Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

Supplement to: Rugo HS, Seneviratne L, Beck JT, et al. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial. Lancet Oncol 2017; published online March 14. http://dx.doi.org/10.1016/S1470-2045(17)30109-2.

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Supplementary appendix Supplement to: Rugo HS, Seneviratne L, Beck JT, et al. Prevention of everolimus/exemestane–related stomatitis in women with hormone receptor–positive metastatic breast cancer using dexamethasone mouthwash: results from the phase 2, single-arm SWISH trial.

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Appendix Figure Appendix Figure 1. Study design.

aEVE dose modification/dose interruption was permitted for adverse event management; EVE held for grade 2/3 stomatitis until

recovery to grade ≤1. bRoxane Laboratories/West-Ward Pharmaceuticals, Eatontown, NJ.

cAll 3 treatments initiated on day 1 of cycle 1 (1 cycle = 28 days). At 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. dFollowing dexamethasone mouthwash administration, optional use of oral nystatin suspension or other topical antifungal agents were allowed by provider preference.

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Appendix Figure 2. ECOG performance status between baseline and 8 weeks

*11 patients had missing data at 8 weeks. ECOG: Eastern Cooperative Oncology Group

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Appendix Tables Appendix Table 1. Dose intensity of everolimus and exemestane

Outcomes

Dose intensity, mg Number of mouthwash applications per day*

Everolimus Exemestane

8 weeks* 12 weeks† 8 weeks* 12 weeks†

Mean (SD) 9·6 (1·15) 9·4 (1·33) 24·5 (2·17) 24·4 (2·53) 3·80 (0·364)

Median (range) 10 (3–10) 10 (2.8–10) 25 (8–25) 25 (4–25) 3·95 (1.9–4.0) *Analysis of the full analysis set (N=86). †Analysis of the safety set (N=92). SD: standard deviation.

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Appendix Table 2: Cumulative drug exposure

Cumulative Exposure Everolimus n (%)

Exemestane n (%)

Dexamethasonea n (%)

Any n (%)

N 92† 92 86* 92

≥ 8 weeks 71 (77·2) 70 (76·1) 64 (74·4) 71 (77·2)

≥ 12 weeks 53 (57·6) 52 (56·5) 41 (47·7) 53 (57·6)

≥ 16 weeks 33 (35·9) 32 (34·8) 18 (20·9) 33 (35·9) aTreatment was optional after week 8. *Full analysis set evaluated by CTCAE 4.0, NDS and VAS through 8 weeks. †Safety set evaluated by CTCAE 4.0.

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Appendix Table 3. Clinical trial site details

Site Principle investigator Number of patients recruited

Los Angeles Hematology/Oncology Medical Group 1245 Wiltshire Boulevard Suite 303 Los Angeles, CA, 90017 USA

Lasika Seneviratne 12

Anderson Cancer Center 1515 Holcombe Boulevard, Unit 1354 Houston, TX, 77230-1439 USA

Jennifer Litton 10

Highlands Oncology Group 3232 N. North Hills Blvd. Fayetteville, AR, 72703 USA

Joseph Thaddeus Beck 9

University of California at Los Angeles 100 Medical Plaza Suite 500 Los Angeles, CA, 90024

John A. Glaspy 8

Oncology Consultants 925 Gessner Suite 600 Houston, TX, 77024 USA

Julio Peguero 7

Saint Luke's Hospital 4321 Washington, Medical Plaza III, Suite 5100 Kansas City, MO, 64111 USA

Timothy Pluard 6

Southeastern Regional Medical Center 600 Celebrate Life Parkway North Newnan, GA, 30265 USA

Ricardo Alvarez (formerly Navneet Dhillon)

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University of California San Francisco Helen Diller Comprehensive Cancer Center, UCSF 1600 Divisadero Street, Rm B612 San Francisco, CA 94143 USA

Hope S. Rugo 4

University of California Irvine 101 The City Drive South Orange, CA, 92868 USA

Chaitali Nangia 4

Atlantic Permanente Research Institute 655 Watkins Mill Road Gaithersburg, MD, 20879 USA

Leon Hwang 4

California Pacific Medical Center 2100 Webster Street, Suite 326 San Francisco, CA 94115 USA

Wei Tang 3

Delta Oncology Associates 104 Palmyra Drive Suffolk, VA, 23434 USA

Lloyd A. Shabazz 3

Oncology Specialists, SC 7900 Milwaukee Ave., Suite 16 Niles, IL, 60714 USA

Sigrun Hallmeyer 2

Hematology Oncology Associates of Northern New Jersey PA 100 Madison Ave. 2nd Floor Morristown, NJ, 07962 USA

Steven Papish 2

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Site Principle investigator Number of patients recruited

Wayne State University/Karmanos Cancer Institute 4100 John R. HW04HO Detroit, MI, 48201 USA

Michael Simon (formerly Sayeh Lavasani)

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Kaiser Permanente Medical Group 3288 Moanalua St. Honolulu, HI, 96819

Jennifer Carney 2

Northwest Medical Specialties 2920 S. Meridian, Suite 100 Puyallup, WA, 98372 USA

Sibel Blau 2

OnCare Hawaii 98-211 Pali Momi St. Suite 320 Aiea, HI 96701 USA

Arnold K. N. Yee 2

M. Francisco Gonzalez M.D. P.A. Hematology Oncology Center 3 Medical Court Sumter, SC, 29150 USA

M. Francisco Gonzalez 1

Northshore University Health System 2650 Ridge Avenue Evanston, IL, 60201 USA

Douglas Merkel 1

University of Maryland School of Medicine 650 West Baltimore Street, 7N Baltimore, MD, 21201 USA

Timothy Meiller 1

University of Connecticut Health Center 263 Farmington Avenue Farmington, CT, 06030-3940 USA

Rajesh V. Lalla 1

Regional Cancer Care Associates 1930 E. Route 70, Suite V107 Cherry Hill, NJ 08003 USA

Priya Gor 1

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Appendix Table 4. Exclusion criteria Patients eligible for enrollment in this study must not meet any of the following criteria: 1 Patients currently receiving anticancer therapies (except bisphosphonates, denosumab) 2 Patients who currently have stomatitis/oral mucositis/mouth ulcers 3 Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus,

temsirolimus) 4 Known impairment of GI function or GI disease that may significantly alter the absorption of oral

everolimus 5 Uncontrolled diabetes mellitus as defined by HbA1c > 8% despite adequate therapy. Patients with a known

history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary

6 Patients who have any severe and/or uncontrolled medical conditions such as: •Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to start of everolimus, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease •Symptomatic congestive heart failure of New York heart Association Class III or IV •Active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease (except for Hepatitis B and Hepatitis C positive patients) •Known severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air) •Active, bleeding diathesis

7 Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or inhaled corticosteroids are allowed

8 Known history of HIV seropositivity 9 Patients who have received live attenuated vaccines within 1 week of start of everolimus and during the

study. Patient should also avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines

10 Patients who have a history of another primary malignancy, with the exceptions of: non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from which the patient has been disease free for ≥3 years

11 Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study or patient diaries

12 Patients who are currently part of any clinical investigation or who has not had resolution of all acute toxic effects of prior anti-cancer therapy to NCI CTCAE version 4.03 Grade 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator’s discretion).

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Appendix Table 5. Incidence of stomatitis in SWISH and BOLERO-2 studies Stomatitis SWISH 8 weeks

N=85 n (%) (95% CI)

BOLERO-2 ~13 months N=482

n (%) (95% CI)

BOLERO-2 8 weeks N=482

n (%) (95% CI) Any grade 18 (21·2%) (13·06–31·39) 321 (66·6%) (62·8–70·8) 295 (61·2%) (56·7–65·6) Grade 1 16 (18·8%) (11·16–28·76) 162 (33·6%) (29·4–38·0) 163 (33·8%) (29·6–38·2) Grade 2 2 (2·4%) (0·29–8·24) 120 (24·9%) (21·1–29·0) 97 (20·1%) (16·6–24·0) Grade 3 0 (0·0%) (0·0–4·25) 39 (8·1%) (5·8–10·9) 35 (7·3%) (5·1–10·0) Grade 4 0 (0·0%) (0·0–4·25) 0 (0·0–0·8) 0 (0·0–0·8)

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Table 6. Sites of metastases at baseline

Metastatic sites, n (%) N=86

Spinal cord 70·84 (4·7)

Brain 2 (2·3)

Meninges 0

Pleura 7 (8·1)

Pleura effusion (malignant) 9 (10·5)

Lung 28 (32·6)

Pericardial effusion (malignant) 1 (1·2)

Cervical lymph nodes 3 (3.5)

Thoracic lymph nodes 9 (10·5)

Spleen 1 (1·2)

Liver 31 (36·0)

Para-aortic abdominal lymph nodes 1 (1·2)

Peritoneum 3 (3·5)

Ascites (malignant) 1 (1·2)

Breast 15 (17·4)

Axillary lymph nodes 18 (20·9)

Ovary 1 (1·2)

Skin 2 (2·3)

Bone marrow 4 (4·7)

Bone, cervical vertebrae 11 (12·8)

Bone, thoracic vertebrae 26 (30·2)

Bone, lumbar vertebrae 29 (33·7)

Bone, sacrum 11 (12·8)

Bone, pelvis 27 (31·4)

Bone, femur 18 (20·9)

Bone, scapulae and humeri 10 (11·6)

Bone, other 16 (18·6)

Bone, sternum and ribs 26 (30·2)

Other, specify 31 (36·0)

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Table 7. Previous antineoplastic therapy

Therapeutic Class N=86 n (%)

Anthracyclines and related substances 41 (47·7)

Bisphosphonates 7 (8·1)

Combinations of antineoplastic agents 6 (7·0)

Gonadotropin releasing hormone analogues 4 (4·7)

Monoclonal antibodies 6 (7.0)

Nitrogen mustard analogues 50 (58·1)*

Other antineoplastic agents 2 (2·3)

Other cytotoxic antibiotics 5 (5·8)

Other drugs affecting bone structure and mineralization 7 (8·1)

Other immunosuppressants 3 (3·5)

Other therapeutic products 10 (11·6)

Platinum compounds 7 (8·1)

Pyrimidine analogues 24 (27·9)†

Taxanes 49 (57·0)

Vinca alkaloids and analogues 1 (1·2) *49 (57.0%) of patients received cyclophosphamide, and 1 (1.2%) received cyclophosphamide with doxorubicin †13 (15·1%) of patients received capecitabine.