Oral toxicities of immune checkpoint inhibitors Emmanuelle Vigarios (1) Vincent Sibaud (1,2) (1) Oral medicine department (2) Onco-dermatology and clinical research departments Institut Claudius Regaud, Institut Universitaire du Cancer Toulouse Oncopole december 2016
Conflicts of interest Emmanuelle Vigarios declares to have the following links of interest: Pierre Fabre . Vincent Sibaud declares to have the following links of interest: Roche, BMS, MSD, GSK, Pierre Fabre, Novartis, Bayer, Pfizer, Boehringer Ingelheim .
Oral lichenoïd reactions induced by anti-PD-1 and anti-PD-L1 therapies • recently, few cases of oral lichenoid reactions therapies have been sporadically described • we report here a case series of 9 patients treated for advanced solid cancers with anti PD-1/PD-L1 • 6 patients were receiving anti PD-1 therapy ( nivolumab or pembrolizumab ) and 3 patients were receiving anti PDL-1 ( atezolizumab ) as part of Phase III clinical study (NCT02420821) or as part of Phase I clinical study (NCT02323191) • observations in 2 comprehensive cancer centers ( Institut Universitaire du Cancer Toulouse Oncopole, France and Memorial Sloan Kettering Cancer Center, New York ). Sibaud V, Meyer N, Lamant L, Vigarios E, Mazieres J, Delord JP. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol 2016; 28:254-63. Vigarios E, Epstein JB, Sibaud V. Oral mucosal changes induced by anticancer targeted therapies ad immune checkpoint inhibitors. Support Care Cancer (submitted) Eid C, Vigarios E, Belum R, Motzer R, Delord JP, Lacouture ME, Sibaud V. Anti-PD-1/PD-L1 Induced Oral Lichenoid Reactions: A Case Series. Br J of Dermatol (in progress)
Cycles Received Before Clinical Associated Cutaneous or Treatment/ No Sex/Age Cancer type Treatment Clinical Description Diagnosis Severity(grade) Other Site Involvement Clinical outcome 1 M, 53 Multiple Myeloma nivolumab 2 -Asymptomatic 2 Yes, Lichenoid cutaneous Topical corticosteroids/ Resolution at 3 -Numerous discrete whitish papules on the reaction weeks lips, tongue, buccal mucosa (bilateral) 2 M, 62 Renal Cell Carcinoma nivolumab 23 -Asymptomatic 1 No None/ Spontaneous resolution noted 8 -Reticular white streaks on buccal mucosa; weeks after interrupting nivolumab -Swollen tongue with faint linear streaks 3 M, 42 Glioblastoma multiforme nivolumab 2 -Asymptomatic 2 No Topical corticosteroids and anti-fungal -Pinkish white papules on the lips, tongue and lozenges/ Unknown evolution buccal mucosa 4 F, 70 Extranodal marginal nivolumab 6 -Irritation and bleeding of the gums 2 Yes, Lichenoid cutaneous Topical and oral corticosteroids (given zone lymphoma of the -Reticular white streaks on buccal and labial eruption simultaneously for pneumonitis)/ lung mucosa, gingiva, floor of the mouth, soft Resolution at following palate and tongue Examination -Erythema and atrophy of the ventral surface of the tongue -Erythema of the attached gingiva 5 F, 41 Breast pembrolizumab 10 -Asymptomatic 1 No None/ Unknown evolution -White papules and plaques on the dorsum of the tongue 6 M, 63 Adenocarcinoma of the nivolumab 3 -Asymptomatic 1 Yes; non specific macular None/ Unknown evolution lung -Reticular white streaks on buccal mucosa papular rash and soft palate 7 M, 56 Renal atezolizumab 11 -Asymptomatic 2 Yes, Lichenoid cutaneous Topical corticosteroids/ Unknown -Cobblestoning of the dorsum of the tongue eruption and nail changes evolution -Reticular white streaks of the hard palate 8 M, 66 Tubuloglandular atezolizumab 14 -Xerostomia 1 No None/ Unknown evolution adenocarcinoma of the -Reticular white streaks on buccal mucosa esophagus 9 M, 54 Renal cell carcinoma, atezolizumab 5 -Sensitive and swollen tongue w/ decreased 1 No Topical corticosteroids/ Resolved metastatic mobility eventually -Xerostomia -White superficial ulcers on floor of mouth -Hypopigmentation of lower gingivae
• number of cycles received before diagnosis varied between 2 and 23 cycles, • occurrence of lesions independent of dose or number of cycles received, • oral lichenoid lesions were mild to moderate, • most of the patients were asymptomatic and were graded 1 following the CTCAE (Common Terminology Criteria for Adverse Events) clinical grading system, • 3 patients had symptoms (soreness and irritation) and were graded 2 , • 1 patient presented an erosive form with superficial ulcers
• topical corticosteroids were introduced for 4 patients and allowed significant improvement, • 3 patients presented concomitantly a lichenoid cutaneous reaction , • 1 patient had lichenoid nail changes (that has not yet been reported in the literature to our knowledge), • treatments were continued in all cases , whithout temporary interruption
2 mois après l’arrêt du nivolumab Après 23 cycles de nivolumab After 23 cycles of nivolumab 2 months after nivolumab discontinuation
Atteinte lichénoïde de la face dorsale de la langue (anti PD-1) Agression lichénoïde caractérisée par un infiltrat lympho-histiocytaire en bande avec effraction partielle de la membrane basale Lichenoïd lesion of the dorsum of the tongue (anti PD-1) band like lymphocytic infiltrate in the upper lamina propria along with partial disruption of the basement membrane zone consistent with a lichenoid pattern
• oral and cutaneous lichenoid reactions correspond to a class effect of anti-PD-1 / PD-L1, • the activation of cytotoxic T lymphocytes mechanism by anti-PD-1 and anti-PD-L1 may potentially explain this type of autoimmune lichenoid reactions, • oral toxicity probably under-reported, • systematic oral examination as part of the routine skin examination in all patients receiving anti PD-1/PDL-1 therapy is recommended and may allow to specify the incidence of these induced lesions, • monitoring of oral lichenoid lesions (potential for malignant transformation) and biopsy in case of doubt, • largest serie detailing this oral toxicity. Eid C, Vigarios E, Belum R, Motzer R, Delord JP, Lacouture ME, Sibaud V. Anti-PD-1/PD-L1 Induced Oral Lichenoid Reactions: A Case Series. Br J of Dermatol (in progress)
Xerostomia grade 1-2 (CTCAE) : reported for 6% of treated patients with nivolumab (melanoma) and from 4 to 7% with pembrolizumab . (data from pivotal studies) grade 3 (CTCAE) : rare Sibaud V, Meyer N, Lamant L, Vigarios E, Mazieres J, Delord JP. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol 2016; 28:254-63. Vigarios E, Epstein JB, Sibaud V. Oral mucosal changes induced by anticancer targeted therapies ad immune checkpoint inhibitors. Support Care Cancer (submitted)
Sicca syndrome X10 Syndrome de Goujerot-Sjögren like sous Infiltrat lymphocytaire avec marquage de l’anticorps anti-PD1 des nivolumab, séronégatif glandes salivaires accessoires. Severe Gougerot-Sjögren syndrome-like lymphohistiocytic infiltrate surrounding salivary glands with positive xerostomia (nivolumab) without anti SSA, SSB antiPD-1 immunostaining. antibodies
Xerostomia: management • basic oral care • dietary recommendations • hydratation • sugar-free gum or candy stimulants • sialogogues: pilocarpine, sulfarlem • artificial saliva substitutes (palliation) • thermal water
Dysgeusia • mild to moderate dysgeusia ( grade 1 or 2 CTCAE ) clinical grading system for less than 3% anti PD-1 and anti PD-L1 treated patients (data from pivotal studies) • no treatment modification • This toxicity is frequently overlooked and evaluation of the impact on quality of life, weight loss, nutrition is recommended • management
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sibaud.vincent@iuct-oncopole.fr
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