MESA II: MISCELÁNEA Mucositis secundaria a inhibidores de m-TOR

Mireia Margelí Vila Hospital Universitari Germans Trias i Pujol (ICO-Badalona)

INTRODUCCIÓN The most common adverse event associated with everolimus is stomatitis Stomatitis is a class effect associated with mTOR inhibition The onset and pattern of mTOR inhibitor stomatitis have been well characterised It presents as aphthous-like oral lesions, characterised by discrete shallow ulcerations. Are multiple or singular round to ovoid ulcerations with regular borders The lesions are commonly less than 0.5 cm in diameter in size and nearly exclusively involve the nonkeratinized oral mucosa (tongue, floor of the mouth, and labial or buccal mucosa

INTRODUCCIÓN

CARACTERISTICAS: -Lesiones aftosas, pequeñas y superficiales. -Halo eritematoso periférico. -En labios, lengua y paladar blando. Raro en paladar duro. -No peudomembrana, típica de mucositis por QT o RT.

Mucositis grado 1: No suspender tratamiento Mucositis grado 2: Interrumpir hasta recuperación a ≤ grado 1. Reiniciar a misma dosis Mucositis grado 3: Interrumpir hasta recuperación a ≤ grado 1. Reiniciar a nivel inferior de dosis Mucositis grado 4: Suspender

INTRODUCCIÓN Everolimus provoca daño epitelial que se manifiesta por cambios morfológicos, aumento de la apoptosis y disminución de la proliferación con la liberación simultánea de queratinocitos derivados de citoquinas proinflamatorias. La extensión del efecto es concentración y tiempo dependiente. La mucositis secundaria a inhibidores de mTOR probablemente se inicia por lesión epitelial directa, independiente del microbioma. La liberación de citoquinas de queratinocitos probablemente podría desempeñar un papel en la aceleración de un infiltrado inflamatorio. On the pathogenesis of mTOR-associated stomatitis (mIAS)- studies using an organotypic model of

the oral mucosa Sonis et alOral Diseases 2017

INTRODUCCIÓN

On the pathogenesis of mTOR-associated stomatitis (mIAS)- studies using an organotypic model of the oral mucosa Sonis et alOral Diseases 2017

INTRODUCCIÓN

All grade Grade 3/4

Everolimus 44-78% 4-9%

Temsirolimus 41% 3%

Ridaforolimus 54.6% 8.2%

Sirolimus 2-10% 0-2%

Oral mucosal lesion prevalence

INTRODUCCIÓN Management of mTOR inhibition-associated stomatitis by dose delays, reductions, or discontinuation of the mTOR inhibition migth compromise duration and intensity of mTOR inhibitors And may affect decisions to inictiate treatment with mTOR inhibitors

In a meta-analysis of phase III trials 89% of all-grade stomatitis was prominent within 8 weeks of starting everolimus In BOLERO-3, at a median follow-up of 13 months, all-grade stomatitis occurred in 321 (67%) of 483 patients, including grado 2 or worse in 159 (33%) and grade 3 severity in 39 (8%).

INTRODUCCIÓN

Rugo et al Ann Oncol 2016

Rugo et al Ann Oncol 2016

BOLERO-2 (18-mo f/up): Clinical Management and Resolution of Stomatitis and Related Events

Stomatitis and Related Events Characteristics EVE + EXE N = 482

PBO + EXE N = 238

All grade, % 67% 12%

Grade 3, % 8% <1%

Grade 4, % 0% 0%

Median time for complete resolution of grade 2 stomatitis and related events; % (n) of patients

16 days; 98% (118 of 121)

8 days; 80% (4 of 5)

Dose interruptions, % (n) 24% (118) 1% (3)

Treatment discontinuation related to stomatitis, % (n) 3% (14) <1% (1)

Treatment-emergent stomatitis was of mild to moderate intensity, occurred shortly after treatment initiation, and was generally reversible Most were successfully managed with palliative interventions and temporary dose modifications

The main objective of the dexamethaSone mouthWash for everolimus-related stomatitis prevention in HR+ MBC (SWISH) study was:

– To evaluate an alcohol-free, steroid-based mouthwash to prevent

stomatitis (grade ≥2) in patients with HR+, HER2- ABC receiving EVE and EXE treatment and to compare with BOLERO-2 historical controls

Rugo et al The Lancet 2017

Methods Study Design

US-based, multicenter, single-arm, phase 2 prevention trial (NCT02069093) 23 investigational sites Enrollment: May 2014 to October 2015

aRoxane Laboratories/West-Ward Pharmaceuticals, Eatontown, NJ. bAt the completion of cycle 2 (day 56), the treating clinician determined whether to continue the patient’s assigned mouthwash regimen. Patients could continue to receive their mouthwash regimen from Novartis for an additional 56 days.

ECOG: Eastern Cooperative Oncology Group; EVE: everolimus; EXE: exemestane; HER2: human epidermal growth factor receptor 2-negative; HR: hormone receptor; NDS, Normalcy of Diet Scale; QID, four times a day; VAS, visual analog scale

Treatment cycles (cycle 1, 2), optional cycles (cycles 3, 4)b, and safety follow-up cycle; each cycle = 28 days

N = 92 • Females ≥18 years • Postmenopausal locally advanced or

metastatic HR+, HER2- breast cancer • Prescribed EVE 10 mg + EXE 25 mg • ECOG performance status ≤ 2

Endpoints

Primary: compare grade ≥2 stomatitis incidence at 8 weeks with BOLERO-2 results Secondary: Mouthwash use by average times/day, EVE/EXE dose intensity, all-grade stomatitis incidence and time to resolution to grade ≤1, oral pain scale, normalcy of diet

Baseline • Oral pain assessment • VAS score • NDS score

• Routine good oral care • EVE 10 mg/day • EXE 25 mg/day • Alcohol-free steroid-based mouthwasha

− 10 mL (0.5 mg/5 mL dexamethasone oral solution) swish for 2 mins and spit QID four times daily

Open label, phase II, single arm

Rugo et al The Lancet 2017

Methods Study Endpoints and Assessments

Primary • Incidence of grade ≥2 stomatitis at 8 weeks compared to BOLERO-2 historical controls

– Confirmed by physical exam or interview, and ≥1: • NDS (Normal Diet Scale) ≤50, and/or • Patient-reported VAS score of 7 on 2 consecutive days or 8, 9, or 10 on any 1 day

Secondary • Average number/day mouthwash regimen at 8 weeks • Dose intensity of EVE/EXE at 8 weeks • Incidence of all-grade stomatitis at 8 weeks • Time to resolution (days) from grade ≥2 stomatitis diagnosis to grade ≤1

Additional Assessment • Safety assessments including:

– AEs, SAEs, AEs leading to study drug discontinuation (CTCAE by v4), and laboratory abnormalities

• Patient-reported outcomes – Recorded in a daily log of oral pain scores and normalcy of diet ratings

• Pharmacokinetics*

BOLERO-2, The Breast Cancer Trials of Oral Everolimus-2; CTCAE: Common Terminology Criteria for Adverse Events; EVE: everolimus; EXE: exemestane; NDS: Normalcy of Diet Scale; SAE: serious adverse events; VAS: visual analog scale

Methods Study Interventions

• EVE 10 mg plus EXE 25 mg once daily • 10 mL of alcohol-free dexamethasone 0.5 mg/5 mL oral solution*

• Swish for 2 minutes and spit QID for 8 weeks • NPO for 1 hour after mouthwash

• All 3 treatments initiated on day 1 of cycle 1 (1 cycle = 28 days) • Patients could continue dexamethasone mouthwash regimen after

the first 2 cycles by clinician discretion (total study maximum of 4 cycles)

• Dose modification/dose interruption of EVE was permitted for the management of AEs • EVE was held for grade 2/3 stomatitis until recovery to grade ≤1

*Roxane Laboratories/West-Ward Pharmaceuticals, Eatontown, NJ

AE: adverse event; EVE: everolimus; EXE: exemestane; mg, milligram; mL, milliliter; NPO: nothing by mouth; QID: four times a day

Methods Patient Education and Instructions

• Patients received instructional materials • Information on stomatitis • Routine good oral hygiene

• Brushing teeth with a soft-bristled toothbrush • Daily flossing • Continuing routine dental care/maintenance with their

dentist • Timer to monitor duration of mouthwash treatment

• Patients instructed to complete daily logs to document NDS and VAS scores, and number of doses of mouthwash

NDS: Normalcy of Diet Scale; VAS: visual analog scale

• 92 patients enrolled and 86 were evaluable from 23 centres • 6 patients were unevaluable; receipt of at least 1 dose of

dexamethasone mouthwash could not be confirmed • Median age was 61 years (range 34-87); 61.6% were Caucasian;

93% were classified with ECOG performance status of 0-1 • More than 35% of patients received EVE and EXE treatment in

≥2nd-line setting • 20 (23%) patients received optional antifungal oral prophylaxis

against oral thrush

Results Patient Demographics and Characteristics

Results Patient Demographics and Characteristics

Results

Incidence of Stomatitis

The incidence of grade ≥2 stomatitis at 8 weeks was 2.4% (n=2, 95% CI 0.29-8.24, P<0.001) compared with total of 27% in BOLERO-2

Results • The incidence of all-grade stomatitis at 8 weeks was 21.2% (n=18,

95% CI 13.06-31.39), a reduced incidence rate compared with all-grade stomatitis reported in BOLERO-2 (67%) • The rate of grade 1 stomatitis was 18.8% • Of the 18 patients who developed stomatitis, 3 used

antifungal prophylaxis • Of the 20 patients who used antifungal prophylaxis, 7

developed stomatitis • In the 2 patients who developed grade ≥2 stomatitis, resolution

to grade ≤1 occurred after a duration of 11 days for 1 patient and 15 days for the other patient

• 95% of patients used dexamethasone mouthwash 3-4 times/day (median 3.95 [range 1.9-4])

• >70% of patients remained on all 3 drugs at ≥8 weeks • The median dose intensities of EVE and EXE were 10 mg and 25 mg,

respectively

Secondary Outcomes

Outcomes

Number of mouthwash applications/day, median (range) 3.95 (1.9-4.0)

Actual dose intensity, mg, median (range)

Everolimus 10 (3-10)

Exemestane 25 (8-25)

Results Secondary Outcomes

Stomatitis with first onset after week 8 (day 56) by patient number

Adverse events with a total incidencie of ≥5% regardless of casuality (n=92)

Results

Results

• Two patients developed oral candidiasis during antifungal prophylaxis (one treatment related and one not) that resolved with nystatin or oral fluconazole treatment

• Six (30%) of 20 patients who received oral antifungal prophylaxis of nystatin developed stomatitis during the study

• There was no apparent association between antifungal prophylaxis and prevention of stomatitis or oral candidiasis

Discussion and Conclusions • Prophylaxis with dexamethasone mouthwash 3-4 times/day

significantly minimized or prevented the incidence of all grades, especially grade ≥2, stomatitis in postmenopausal patients receiving EVE 10 mg/EXE 25 mg for HR+, HER2– aBC or mBC compared to that seen in the BOLERO-2 trial

• Preventive use of dexamethasone mouthwash resulted in a greater than 10-fold reduction in the incidence of grade ≥2 stomatitis compared with BOLERO-2 patients

• Patient-reported outcomes monitoring diet and oral pain supported efficacy of the dexamethasone mouthwash

• Dexamethasone mouthwash was well tolerated with minimal toxicity

• This treatment may have contributed to the favorable dose intensity of EVE/EXE seen in the SWISH study.

• No new safety signals were observed; the incidence of AEs was consistent with previous observations of EVE-based therapy, and AEs associated with corticosteroid use (eg, oral thrush or an increase in hyperglycemia) were minimal

• An association between antifungal prophylaxis and stomatitis was not apparent

• Patients were compliant with the treatment regimen and maintained good daily oral care

• Steroid mouthwash as prophylaxis for EVE-related stomatitis is a new standard of care for patients receiving EVE/EXE for treatment of HR+, HER2– advanced or metastatic BC

Discussion and Conclusions

Elaboración 1. Elaboración de alguna formula magistral (con corticoide) para la prevención/tratamiento de mucositis por everólimus.

Gel de Dexametasona 0.1 mg/ ml Composición (100 ml) Dexametasona 0.01% (principio activo, polvo) Carboximetilcelulosa sódica, 1% Glicerina, 15% Tween 20® 1 a 2 gotas Agua purificada csp, 100 ml

Fernando Moreno Antón Hospital Clinico San Carlos, Madrid

Elaboración 2. Existen varias presentaciones comerciales en el extranjero con dexametasonae solución para vía oral sin alcohol que se han utilizado para esta indicación (En España no están disponibles) https://www.medicines.org.uk/emc/medicine/31173https://www.medicines.org.uk/emc/medicine/31173 3. También hay descritas varias fórmulas magistrales con dexametasona por vía oral : http://www.stabilis.org/Monographie.php?IdMolecule=893 http://formulacionpediatrica.es/wp-content/uploads/2011/06/31dexametasona.pdf http://pharminfotech.co.nz/manual/Formulation/mixtures/dexamethasone.htmlhttp://pharminfotech.co.nz/manual/Formulation/mixtures/dexamethasone.html

Elaboración

4. Según el centro, de momento optamos por utilizar las ampollas de Fortecortin 4 mg. 1 ampolla de 4 mg se diluye en agua 40 ml. Obtenemos así una solución de concentración 0.1mg/ml (que es la que recomienda el estudio). Recomendamos a las pacientes que diluyan la ampolla antes de realizar los enjuagues. 5. Por otro lado también podríamos recetar estos enjuagues que los preparan algunas farmacias: P. Ejemplo.: Podrian preparar la solución de dexametasona a 0.1mg/mL. La dosis también seria 10ml. La estabilidad aproximada es de unos 3 meses, y tardarian en preparar-la entre 24 y 48h. Ya que los enjuagues estan financiados por el CatSalut, en la receta se habría de indicar en observaciones: Enjuagues de dexametasona 0.1 mg/mL, SIN EXCIPIENTE ALCOHOLICO .

CONCLUSIONES • Los inhibidores de mTOR son ampliamente usados en oncología • La estomatitis es un efecto adverso frecuente, que conduce a reducciones

de dosis • La profilaxis con enjuagues de corticoides reduce muy significativamente

la incidencia de mucositis y permite continuar el tratamiento, evitar reducciones de dosis y mejorar la calidad de vida

GRACIAS