Abstract PS5-02-30: Prolonged survival following PD-L1/PD-1 immune checkpoint inhibitor therapy after leronlimab induced PD-L1 upregulation on cancer-associated macrophage-like cells and circulating tumor cells in patients with metastatic or locally

Abstract Background. Pretreated patients with metastatic triple-negative breast cancer (mTNBC) have a poor prognosis. In clinical trials among previously treated mTNBC patients the median overall survival (mOS) has been reported as 6.6 months for ≥3rd line chemotherapy, 11.8 months for ≥2nd line sacituzumab govitecan, and 9.9 months for ≥1st line pembrolizumab. It has also been reported that in the real-world, after first line therapy around a third of patients die before receiving 2nd line treatment. Furthermore, there remains an unmet need in the PD-L1 negative mTNBC patient population. It has been shown that >95% of TNBCs are positive for C-C chemokine receptor 5 (CCR5). Leronlimab (LRM) is a humanized monoclonal antibody that blocks CCR5 and reduces TNBC metastasis by >98% in preclinical models. Methods. In a retrospective post hoc analysis, data were pooled from 28 patients with mTNBC from 3 LRM clinical trials (NCT03838367 [N=10]; NCT04313075 [N=16]; NCT04504942 [N=2]). LRM was given subcutaneously weekly at a dose of 350 mg (N=10), 525 mg (N=15), or 700 mg (N=3) in combination with various chemotherapies ± immune checkpoint inhibitors (ICI). PD-L1 staining was measured on cancer-associated macrophage-like cells (CAMLs) and circulating tumor cells (CTCs) prior to and after (≈40 days) LRM treatment. Cox proportional univariate analyses were run to determine Hazard Ratios (HRs) for progression-free survival (PFS) and overall survival (OS) at 48 months. Results. Median age was 48.5 years (range 32-83) with a median of 2 prior metastatic therapies (range 0 to ≥3). Overall, 18% (5/28) of patients had PD-L1 positive tumor staining (CPS≥10%). LRM was well tolerated with no patients withdrawing due to LRM-related adverse events and no dose-limiting toxicities. Overall, mPFS was 3.8 months and mOS was 6.8 months. Survival at 1, 2, 3, and 4 years was 35.7%, 21.4%, 17.9%, and 17.9%, respectively. An upregulation from baseline of PD-L1 was observed in CAMLs/CTCs in 76% (16/21) of patients (7 patients had no post-baseline samples) after any dose of LRM, and in 88% (15/17) of patients receiving the 525 mg or 700 mg doses. Sixteen patients showed a drop in CAMLs/CTCs after initiating LRM while 12 showed an increase. The mOS for patients who showed a drop in CAMLs/CTCs was 17.2 months (95% CI, 9.4–N/A) compared to 3.7 months (95% CI, 1.7–5.6) for those patients who showed an increase in CAMLs/CTCs after LRM treatment (HR: 7.11 [95% CI, 2.5–20.2; p=0.0007]). Further, of the seven patients treated with an ICI with, or after LRM, 5/5 (100%) patients with PD-L1 upregulation remained alive at 4 years, compared to none of the 21 patients (0%) who did not receive an ICI with or after LRM (HR: 4.14 [95% CI, 1.7–10.2; p=0.0041]). Conclusions. In this retrospective pooled analysis of 28 mTNBC patients, LRM was well tolerated. A 4-year OS rate of 17.9% (5/28) in a population with a median of 2 prior metastatic therapies is encouraging. Among a key subgroup, all 5 patients with PD-L1 upregulation who subsequently received ICI remained alive at 4 years possibly indicating a correlation with durable responses. A reduction in CAMLs/CTCs after LRM treatment may relate to improved survival, suggesting its potential as a prognostic biomarker. These findings support the hypothesis that LRM may enhance PD-L1 expression on CAMLs/CTCs, potentially priming tumors for improved responses to ICIs. In an evolving treatment landscape these data warrant prospective evaluation of LRM, particularly in combination with ICIs in mTNBC. Citation Format: M. V. Dolezal, V. G. Abramson, N. Chittoria, S. Ehsani, R. G. Pestell, H. S. Rugo, H. Rui, D. L. Adams, J. Meidling, M. Lataillade, J. P. Lalezari. Prolonged survival following PD-L1/PD-1 immune checkpoint inhibitor therapy after leronlimab induced PD-L1 upregulation on cancer-associated macrophage-like cells and circulating tumor cells in patients with metastatic or locally advanced triple-negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-02-30.