A phase I study of pomalidomide and nivolumab (Pom/Nivo) in patients with virus-associated malignancies with and without HIV.

2663 Background: Up to 15% of cancers worldwide are associated with oncogenic viruses and disproportionately affect people with HIV (PWH). Epstein–Barr virus (EBV) is linked to several malignancies, particularly lymphomas; Kaposi sarcoma herpesvirus (KSHV) to Kaposi sarcoma (KS) and primary effusion lymphoma (PEL); and human papillomavirus (HPV) to anogenital and head and neck cancers. Virus-associated tumors evade immune surveillance through mechanisms such as T-cell exhaustion. In vitro studies show that pomalidomide (Pom), an immunomodulatory drug, enhances T-cell co-stimulation and increases immune surface marker expression in virus-infected cell lines. Pom may synergize with nivolumab (Nivo), an anti-PD-1 monoclonal antibody, to reverse immune exhaustion and enhance antitumor immunity. Methods: This phase I study enrolled participants (pts) with advanced virus-associated malignancies (EBV, KSHV, HPV). PWH were required to receive antiretroviral therapy for ≥4 weeks with an HIV viral load (VL) ≤400 copies/mL. There was no CD4 T-cell requirement; however, major opportunistic infections (with limited exceptions) were not permitted within 6 months of enrollment. Intravenous Nivo (480 mg) was administered every 28 days with Pom given once daily on days 1-21 of a 28-day cycle using a 3+3 dose-escalation design (DL1=3 mg, DL2=4 mg, optional DL-1=2 mg) for up to 24 cycles. The primary objective was safety and tolerability of the combination (using CTCAE v5.0). The secondary objective was to evaluate the anti-tumor activity of Pom/Nivo using disease-specific criteria (RECIST 1.1, Lugano criteria, or modified ACTG criteria for KS). Results: Sixteen pts (75% male, 56% White and 37% Hispanic) were enrolled, including 9 PWH with a baseline median (med) CD4 T-cell of 253 cells/mm³ (range 61-616) and HIV VL 37 copies/mL. After a med of 7 cycles (range 1-24), the most common Grade (G) 1/2 toxicities were anemia, lymphopenia, and maculopapular rash. Five pts had G3 or G4 neutropenia that was managed with growth factor support and Pom dose reductions. The only dose-limiting toxicity was observed in 1 pt with metastatic anal cancer in DL1 who developed G3 dyspnea; the maximum tolerated dose of Pom was 4 mg. Five pts were not evaluable for an objective response (2 died from progressive disease (PD), 2 declined further treatment, 1 was deemed ineligible), among 11 pts who received ≥3 cycles, all 4 pts with KS had a response (2 partial and 2 complete responses), 1 pt with PEL had stable disease (SD), 1 of 4 pts with HPV-malignancies had SD and 1 of 2 with nasopharyngeal carcinoma had SD, and 4 pts had PD. Among PWH, CD4 T-cell count did not change from baseline to the end-of-treatment (p=0.46). Conclusions: Pom/Nivo is a chemotherapy-sparing regimen with acceptable safety in advanced virus-associated cancers and promising activity in KS. Based on these results, an expanded KS cohort will be added to the trial. Clinical trial information: NCT04902443 .