-PD-1. Pembrolizumab has proven sturdy antitumor pastime and a positive protection profile in a lot of tumor types, and it's far presently authorized in extra than 60 nations for 1 or extra superior malignancies, which includes recurrent or metastatic head and neck squamous carcinoma that advanced on or after platinum-primarily based totally chemotherapy withinside the United States\u003csup\u003e13,14,15\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWith the inclusion of immunotherapy, either alone or in combination with chemotherapy, the newly released KEYNOTE-048 trial established a new standard in this situation\u003csup\u003e16\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis article reports a unique case of unresectable advanced high grade mucoepidermoid carcinoma of the salivary gland with complete response after Pembrolizumab treatment as a first line therapy. A similar strategy has never been tried in high grade salivary gland tumors, and complete radiological and pathological responses have never been reported before in this kind of tumors.\u003c/p\u003e \u003cp\u003eThis treatment resulted in downstaging of the tumor and led to its successful surgical resection.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 68-year-old male, diabetic with a forty pack-year smoking history presented with an enlarging left, slightly tender, rapidly progressive swelling of the left parotid gland during the previous 6 months before our first examination. The patient was referred to head and neck clinic, Department of Otolaryngology Head and Neck Surgery, Ziv Medical Center in Safed, in the north of Israel.\u003c/p\u003e \u003cp\u003ePhysical examination showed a firm, immobile, slightly tender, 3 \u0026times; 3 cm left parotid mass with overlying skin change \u003cb\u003e(Fig.\u0026nbsp;1)\u003c/b\u003e, with multiple hard, immobile lymph nodes, 3 * 2 cm, at level II,III,V of the left neck, the remainder of the head and neck examination was unremarkable. Flexible nasendoscopy findings of the nasopharynx, oropharynx, and larynx were unremarkable.\u003c/p\u003e \u003cp\u003eFine needle aspiration (FNA) of the left parotid mass was consistent with positive malignant cells for high grade mucoepidermoid carcinoma with mitosis.\u003c/p\u003e \u003cp\u003eContrast-enhanced magnetic resonance imaging (MRI) revealed a lobulated, irregular mass, 37*39*47 mm located in the posteroinferior segment of the superficial and deep lobe in the left parotid gland, with areas of extensive central necrosis, septation, and peripheral wall enhancement contiguous with the anterior portion of external auditory canal and SCM muscle with subcutaneous tissue and skin involvement, several nodules in the left infraparotid area and level II were calcified \u003cb\u003e(Fig.\u0026nbsp;2).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe 18F-FDG PET/CT revealed hypermetabolic activity within the mass in the left parotid gland with involvement of the skin, SCM muscle and several nodules in the left infraparotid area and level II,III in the left neck \u003cb\u003e(Fig.\u0026nbsp;3).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe final diagnosis was clinical stage IV (T4aN2bM0).\u003c/p\u003e \u003cp\u003eThe patient was considered as high-grade MECs which progressed rapidly and caused pain, soft tissue invasion; these MECs are associated with poor overall survival, which approaches 40\u0026ndash;50% at 5 years, and with an increased risk for locoregional and distant failures\u003csup\u003e17,18,19\u003c/sup\u003e .\u003c/p\u003e \u003cp\u003eThe recommended therapy for high-grade MECs includes surgical resection with selective neck dissection followed by adjuvant radiotherapy \u003csup\u003e20\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn our case, the high morbidity and mortality associated with the need of extensive surgical resection with free flap reconstruction and the massive loss of tissue with possible facial nerve sacrifice, in addition to increased risk for locoregional and distant failures led us to think about neoadjuvant treatment.\u003c/p\u003e \u003cp\u003ePembrolizumab monotherapy was generally well tolerated in advanced Salivary Gland Carcinoma (SGC), with a safety profile that reflects previous experience of pembrolizumab in patients with advanced cancers\u003csup\u003e21\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTreatment plan was made by a multidisciplinary team and after multiple discussions with the goal of maximizing survival with preservation of form and function.\u003c/p\u003e \u003cp\u003eOur patient received pembrolizumab intravenously at 200 mg every 2 weeks, with a good compliance.\u003c/p\u003e \u003cp\u003eFrom September 2021 to November 2021, he underwent 2 cycles of pembrolizumab with no side effects.\u003c/p\u003e \u003cp\u003eThe MRI scan after 3 cycles revealed a significant decrease in the tumor or even its disappearance and on follow-up, the patient had attained a complete remission in the clinic examination \u003cb\u003e(Fig.\u0026nbsp;4,5).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eRestaging with 18FDG PET-CT at 6 weeks after completion of immunologic treatment demonstrated a full resolution of the parotid gland metabolic activity. In the left neck, the nodal status had generally improved with no signs of hypermetabolic activity. High metabolic uptake was not seen elsewhere. \u003cb\u003e(Fig.\u0026nbsp;6 ).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAs a precaution, left parotidectomy and unilateral neck dissection levels I,II,III,IV were recommended for locoregional control and because of remaining morphological masses on ct. \u003cb\u003e(Fig.\u0026nbsp;7).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAll the 18FDG PET-CT scans performed are summarized in (Fig.\u0026nbsp;8\u003cb\u003e).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eFinal pathological results showed no evidence of carcinoma neither in the parotid gland nor in the neck lymph nodes and had free margins .\u003c/p\u003e \u003cp\u003eThe patient has continued to be supervised with CT scans and serum tumor marker measurements every 3 or 4 months and is still in complete remission at this time.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first report that describes complete resolution of high grade malignant salivary gland mucoepidermoid carcinoma with Pembrolizumab as a \u0026ldquo;first line\u0026rdquo; therapy treatment.\u003c/p\u003e \u003cp\u003eCohen et al \u003csup\u003e21\u003c/sup\u003e published the results of the phase Ib KEYNOTE-28 study, which used a single-agent pembrolizumab 10 mg/kg once every two weeks in 38 PDL1-expressing recurrent-metastatic salivary gland carcinomas. The majority of the included subjects had adenocarcinomas, and there was no evidence of progression prior to participation in this trial. Three of the 38 individuals enrolled had a Partial Response (PR), with an overall response rate of 12% and a median response duration of three months. There were no replies indicating complete remission.\u003c/p\u003e \u003cp\u003eThere is no gold standard for the treatment of advanced SGC, and present medicines are often ineffective. Small studies, many of which were completed before present analytical concepts (e.g., RECIST)\u003csup\u003e22\u003c/sup\u003e, are available to support the use of classical cytotoxic chemotherapy.\u003c/p\u003e \u003cp\u003eSmall phase I and II clinical trials, again with heterogeneous histologies and variances in design and eligibility for such treatment, make up the prospective experience with antiPD1 checkpoint inhibitors in salivary gland carcinomas.\u003c/p\u003e \u003cp\u003e Although pembrolizumab has a primary site agnostic approval from the US Food and Drug Administration for mismatch repair\u0026ndash;deficient cancers, it is crucial to highlight that this was based on a nine-patient cohort of non-colorectal cancer patients with no salivary gland malignancies23,24.\u003c/p\u003e \u003cp\u003eIn SGCs, the role of tumor mutation burden (TMB) is unknown. The KEYNOTE-158 trial's TMB subgroup analysis resulted to the approval of pembrolizumab as an agnostic therapy for patients with TMB\u0026thinsp;\u0026gt;\u0026thinsp;10 mut/Mb. Three patients with salivary histology and elevated TMB were treated, with one of them achieving a partial response\u003csup\u003e23\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAlthough the current data from salivary gland malignancies trials are limited, our result in using Pembrolizumab as a first line agent in advanced high grade mucoepidermoid carcinoma suggests that this treatment remains a promising cancer therapy .\u003c/p\u003e \u003cp\u003eMore study is needed to assess Pembrolizumab's efficacy in front-line and maintenance settings, as well as trials of combinations with chemotherapy, radiation, or other immune checkpoints.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, Pembrolizumab has demonstrated a promising antitumor activity in pre-treated patients with high grade salivary gland mucoepidermoid carcinoma, and offered a clinically, radiological and pathological response with a meaningful therapeutic option.\u003c/p\u003e \u003cp\u003eFurther studies that move the treatment of Pembrolizumab to front-line, maintenance settings and combinations with other treatment methods are necessary. These studies should include the time and duration of the pharmacotherapy in relation to the needed time of surgery. Side effects of the drugs should also be followed as well as patient compliance.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contribution:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConceptualization:\u003c/strong\u003e Raed Farhat, Shlomo Merchavy\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eData curation:\u0026nbsp;\u003c/strong\u003eRaed Farhat,\u003cem\u003e\u0026nbsp;\u003c/em\u003eNidal Elkhatib.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eFormal analysis:\u0026nbsp;\u003c/strong\u003eRaed Farhat,\u003cem\u003e\u0026nbsp;\u003c/em\u003eAshraf Khater,Majd Asakla,Alaa Safia.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eInvestigation:\u0026nbsp;\u003c/strong\u003eRaed Farhat\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003eShlomo Merchavy\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSupervision:\u0026nbsp;\u003c/strong\u003eShlomo Merchavy, Noam Asna.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eValidation:\u0026nbsp;\u003c/strong\u003eShlomo Merchavy, Yaniv Avraham\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eVisualization:\u0026nbsp;\u003c/strong\u003eRaed Farhat\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003eShlomo Merchavy\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eWriting-original draft:\u0026nbsp;\u003c/strong\u003eRaed Farhat\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eWriting-review \u0026amp; editing: Raed Farhat,\u0026nbsp;\u003c/strong\u003eShlomo Merchavy\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eType of Manuscript:\u0026nbsp;\u003c/strong\u003eCase Report .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments: \u0026nbsp;\u003c/strong\u003ewe would like to thank the entire department of Otolaryngology head and neck surgery and Oncology Department for their help and support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest statement and funding:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCarvalho AL, Nishimoto IN, Califano JA, Kowalski LP. Trends in incidence and prognosis for head and neck cancer in the United States: a sitespecific analysis of the SEER database. Int J Cancer. (2005) 114:806\u0026ndash;16. doi: 10.1002/ijc.20740\u003c/li\u003e\n\u003cli\u003eMukaigawa, T. et al. Programmed death ligand-1 expression is associated with poor disease free survival in salivary gland carcinomas. J Surg Oncol 114, 36\u0026ndash;43, https://doi.org/10.1002/jso.24266 (2016).\u003c/li\u003e\n\u003cli\u003eGarden, A. S. et al. Postoperative radiotherapy for malignant tumors of the parotid gland. Int J Radiat Oncol Biol Phys 37, 79\u0026ndash;85 (1997).\u003c/li\u003e\n\u003cli\u003eTerhaard, C. H. et al. The role of radiotherapy in the treatment of malignant salivary gland tumors. Int J Radiat Oncol Biol Phys 61, 103\u0026ndash;111, https://doi.org/10.1016/j.ijrobp.2004.03.018 (2005).\u003c/li\u003e\n\u003cli\u003eStrutz J and Mann WJ: Praxis der HNO-Heilkunde. Thieme, Stuttgart, p. 579, 2009.\u003c/li\u003e\n\u003cli\u003eGoode RK and El-Naggar AK: Mucoepidermoid carcinoma (Head and Neck). In: Barnes L, Eveson JW, Reichart P and Sidransky D (eds.): Pathology and genetics of Head and Neck Tumours. World Health Organization Classification of Tumours. IARC Press, Lyon, pp. 219-222, 2005.\u003c/li\u003e\n\u003cli\u003eOsborn, V. et al. Characterization, treatment and outcomes of salivary ductal carcinoma using the National Cancer Database. Oral Oncol 71, 41\u0026ndash;46, https://doi.org/10.1016/j.oraloncology.2017.05.005 (2017).\u003c/li\u003e\n\u003cli\u003eSridharan, V. et al. Immune Profiling of Adenoid Cystic Carcinoma: PD-L2 Expression and Associations with Tumor-Infiltrating Lymphocytes. Cancer Immunol Res 4, 679\u0026ndash;687, https://doi.org/10.1158/2326-6066.CIR-16-0031 (2016).\u003c/li\u003e\n\u003cli\u003eLaurie, S. A., Ho, A. L., Fury, M. G., Sherman, E. \u0026amp; Pfister, D. G. Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review. Lancet Oncol 12, 815\u0026ndash;824, https://doi.org/10.1016/ S1470-2045(10)70245-X (2011).\u003c/li\u003e\n\u003cli\u003eAlberts, D. S., Manning, M. R., Coulthard, S. W., Koopmann, C. F. \u0026amp; Herman, T. S. Adriamycin/cis-platinum/cyclophosphamide combination chemotherapy for advanced carcinoma of the parotid gland. Cancer 47, 645\u0026ndash;648 (1981).\u003c/li\u003e\n\u003cli\u003eTopalian, S. L., Taube, J. M., Anders, R. A. \u0026amp; Pardoll, D. M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16, 275\u0026ndash;287, https://doi.org/10.1038/nrc.2016.36 (2016).\u003c/li\u003e\n\u003cli\u003eDolan, D. E. \u0026amp; Gupta, S. PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control 21, 231\u0026ndash;237 (2014).\u003c/li\u003e\n\u003cli\u003eMerck Sharp \u0026amp; Dohme Corp. Keytrudas (Pembrolizumab) injection, for Intravenous Use. Whitehouse Station, NJ: Merck Sharp \u0026amp; Dohme Corp., 2017.\u003c/li\u003e\n\u003cli\u003eChow LQM, Haddad R, Gupta S, et al. 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\u0026ndash;3845.\u003c/li\u003e\n\u003cli\u003eSeiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an openlabel, multicentre, phase 1b trial. Lancet Oncol. 2016,17:956\u0026ndash;965.\u003c/li\u003e\n\u003cli\u003eBurtness, B., Harrington, K.J., Greil, R., Souli\u0026egrave;res, D., Tahara, M., de Castro, G., Psyrri, A., Bast\u0026eacute;, N., Neupane, P., Bratland, A., et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or meta-static squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study. Lancet 2019, 394, 1915\u0026ndash;1928. [CrossRef]\u003c/li\u003e\n\u003cli\u003eMcHughCH, RobertsDB, El-NaggarAK, et al: Prognostic factors in mucoepidermoid carcinoma of the salivary glands. Cancer 118:3928-3936, 2012.\u003c/li\u003e\n\u003cli\u003eChenAM, LauVH, FarwellDG, et al: Mucoepidermoid carcinoma of the parotid gland treated by surgery and postoperative radiation therapy: Clinicopathologic correlates of outcome. Laryngoscope 123:3049-3055, 2013.\u003c/li\u003e\n\u003cli\u003eBrandweinMS, IvanovK, WallaceDI, et al: Mucoepidermoid carcinoma: A clinicopathologic study of 80 patients with special reference to histological grading. Am J Surg Pathol 25:835-845, 2001Crossref,Medline,Google Scholar\u003c/li\u003e\n\u003cli\u003eNational Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf (Accessed on January 04, 2021).\u003c/li\u003e\n\u003cli\u003eCohen, R., Delord, J., Doi, T., Piha-Paul, S., Liu, S., Gilbert, J., Algazi, A., Damian, S., Hong, R., Le Tourneau, C., Day, D., Varga, A., Elez, E., Wallmark, J., Saraf, S., Thanigaimani, P., Cheng, J. and Keam, B., 2021. \u003cem\u003ePembrolizumab for the Treatment of Advanced Salivary Gland Carcinoma\u003c/em\u003e.\u003c/li\u003e\n\u003cli\u003eLaurie SA, Licitra L. Systemic therapy in the palliative management of advanced salivary gland cancers. J Clin Oncol. 2006,24: 2673\u0026ndash;2678.\u003c/li\u003e\n\u003cli\u003eMarabelle A, Fakih M, Lopez J, et al: Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: Prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 21:1353-1365, 2020\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"discover-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dion","sideBox":"Learn more about [Discover Oncology](https://www.springer.com/12672)","snPcode":"","submissionUrl":"","title":"Discover Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Pembrolizumab, salivary gland cancers (SGCs): immunotherapy, complete response (CR).","lastPublishedDoi":"10.21203/rs.3.rs-1433947/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1433947/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cu\u003eBackground:\u003c/u\u003e Patients with advanced salivary gland malignancies (SGCs) have few therapy options. Although results from newly published trials suggest that checkpoint inhibition may be useful in a subgroup of patients, there are no clear criteria for PD-L1 score in SGCs. Chemotherapy benefits were observed to be limited, with a dismal prognosis in unresectable and high-grade SGC.\u003c/p\u003e\u003cp\u003eImmunotherapies have demonstrated extraordinary efficacy in a variety of cancers, including non-small cell lung cancer and malignant melanoma. Anti-PD-1 antibody pembrolizumab has been shown to have potent anti-tumor action in a number of clinical trials.\u003c/p\u003e\u003cp\u003e\u003cu\u003eCase presentation:\u003c/u\u003e We report a unique case of advanced high grade mucoepidermoid carcinoma of the parotid salivary gland after Pembrolizumab treatment as a first line therapy. \u003c/p\u003e\u003cp\u003eThe tumor was downstaged as a result of the pembrolizumab treatment, allowing for a successful surgical excision with no facial nerve sacrifice and no major neoadjuvant treatment adverse effects, and the final specimen pathology was tumor-free. In these types of malignancies, a similar technique resulted in a complete response (CR) radiologically and pathologically has never been discussed before.\u003c/p\u003e\u003cp\u003e\u003cu\u003eConclusions:\u003c/u\u003e In pretreated patients with high-grade salivary gland mucoepidermoid carcinoma, pembrolizumab showed good anticancer activity and provided a clinically, radiologically, and pathological response with a viable treatment choice. More research is needed to bring Pembrolizumab to the front-line of treatment. The time and duration of medication should be compared to the time required for surgery in these investigations.\u003c/p\u003e","manuscriptTitle":"Pembrolizumab as a first line therapy in a patient with extensive Mucoepidermoid salivary gland carcinoma. A complete clinical, radiological and pathological response. 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