Oral toxicities of immune checkpoint inhibitors Emmanuelle Vigarios - - PowerPoint PPT Presentation

Oral toxicities of immune checkpoint inhibitors

Emmanuelle Vigarios (1) Vincent Sibaud (1,2)

december 2016

(1) Oral medicine department (2) Onco-dermatology and clinical research departments

Institut Claudius Regaud, Institut Universitaire du Cancer Toulouse Oncopole

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)

No Sex/Age Cancer type Treatment Cycles Received Before Diagnosis Clinical Description Clinical Severity(grade) Associated Cutaneous or 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 Yes, Lichenoid cutaneous reaction Topical corticosteroids/ Resolution at 3 weeks 2 M, 62 Renal Cell Carcinoma nivolumab 23

• Asymptomatic
• Reticular white streaks on buccal mucosa;
• Swollen tongue with faint linear streaks

1 No None/ Spontaneous resolution noted 8 weeks after interrupting nivolumab 3 M, 42 Glioblastoma multiforme nivolumab 2

• Asymptomatic
• Pinkish white papules on the lips, tongue and

buccal mucosa 2 No Topical corticosteroids and anti-fungal lozenges/ Unknown evolution 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
• f the tongue
• Erythema of the attached gingiva

2 Yes, Lichenoid cutaneous eruption Topical and oral corticosteroids (given simultaneously for pneumonitis)/ Resolution at following Examination 5 F, 41 Breast pembrolizumab 10

• Asymptomatic
• White papules and plaques on the dorsum of

the tongue 1 No None/ Unknown evolution 6 M, 63 Adenocarcinoma of the lung nivolumab 3

• Asymptomatic
• Reticular white streaks on buccal mucosa

and soft palate 1 Yes; non specific macular papular rash None/ Unknown evolution 7 M, 56 Renal atezolizumab 11

• Asymptomatic
• Cobblestoning of the dorsum of the tongue
• Reticular white streaks of the hard palate

2 Yes, Lichenoid cutaneous eruption and nail changes Topical corticosteroids/ Unknown evolution 8 M, 66 Tubuloglandular adenocarcinoma of the esophagus atezolizumab 14

• Xerostomia
• Reticular white streaks on buccal mucosa

1 No None/ Unknown evolution 9 M, 54 Renal cell carcinoma, metastatic atezolizumab 5

• Sensitive and swollen tongue w/ decreased

mobility

• Xerostomia
• White superficial ulcers on floor of mouth
• Hypopigmentation of lower gingivae

1 No Topical corticosteroids/ Resolved eventually

• 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 2 months after nivolumab discontinuation Après 23 cycles de nivolumab After 23 cycles of nivolumab

band like lymphocytic infiltrate in the upper lamina propria along with partial disruption of the basement membrane zone consistent with a lichenoid pattern Agression lichénoïde caractérisée par un infiltrat lympho-histiocytaire en bande avec effraction partielle de la membrane basale Atteinte lichénoïde de la face dorsale de la langue (anti PD-1) Lichenoïd lesion of the dorsum of the tongue (anti PD-1)

• 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.

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)

(data from pivotal studies)

Infiltrat lymphocytaire avec marquage de l’anticorps anti-PD1 des glandes salivaires accessoires. lymphohistiocytic infiltrate surrounding salivary glands with positive antiPD-1 immunostaining. Syndrome de Goujerot-Sjögren like sous nivolumab, séronégatif Severe Gougerot-Sjögren syndrome-like xerostomia (nivolumab) without anti SSA, SSB antibodies X10

Sicca syndrome

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