*Local guidelines, or eg. ESC or AHA guidelines ESC guidelines website: https://www.escardio.org/Guidelines/Clinical- Practice- Guidelines AHA guidelines website: http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 Endocrine irAEs Endocrine Disorder Initial Management Follow -up Management Grade 1 or Grade 2 endocrinopathies (hypothyroidism, hyperthyroidism, adrenal insufficiency, type I diabetes mellitus) Consider continuing M7824 Consider endocrinology consult if needed Consider continuing hormone replacement/suppression and monitoring of endocrine function as appropriate. 48 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 Consider s tarting thyroid hormone replacement therapy (for hypothyroidism), anti -thyroid treatment (for hyperthyroidism), corticosteroids (for adrenal insufficiency) or insulin (for Type I diabetes mellitus) as appropriate. Consider ruling- out secondary endocrinopathies (i.e. hypopituitarism / hypophysitis) Grade 3 or Grade 4 endocrinopathies (hypothyroidism, hyperthyroidism, adrenal insufficiency, type I diabetes mellitus) Consider w ithholding or permanently discontinuing M7824 for Grade 3-4 events based upon if the clinical condition can be safely managed. Consider hospitalization Consider endocrinology consult Consider s tarting thyroid hormone replacement therapy (for hypothyroidism), anti -thyroid treatment (for hyperthyroidism), corticosteroids (for adrenal insufficiency) or insulin (for type I diabetes mellitus) as appropriate. Consider ruling- out secondary endocrinopathies (i.e. hypopituitarism / hypophysitis) Consider resuming therapy once symptoms and/or laboratory tests improve to Grade ≤ 1 (with or without hormone replacement/suppression). Consider continuing hormone replacement/suppression and monitoring of endocrine function as appropriate. Hypopituitarism/Hypophysitis (secondary endocrinopathies) If secondary thyroid and/or adrenal insufficiency is confirmed (i.e. subnormal serum FT4 with inappropriately low TSH and/or low serum cortisol with inappropriately low ACTH): • Consider r eferring to endocrinologist for dynamic testing as indicated and measurement of other hormones (FSH, LH, GH/IGF -1, PRL, testosterone in men, estrogens in women) • Consider hormone replacement/suppressive therapy as appropriate • Consider perform ing pituitary MRI and visual field examination as indicated If hypophysitis confirmed: Consider r esuming therapy once symptoms and hormone tests improve to Grade ≤ 1 (with or without hormone replacement). In addition, for hypophysitis with abnormal MRI, consider resum ing M7824 only once shrinkage of the pituitary gland on MRI/CT scan is documented. Consider continuing hormone replacement/suppression therapy as appropriate. 49 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 • Continue M7824 if mild symptoms • Consider w ithholding M7824 and if moderate, severe or life - threatening symptoms of hypophysitis . Consider hospitalization.