Evaluation of intra-tumoral (IT) SD-101 and pembrolizumab (Pb) in combination with paclitaxel (P) followed by AC in high-risk HER2-negative (HER2-) stage II/III breast cancer: Results from the I-SPY 2 trial.

Abstract

508 Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. SD-101 is an investigational Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide that stimulates the production of IFN-α and interleukin (IL)-12, functional maturation of plasmacytoid dendritic cells, and production of cytotoxic antibodies. IT SD-101 was combined with systemic anti-PD-1 antibody Pb to investigate the antitumor and immunologic activity of this novel immunotherapeutic strategy. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only pts (pts) with HER2- disease were eligible for this treatment. Treatment included weekly P x 12 in combination with IT SD-101 2 mg/ml (1 ml for T2 tumors, 2 ml for >T3 tumors) weekly x 4, then q3 weeks x 2, and IV Pb q3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) q2-3 weeks x 4 (SD-101+Pembro 4). Pts in the control arm received weekly P x 12 followed by AC q2-3 weeks x 4. The I-SPY 2 methods have been previously published. This investigational arm was eligible for graduation (>85% chance of success in a 300-person phase 3 neoadjuvant trial) in 3 of 10 pre-defined signatures: HER2-, hormone receptor (HR)+/HER2- and HR-/HER2-. Results: 75 pts were randomized and evaluable in SD-101+Pembro 4 treatment arm. The control arm included 329 historical controls enrolled since April 2010. The study arm was stopped due to maximal patient accrual. Pt characteristics were balanced; 56% HR+, 44% HR-. The probability that SD-101+Pembro4 was superior to control exceeded 97% for all eligible tumor signatures, but did not reach the threshold for graduation in any of the signatures. However, it is notable that the rate of pCR/Residual Cancer Burden 1 (RCB1) in the HR+/HER2- signature was 51%. Preliminary safety events for SD-101+Pembro 4 include increased rates of fever, neutropenia, febrile neutropenia, transaminitis, and immune-related events, including adrenal insufficiency. Conclusions: The SD-101+Pembro 4 regimen was active but did not meet the pre-specified threshold for graduation in I-SPY 2. pCR/RCB 1 analysis suggests improved response in the HR+/HER-negative signature compared to control. The clinical significance of these findings needs to be weighed against the potential risk of immune-related toxicities. Clinical trial information: NCT01042379. [Table: see text]

Progress and pitfalls in the use of immunotherapy for patients with triple negative breast cancer

“…The possibility to combine different approaches to increase the tumor recognition and response from the immune system is also being explored. SD-101 is a synthetic oligonucleotide that binds and activates tolllike receptor 9 in DCs, thus stimulating antigen presentation and cytotoxic T cells activity [76]. The combination of NACT with pembrolizumab and SD-101 was compared with anthracycline-and taxane-based NACT in patients with HER2-negative early BC in the adaptive I-SPY2 study [35,76].…”

Immunotherapy in triple negative breast cancer: beyond checkpoint inhibitors

“…The combination of neoadjuvant SD-101 and pembrolizumab in addition to weekly paclitaxel followed by doxorubicin and cyclophosphamide was investigated in a treatment arm of the I-SPY 2 trial (NCT01042379). Results showed a non-statistically significant increase in estimated pCR rates in seventy-five patients with high-risk, HER2-negative stage II/III breast cancer (~30 patients with TNBC) 112 .…”

Facts and Hopes in Immunotherapy for Early-Stage Triple-Negative Breast Cancer

“…In line with this, a phase II neoadjuvant clinical trial on IRX-2, a cell-derived biological with multiple active cytokine components, in combination with aPD-1 and chemotherapy in TNBC is exploring the role of cytokine-based or augmented therapy (NCT04373031). The I-SPY2 trial has reported relevant activity from the neoadjuvant combination of chemotherapy, pembrolizumab, and a TLR-9 agonist in stage II/III breast cancer, leading to an increase in pCR and RCB I outcomes at surgery ( 54 ). However, the addition of the TLR-9 agonist did not meet the prespecified threshold for graduation in I-SPY2.…”