Safety and tolerability of dostarlimab in combination antiretroviral therapy–refractory HIV-associated Kaposi sarcoma: Preliminary results from the StarKap phase Ib trial.

Abstract

e14588 Background: HIV-associated Kaposi’s Sarcoma (KS) is a rare malignancy associated with Human Herpesvirus-8 (HHV-8) in people living with HIV. Programmed Cell Death-1 (PD-1) blockade may lead to anti-tumour immune reconstitution. Methods: Starkap (NCT05646082) enrols patients (pts) with well-controlled HIV and anti-retroviral (cART) refractory KS to receive 4-weekly dostarlimab 500 mg for 4 cycles followed by 6-weekly 1000 mg for up to 1 year. Study objectives are safety per CTCAE v.5.0 and efficacy by ACTG criteria. Funding and Product for this study was provided by GSK. Results: As of 12/2024, 10 of 13 pts were evaluable for safety and efficacy at cycle 4 (C4). All pts were cisgender male, median age was 56 (IQR:49-60); HIV-viral load (VL) was < 200 copies/ml in all; median CD4 count: 622 cells/mm 3 (IQR:494-800). Four had high-risk KS (oedema/ulceration). One pt was chemo-naïve; the median number of treatment lines was 2 (range:0-10). All pts had >1 adverse event (AEs), 4 of grade >3. Treatment-related AEs occurred in 7 pts, all of grade 1-2 and not requiring steroid. At C4, objective response rate and disease control rate were 30% and 90%, respectively. HHV-8 DNA declined at C4 (208 vs 41 copies/ml, p = 0.035), with no HIV-VL or CD4 changes. Spatial transcriptomic analysis of paired screening/C4 tumour samples (N = 10), demonstrated a significant enrichment in pathways associated with interferon type I, chemokine receptors activation, NFkb and TLR cascade at C4, and marked enrichment in immunoglobulin transcripts in non-responders. Immune deconvolution showed increased T-regs (p = 0.035) and decreased macrophages (p = 0.048) at C4. A non-significant rise was seen in NK, CD4, and CD8 naïve cells. Non-responders had higher B-naïve/CD4 memory infiltration and lower NK and monocyte at baseline. ImmunoSeq-based TCRbeta-chain sequencing of paired screening/C4 tumour and blood samples identified 9 clones in matched screening/C4 bloods and tumour, expanded in both compartments throughout treatment. Of these, according to public datasets (IEDB), 6 had unknown antigen specificity, 1 targeted HBV, and 2 targeted CMV. In all but 2 patients, a total of 39 new intra-tumoral clones were detected at C4, with 37 of unknown specificity. Of the remaining 2, 1 was specific for SARS-CoV-2, and the other one for EBV and CMV. Conclusions: Dostarlimab is tolerable and has anti-tumour activity in cART-refractory KS, mirrored by longitudinal HHV-8 DNA decline. Translational analyses suggest post-treatment changes in the tumour microenvironment, with PD-1 inhibition driving pre-existing T-cell clonal expansion and intra-tumoral generation of new clones. Clinical trial information: NCT05646082 .