Immunotherapy vs. chemotherapy run-in followed by pembrolizumab plus nab-paclitaxel in metastatic triple negative breast cancer (mTNBC): Results from a phase II study.

1112 Background: Pembrolizumab (pembro) with chemotherapy has shown survival benefit in PD-L1+ (CPS10+) mTNBC, but many responses are not durable, and patients with PD-L1 negative/low tumors do not benefit from the combination. Data from GeparNuevo and TONIC suggest that induction therapy can remodel the tumor immune environment and improve responses. We have conducted a trial with two run-in cohorts and mandatory serial tissue and blood collections in 50 mTNBC patients, comparing pembro vs. nab-paclitaxel (nab-P). Methods: Single-arm, single institution phase II study (NCT02752685) to evaluate safety and clinical activity of nab-P+pembro in PD-L1 unselected mTNBC, 0-2 prior lines of chemotherapy allowed. Patients (n = 50) were enrolled sequentially into two cohorts: chemotherapy run-in (cTNBC, nab-P before nab-P+pembro) and immunotherapy run-in (iTNBC, pembro before nab-P+pembro). Serial tumor biopsies assessed by IHC (Dako 22C3), quantitative multiplex immunofluorescence (qMIF), and gene expression (NanoString). Overall response rates assessed using irRECIST. Tumoral T- and myeloid-cell phenotypes, peripheral lymphocyte-to-neutrophil ratio (LNR), and monocyte-to-lymphocyte ratio (MLR) were correlated with overall response rate (ORR) and survival outcomes. Results: 50 patients enrolled and completed treatment, for 80% of patients: treatment was 1L for metastatic disease. Median follow-up is 19.9 months, clinical results for cTNBC and iTNBC cohorts shown in table. Across both cohorts higher LNR was associated with improved OS ( R = 0.37, p = 0.0075), conversely, higher MLR was associated with poorer OS ( R = -0.46, p = 0.00087). Tumor immune cell subpopulations showed no significant differences between iTNBC and cTNBC at baseline. Analyses of on-treatment samples will be presented at the meeting. PD-L1 expression, while not different at baseline, remained unchanged in cTNBC but increased significantly in iTNBC ( p < 0.02), possibly reflecting pembrolizumab-driven immune modulation. With the caveat of comparing sequential cohorts, the iTNBC cohort showed a trend for higher ORR (47% vs. 23%, p = 0.08) and longer median PFS (8.4 vs. 5.5 months, HR = 0.68, 95%CI: 0.37-1.24), with significantly longer OS (25.8 vs. 18 months, HR = 0.50, 95%CI: 0.26-0.98, p = 0.043) compared to cTNBC. Conclusions: Timing of pembro administration may influence PD-L1 expression and clinical outcomes in mTNBC. We show that the immunotherapy run-in strategy converts more PD-L1-negative/low into PD-L1-positive tumors, possibly rendering more patients eligible for chemoimmunotherapy and improving outcomes. Clinical trial information: NCT02752685 . cTNBC (n=30) iTNBC (n=20) PD-L1 CPS >/=10 5/23 (22%) 2/16 (12%) PD-L1 CPS conversion (CPS<10 to CPS>/=10) 2/14 (14%) 4/13 (31%) Confirmed ORR (CR+PR) 7/30 (23%) 9/19 (47%) mPFS (months) 5.5 8.4 mOS (months) 18.0 25.8