Incidence, Characteristics, and Management of Alpelisib-Associated Rash in Patients With Advanced Breast Cancer Anisha B. Patel, MD1,a; Lucia Seminario-Vidal, MD, PhD2  1University of Texas MD Anderson Cancer Center, Houston, TX; 2H. Lee Moffitt Cancer Center, Tampa, FL Authors contributed equally to this work aPresenting author Presented at: 2020 Fall Clinical Dermatology Conference. October 29-November 1, 2020. Las Vegas, NV. Synopsis • Hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) breast cancer is the most common subtype of advanced breast cancer (ABC).1 • ~40% of patients with HR+, HER2– breast cancer have mutations in the PIK3CA gene, which encodes the α subunit of phosphatidylinositol-3-kinase (PI3K).2-4 – PIK3CA mutations have been associated with the development of resistance to endocrine therapy, and are a negative prognostic factor in ABC.4,5 • Alpelisib is an α-selective PI3K inhibitor approved in combination with fulvestrant for the treatment of patients with HR+, HER2– ABC with mutations in the PIK3CA gene who progressed on or after endocrine therapy.6 – U.S. Food & Drug Administration (FDA) approval of this combination was based on improved efficacy data compared with placebo plus fulvestrant, and a manageable safety profile reported in the Phase III SOLAR-1 trial (NCT02437318).7 • Cutaneous toxicities, particularly the development of rash, are a class effect of PI3K pathway inhibitors and have been reported in up to 54% of patients treated with alpelisib.7-9 Objective • The objective of this poster is to provide dermatologists with specific guidance on the management of alpelisib-associated dermatologic adverse events. Methods • This review of alpelisib-associated rash includes safety data from the SOLAR-1 trial, the BYLieve study, and a single-center retrospective study. – SOLAR-1 evaluated alpelisib (300 mg QD) + fulvestrant (500 mg, every 28 days and once on day 15) or placebo + fulvestrant (equal dosing) in women or men with HR+, HER2− ABC who had progressed on or after prior aromatase inhibitor (N=572).7 – BYLieve (NCT03056755), is an ongoing Phase II study evaluating alpelisib (300 mg QD) + fulvestrant (500 mg, every 28 days and once on day 15) or letrozole (2.5 mg QD) in women of any menopausal status and men with HR+, HER2− ABC and confirmed PIK3CA-mutant status who had progressed on or after prior treatments.10 • Results from Cohort A (N=127; cohort of patients previously treated with cyclin-dependent kinase [CDK]4/6 inhibitors) have recently been reported and are included here. – A single-center retrospective study evaluated data from 4 randomized trials and postapproval treatment records involving ABC patients who received alpelisib-based treatments (most frequently combined with endocrine therapy; N=102), with the purpose of characterizing alpelisib-associated cutaneous toxicities and describing management strategies.11 • Alpelisib prescribing information and other available literature are also included. Results Incidence of Alpelisib-Associated Rash • Clinical trials have reported an incidence of any-grade rash (by single preferred term) ranging from 28% to 36% (grade ≥3 = 9%-10%) in alpelisib-treated patients.7,10 – Rash led to treatment discontinuation in 3% to 4% of these patients. – No grade 4 rash was reported in SOLAR-1 or in the retrospective study.7,9,11 Characteristics of Rash • In clinical studies, the median time to rash onset was approximately 2 weeks after starting alpelisib treatment.9,11 • In the retrospective study, median duration of rash was 7 days.11 – In SOLAR-1, the median time to improvement by at least 1 grade in patients with grade ≥3 rash was 11 days.9 • Rash is more frequently localized in the trunk (including chest, abdomen, and back) and extremities; rash on face and scalp is less common.11 • Rash events can be asymptomatic, or present symptoms such as burning pain or pruritus (more common in grade 3 rash).11 36 73 53 70 53 70 41 15 26 20 27 14 23 12 21 10 20 16 0 10 20 30 40 50 60 70 80 No Prophylaxis (n=198) Prophylaxis (n=86) No Prophylaxis (n=117) Prophylaxis (n=10) No Prophylaxis (n=59) Prophylaxis (n=43) No rash Grade 1/2 rash Grade 3/4 rash BYLieve P at ie n ts , % Retrospective StudyaSOLAR-1a CTCAE grading Alpelisib dosing Supporting medication Alpelisib rechallenge Grade 1 <10% BSA with active skin toxicity. No alpelisib dose adjustment required. Initiate class I-III topical corticosteroids (triamcinolone, betamethasone, clobetasol, or fluocinonide). • If presenting with pruritus or burning sensation, add antihistamines in the morning (nonsedating: cetirizine/loratadine) and at night (sedating: hydroxyzine or diphenhydramine). • If presenting with acneiform rash, consider other causative agents (oral contraceptives, antiandrogen medications, dehydroepiandrosterone, etc); avoid diphenhydramine. Alpelisib may be resumed at the same dose once rash resolves to grade ≤1, or at a reduced dose at second occurrence. A graded rechallenge with alpelisib may also be considered while maintaining antihistamine treatment and tapering systemic steroids. Interrupt alpelisib until improved to grade ≤1. Follow grade 1/2 supporting medication, and initiate systemic corticosteroidsb (prednisonec, 10-14 days with taper). Permanently discontinue alpelisib. Grade 2 10%-30% BSA with active skin toxicity. Grade 3 30% BSA with active skin toxicity. Grade 4 Life-threatening; any % BSA with extensive superinfection and IV antibiotics indicated. Conclusions • Rash is a frequently observed alpelisib-associated adverse event that can be managed with medication, such as antihistamines and corticosteroids, and alpelisib dose adjustments and interruptions. – Rash leading to alpelisib treatment discontinuation did not occur frequently in clinical studies and most patients were able to resume anticancer treatment upon rash resolution. • Preventive strategies, such as administration of prophylactic medication, patient education, early detection of symptoms, and prompt treatment, may help minimize the onset and severity of alpelisib-associated rash. • Severe cutaneous reactions (SJS, EM, DRESS, and TEN) are not common in patients treated with alpelisib; if suspected, alpelisib should be interrupted, and permanently discontinued if diagnosis is confirmed. References 1. Blows FM, et al. PLoS Med. 2010;7(5):e1000279. 2. Cancer Genome Atlas Network. Nature. 2012;490(7418):61-70. 3. Mollon L, et al. AACR 2018. Poster 1207. 4. Mosele F, et al. Ann Oncol. 2020;31(3):377-386. 5. Sobhani N, et al. J Cell Biochem. 2018;119(6):4287-4292. 6. Piqray [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019. 7. André F, et al. N Engl J Med. 2019;380(20):1929-1940. 8. Schindler K, et al. J Clin Oncol. 2014;32:e20639. 9. Rugo HS, et al. Ann Oncol. 2020;31(8):1001-1010. 10. Rugo HS, et al. ASCO 2020. Abstract 1006 (oral). 11. Wang DG, et al. Breast Cancer Res Treat. 2020;183(1):227-237. 12. U.S. Department of Health and Human Services, NIH, National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0 (CTCAE). 13. U.S. Department of Health and Human Services, NIH, National Cancer Institute. Common Terminology Criteria for Adverse Events v4.03 (CTCAE). 14. Nunnery SE, Mayer IA. Ann Oncol. 2019;30(suppl 10):x21-x26. 15. Chia S, et al. Curr Oncol. 2015;22(1):33-48. 16. Balagula Y, et al. Cancer. 2012;118(20):5078-5083. 17. BC Cancer. Provincial Health Services Authority. http://www.bccancer.bc.ca/. Accessed August 31, 2020. 18. Tan AU, et al. Int J Womens Dermatol. 2017;4(2):56-71. 19. Tamez-Perez HL, et al. World J Diabetes. 2015;6(8):1073-1081. Acknowledgments Medical editorial assistance was provided by Casandra M. Monzon, PhD, Healthcare Consultancy Group, LLC, and was funded by Novartis Pharmaceuticals Corporation. Prevention of Alpelisib-Associated Rash • Administering prophylactic medication to patients receiving alpelisib before the onset of rash has been shown to reduce the incidence and severity of this adverse event (Figure 1).9 -11 Figure 1. Occurrence of rash in patients who received prophylaxis and those who did not • Strategies that both health care professionals (HCPs) and patients can adopt to prevent the onset of alpelisib-associated rash are described in Figure 2.9 -11 Severe Cutaneous Reactions • Life-threatening skin toxicities, such as Stevens-Johnson syndrome (SJS), erythema multiforme (EM), drug reaction with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN) are not common.6,11 – Patients with a history of severe cutaneous reactions should not start alpelisib treatment.6 – Symptoms may include a prodrome of fever, flu-like symptoms, mucosal lesions, or progressive skin rash.6 – Alpelisib should be interrupted if severe cutaneous reactions are suspected, and permanently discontinued if diagnosis is confirmed or grade 4 rash occurs.6 Management of Alpelisib-Associated Rash • Alpelisib-associated rash is generally reversible with adequate co-medication and, if needed, alpelisib dose adjustments/interruption (mostly in patients experiencing grade 3 rash; Figure 3).7,11 – Retrospective data showed that upon improvement to grade ≤1 rash, 12 of 16 patients (75%) who interrupted treatment were able to resume alpelisib and did not experience rash recurrence (9 of those patients were rechallenged with the initial alpelisib dose); 4 patients (25%) experienced rash recurrence within 24 hours of alpelisib rechallenge and required permanent alpelisib discontinuation.11 • Active management of alpelisib-associated rash may help limit dose adjustments and prevent treatment interruptions to achieve better therapeutic efficacy.9,11 • Management strategies include – Early identification and intervention – Patient education – Clear guidance on preventive treatment – HCP training on supportive medications and dose adjustment protocols • In SOLAR-1, more detailed management guidelines introduced after a protocol amendment resulted in a decrease in incidence of grade 3 rash.9 Figure 3. Management of alpelisib-associated rash based on severity6,7,11,17,18,a • The vast majority of patients who develop alpelisib-associated rash present with maculopapular (morbilliform) rash; acneiform rash can also be observed. Characteristics of these 2 rash types are presented in Table 1.11 • Retrospective data from 2 patients who experienced alpelisib-associated rash showed histology consistent with a hypersensitivity reaction.11 • Laboratory assessment data showed that patients who developed rash had an increase in blood eosinophils after 2 weeks of alpelisib treatment compared with baseline (2.7% vs 4.4%, P<0.05); a trend toward elevated ALT was also observed.11 – No differences in lymphocyte, neutrophil, or monocyte counts were reported between patients who developed rash and those who did not. This presentation is the intellectual property of the author/presenter. Contact them at APatel11@mdanderson.org for permission to reprint and/or distribute. Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission of the authors. Text: Q1ad94 To: 8NOVA (86682) US Only + 18324604729 North, Central, and South Americas; Caribbean; China +447860024038 UK, Europe, and Russia +46737494608 Sweden and Europe Visit the web at: http://novartis.medicalcongressposters.com/ Default.aspx?doc=1ad94 Scan this QR code aNo grade 4 rash was reported in SOLAR-1 or in the retrospective study. aEvaluation by a dermatologist familiar with these toxicities is recommended. bSystemic corticosteroids may worsen alpelisib-associated hyperglycemia. Caution should be exercised.19 cMethylprednisolone or prednisolone are preferred over prednisone for patients with liver disease. BSA, body surface area; CTCAE, Common Terminology Criteria for Adverse Events; IV, intravenous. Table 1. Characteristics of alpelisib-associated rash Rash Type Relative Incidence11 Possible Symptoms11-13 Clinical Features11-15 Histopathological Characterization11,16 Maculopapular (morbilliform) 26 of 29 patients in the alpelisib retrospective study (90%) experienced maculopapular rash; more common in patients receiving alpelisib plus hormone therapy • Pruritic • Burning sensation • Tightness • Presence of macules and papules • Centripetal distribution; mostly localized on upper trunk and extremities • Superficial perivascular dermatitis with focal or mild interface change or folliculocentric spongiosis • May present with lymphocytic infiltration Acneiform 3 of 29 patients in the alpelisib retrospective study (10%) experienced acneiform rash; more common in patients with HER2+ BC receiving alpelisib plus trastuzumab and anti-HER3 Ab • Generally asymptomatic; however, pruritus and tenderness may occur • Presence of papules or pustules • Wide distribution; frequently located on face, scalp, upper chest, and back • Presence of open comedones has been observed with everolimus, which inhibits another node of the PI3K pathway (mTOR) • Histopathology for alpelisib-associated acneiform rash not reported • Patients treated with everolimus have presented with eczematous histology, interface dermatitis, and spongiosis Ab, antibody; BC, breast cancer; HER, human epidermal growth factor receptor; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase. Figure 2. Rash prevention strategies HCPs • Consider prescribing prophylactic nonsedating antihistamines (10 mg/day cetirizine or loratadine) to patients starting alpelisib during the first 8 weeks of therapy. • Educate patients on the signs and symptoms of alpelisib-associated rash for early-reporting and prompt management. Patients • Maintain proper skin hydration. • Avoid sun exposure and irritant skin products to prevent worsening of rash, dryness, and itching.