Oral toxicitiesof immune checkpoint inhibitors

Transcription

1 Oral toxicitiesof immune checkpoint inhibitors Emmanuelle Vigarios (1) Vincent Sibaud (1,2) (1) Oral medicinedepartment (2) Onco-dermatology and clinical research departments Institut Claudius Regaud, Institut Universitaire du Cancer Toulouse Oncopole december 2016

2 Conflictsof interest Emmanuelle Vigarios declares to have the following links of interest: Pierre Fabre. Vincent Sibauddeclaresto have the followinglinks of interest: Roche, BMS, MSD, GSK, Pierre Fabre, Novartis, Bayer, Pfizer, Boehringer Ingelheim.

3

4 Oral lichenoïdreactionsinducedby 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 (NCT ) or as part of Phase I clinical study(nct ) 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: 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)

5 No Sex/Age Cancer type Treatment Cycles Received Before Diagnosis Clinical Description Clinical Associated Cutaneous or Severity(grade) Other Site Involvement Treatment/ Clinical outcome 1 M, 53 Multiple Myeloma nivolumab 2 -Asymptomatic -Numerous discrete whitish papules on the lips, tongue, buccal mucosa (bilateral) 2 M, 62 Renal Cell Carcinoma nivolumab 23 -Asymptomatic -Reticular white streaks on buccal mucosa; -Swollen tongue with faint linear streaks 3 M, 42 Glioblastoma multiforme nivolumab 2 -Asymptomatic -Pinkish white papules on the lips, tongue and buccal mucosa 4 F, 70 Extranodal marginal zone lymphoma of the lung nivolumab 6 -Irritation and bleeding of the gums -Reticular white streaks on buccal and labial mucosa, gingiva, floor of the mouth, soft palate and tongue -Erythema and atrophy of the ventral surface of the tongue -Erythema of the attached gingiva 5 F, 41 Breast pembrolizumab 10 -Asymptomatic -White papules and plaques on the dorsum of the tongue 6 M, 63 Adenocarcinoma of the lung nivolumab 3 -Asymptomatic -Reticular white streaks on buccal mucosa and soft palate 7 M, 56 Renal atezolizumab 11 -Asymptomatic -Cobblestoning of the dorsum of the tongue -Reticular white streaks of the hard palate 8 M, 66 Tubuloglandular adenocarcinoma of the esophagus 9 M, 54 Renal cell carcinoma, metastatic atezolizumab 14 -Xerostomia -Reticular white streaks on buccal mucosa atezolizumab 5 -Sensitive and swollen tongue w/ decreased mobility -Xerostomia -White superficial ulcers on floor of mouth -Hypopigmentation of lower gingivae 2 Yes, Lichenoid cutaneous reaction Topical corticosteroids/ Resolution at 3 weeks 1 No None/ Spontaneous resolution noted 8 weeks after interrupting nivolumab 2 No Topical corticosteroids and anti-fungal lozenges/ Unknown evolution 2 Yes, Lichenoid cutaneous eruption Topical and oral corticosteroids (given simultaneously for pneumonitis)/ Resolution at following Examination 1 No None/ Unknown evolution 1 Yes; non specific macular papular rash 2 Yes, Lichenoid cutaneous eruption and nail changes None/ Unknown evolution Topical corticosteroids/ Unknown evolution 1 No None/ Unknown evolution 1 No Topical corticosteroids/ Resolved eventually

6

7 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

8 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

9 Après 23 cycles de nivolumab After 23 cycles of nivolumab 2 mois après l arrêt du nivolumab 2 months afternivolumab discontinuation

10 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

11 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)

12 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: Vigarios E, Epstein JB, Sibaud V. Oral mucosal changes induced by anticancer targeted therapies ad immune checkpoint inhibitors. Support Care Cancer (submitted)

13 Sicca syndrome Syndrome de Goujerot-Sjögren like sous nivolumab, séronégatif Severe Gougerot-Sjögren syndrome-like xerostomia (nivolumab) without anti SSA, SSB antibodies X10 Infiltrat lymphocytaire avec marquage de l anticorps anti-pd1 des glandes salivaires accessoires. lymphohistiocytic infiltrate surrounding salivary glands with positive antipd-1 immunostaining.

14 Xerostomia: management basic oral care dietary recommendations hydratation sugar-free gum or candy stimulants sialogogues: pilocarpine, sulfarlem artificial saliva substitutes (palliation) thermal water

15 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

16 16

17

18