As-Needed versus Immediate Etoposide Chemotherapy in Combination with Antiretroviral Therapy for Mild or Moderate AIDS-associated Kaposi Sarcoma in Resource-Limited Settings: A5264/AMC-067 M.C. Hosseinipour1,2, M. Kang3, S.E. Krown4, A. Bukuru5, T. Umbleja3, J. Martin6, J. Orem7, C. Godfrey8, B. Hoagland9, N. Mwelase10, D. Langat11, M. Nyirenda12, J. MacRae13, M. Borok-Williams4,14, W. Samaneka14, A. Moses1,2, 4, R. Mngqbisa15, Naftali Busakhala16, O. Martínez-Maza4,17, R. Ambinder4,18, D.P.Dittmer2, 4, M. Nokta19, T.B. Campbell20, A5264/AMC-067 REACT-KS team

Rationale High mortality and sub-optimal treatment response are common for patients with KS in resource limited settings. The current standard of care for initial management of mild-to-moderate KS is ART. Existing data are insufficient to determine if concomitant chemotherapy is beneficial as an adjunct to ART for mild-to-moderate KS. If beneficial in this setting, an inexpensive oral chemotherapy regimen would be advantageous. KS is the most common HIV associated cancer in resource limited settings with associated high mortality and morbidity and suboptimal responses. For KS, the standard of care include ART as a first step. However, Some KS responds to ART alone while more advanced disease often requires chemotherapy. However, for mild to moderate KS, there is insufficient evidence to know if concominant chemotherapy is beneficial as an adjunct to ART. If beneficial, an inexpensive oral chemotherapy would have distinct advantages.

Enrolled HIV positive, mild-to-moderate KS, initiating ART (n=192) Excluded (n=2) ¨  Lost to follow-up (n=17)   Arm A: As-Needed (n=94) ¨ Received ART only (n=62) Received ART and delayed etoposide (n=32) Lost to follow-up (n=16) Arm B: Immediate (n=96) ¨ Received ART and immediate etoposide (50-100mg/d x 7 days, q2wks x 6-8 cycles) (n=96) Randomized (n=190) The ACTG 5264/AMC 067 study randomized 190 participants who were initiating ART who had biopsy confirmed mild to moderate KS to one of 2 arms. This individuals were felt to NOT require chemotherapy immediately Arm A started ART (TDF/FTC/Efavirenz) and oral etoposide chemotherapy if they had disease progression. The Immediate arm started oral etoposide and ART at the sametime. The chemotherapy regimen was 50-100 mg/d x 7 days every 2 week for up to 6 to 8 cycles depending on response. 48 weeks Primary endpoint analysis (n=80) ¨ Excluded due to early closure (n=14) Time-to-event analyses (n=94)   Primary endpoint analysis (n=83) ¨ Excluded due to early closure (n=13) Time-to-event analyses (n=96)

Baseline Characteristics As Needed(94) Immediate (96) Female 28 (30%) 27 (28%) Age3 34 (28, 41) 35 (30, 41) Black or African 89 (95%) 88 (92%) Body Mass Index (kg/m2)3,5 21.9 (19.9, 23.6) 22.0 (19.7, 24.8) Hemoglobin (g/dL)3 12.0 (10.7, 13.3) 11.9 (10.4, 13.3) Neutrophils (per mm3) 1698 (1280, 2790) 2067 (1410, 2765) CD4+ cells (per mm3) 190 (88, 325) 165 (63, 327) HIV RNA (log10 copies/mL)3 5.1 (4.5, 5.5) 5.1 (4.6, 55) KS stage T0 35 (37%) 40 (42%) Oral KS present 55 (59%) 55 (57%) Edema present 57 (61%) 54 (56%) >50 cutaneous KS lesions 43 (46%) 44 (46%) The enrolled participants were similar between the arms. Women represented approximately 30%, most were Black or African, and approximately 40% had KS T0 disease. For those with T1 disease, this was largely due to presence of oral KS or edema that did not interfere with function.

Alternate Chemotherapy Death Lost to follow-up 43 (53.8%) 21 12 10 3  Primary Endpoint As-Needed (N=80) Immediate (N=83) p- value E1 (Failure) ** Progression Alternate Chemotherapy Death Lost to follow-up 43 (53.8%) 21 12 10 3 47 (56.6%) 7 31 8 0.911 E2 (Stable) 13 (16.3%) 9 (10.8%) E3 (Response) Partial response Complete response 24 (30.0%) 27 (32.5%) 23 4 WE found there was no difference in the primary outcome at 48 weeks. Our failure outcome was a composite outcome that included Death, KS progression, initiation of alternate chemotherapy or LTFU. As you can see the Failure percentage was similar at 54% and 57% although the reason failure different with progression more common in the as needed arm and chemotherapy other than etoposide in the immediate arms. Death and LTFU were similar. Notably, the response rate was similar with more individuals having partial response rather than complete response

Time to Failure Time to Progression Time to KS Response Time to KS-IRIS In the time to event response, the immediate arm had a slower time to failure and progression, faster time to KS response and lower incidence of KS-IRIS. So all of these favored immediate chemotherapy but the effect was not durable to 48 weeks.

Conclusions No difference at 48 weeks in primary outcome KS progression and mortality were high in both treatment strategies. Some measures favoured the Immediate arm Delayed KS progression, Decreased occurrence of suspected KS-IRIS Faster time to initial KS response Further research is needed to identify whether specific patient subsets might benefit from immediate etoposide or other chemotherapy plus ART and to improve overall treatment outcomes. In HIV-infected individuals initiating ART with mild-to-moderate KS in low- and middle-income countries, the addition of immediate oral etoposide failed to provide a clinically meaningful benefit at 48 weeks compared to the addition of etoposide in the event of disease progression.  Because rates of KS clinical progression and mortality were unacceptably high amongst patients with mild-to-moderate KS in both treatment strategies we studied, additional research is needed to find new strategies and interventions to improve outcomes in this population. Until such interventions are found, clinicians in resource-limited settings should recognize the lack of evidence for initial treatment of mild-to-moderate KS above and beyond ART alone.  At a minimum, the most active available chemotherapeutic agents against KS should be added if patients progress despite initial ART.  Decisions to add chemotherapeutic agents (other than etoposide) concomitantly with ART must be made on a case-by-case basis taking into account availability, perceived tolerability, and patient preferences