Abstract PO2-03-10: Association of pathologic complete response with the 27-gene IO score and week 3 IOpath response following neoadjuvant pembrolizumab +/- intralymphatic cytokines in the neoIRX trial

Abstract Introduction: Novel biomarker strategies are needed to identify immunotherapy (IO)-sensitive early-stage triple-negative breast cancers (TNBC). We recently reported a phase II trial (neoIRX, NCT04373031) evaluating induction IO (pembrolizumab +/- intralymphatic cytokines, IRX-2, comprised of physiologic doses of IL-2, IFNγ, and other cytokines derived from activated donor lymphocytes) preceding de-escalated neoadjuvant chemotherapy (NAC). Here, we report associations of response with the 27-gene IO score (DetermaIO), a commercially available RT-qPCR assay shown to predict IO response in the neoPACT, I-SPY2, and neoTRIP trials. We also propose a novel surrogate endpoint, entitled “IOpath” response, that characterizes radiographic and pathologic response following single-cycle IO and may be useful for guiding NAC de-escalation or omission. Methods: Subjects with stage II-III TNBC were randomized 1:1 (n=12) to receive induction pembrolizumab (200mg IV) +/- peri-areolar IRX-2 (IRX-2 arm: 1 ml SQ x2 daily for 10 days + cyclophosphamide 300 mg/m2 IV x 1) preceding initiation of pembrolizumab + NAC. The primary endpoint was pathologic complete response (pCR) rate. Post-induction IO response (IOpath) was assessed by week 3 ultrasound (US) and biopsy. IOpath response was designated as IOpath-NR (non-response: radiographic progression and/or biopsy non-response [neither treatment effect nor TILs expansion]), IOpath-PR (partial response: viable tumor with either treatment effect or TILs expansion), IOpath-CR (complete response: treatment effect with no viable tumor), or IOpath-NE (not evaluable). Results: The IRX-2 arm achieved 83% pCR (n=5/6, CI 36-100%) compared to 33% pCR with pembrolizumab alone (n=2/6, CI 4-78%) and was well tolerated (67% grade I skin bruise). Baseline 27-gene IO score predicted pCR (AUC 0.77, IO+: 5/6 pCR; IO-: 2/6 pCR) and week 3 IOpath response (AUC 0.85, IO+: 3/5 IOpath-CR/PR; IO-: 1/4 IOpath-PR), and outperformed TILs (AUC for pCR: 0.66; AUC for IOpath: 0.68) and CPS score (AUC for pCR: 0.63, AUC for IOpath: 0.58). Week 3 IOpath response was associated with 100% pCR (IOpath+: 4/4 pCR; IOpath-: 2/5 pCR). Conclusion: A subset of TNBCs experience brisk IO response following single-cycle IO (IOpath response), which is associated with 100% pCR in this preliminary dataset, highlighting IOpath as a potential surrogate biomarker to guide NAC de-escalation or omission in early-stage TNBC. Baseline 27-gene IO score predicts pCR and week 3 IOpath response. A future study is planned (neoINBRX) to evaluate the feasibility of combining baseline IO score with week 3 IOpath response to identify and treat IO-sensitive tumors with chemotherapy-sparing IO combination therapy. Acknowledgements: The study was funded in part by Merck, Sharpe, & Dohme as part of the Merck Investigator Studies Program, and by BrooklynImmunotherapeutics. Citation Format: David Page, Alan Su, Nicole Moxon, Staci Mellinger, Tracy Kelly, Nicole Fredrich, Amanda Seino, Zheng Topp, Philippa Newell, Kristen Massimino, Shaghayegh Aliabadi, Yaping Wu, Maritza Martel, William Redmond, Yoshinobu Kogushi, Grace Mcgee, Alejandra Mendez-Torres, Zhaoyu Sun, James Imatani, Alison Conlin, Kelly Perlewitz, Tyler Nielsen, Sasha Stanton. Association of pathologic complete response with the 27-gene IO score and week 3 IOpath response following neoadjuvant pembrolizumab +/- intralymphatic cytokines in the neoIRX trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-03-10.