Response and clinical benefit assessment of the combination of the dectin-1 agonist imprime PGG and anti-PD-1 pembrolizumab in chemotherapy-resistant metastatic triple negative breast cancer (TNBC)

Background: Immune checkpoint inhibitor (ICI) monotherapy provides substantial, long-term clinical benefit to patients (pts) with many types of cancer. To date, chemo-refractory, metastatic TNBC pts have realized only limited clinical benefit from ICI monotherapy with ORR of ~5-6%, median overall survival ~9 months and 1 year OS rates ~37-40%. Such limited benefit may reflect a poor underlying immune response with inadequate T cell responses in these pts. Combining ICIs with innate immune modulators may provide a promising approach to instigating an immune response in these pts. Imprime PGG (Imprime) is a novel, systemically-delivered Dectin Receptor agonist that, mechanistically, activates the innate immune system to reprogram the immunosuppressive tumor microenvironment and to stimulate antigen-specific T cell activation. In preclinical cancer models, Imprime significantly enhances the anti-cancer efficacy of ICI therapy. Accordingly, Imprime is currently being studied in combination with pembrolizumab (KEYTRUDA®,pembro), a humanized mAb against PD-1, in a Ph2 trial (NCT02981303) in chemo-refractory metastatic TNBC pts (Biothera in collaboration with Merck \u0026 Co., Inc.). Methods: An open-label, Simon 2 stage study design was employed (12 pts in Stage 1; 32 pts in Stage 2) with full enrollment completed Nov. 2018. Pts received Imprime (4 mg/kg IV days 1, 8, 15 of each 3-week cycle) + pembro 200 mg on D1 of each cycle. CT scans were taken at baseline and every 6 weeks therafter until progression. Primary endpoints were ORR and safety. Secondary endpoints included PFS and OS. Biopsies and blood samples were collected to explore immune activation in tumor tissue and peripheral blood. Results: In the intent-to-treat population (N=44; median duration of follow-up of 14.8 months as of 7/1/2019), confirmed ORR was15.9% (1 CR, 6 PRs). Stable disease (SD) \u003e12 wks as best response was observed in nearly 40% of pts (17/44). Four of these 17 were stable for \u003e24 wks. OS rates at 1 year are ~63% and median OS is currently 18.1 months by K-M estimation (95% CI, 12 mos - not reached). A majority of pts (62.5%) showed target lesion (TL) reduction or stabilization. Treatment discontinuation often (22/41, 53.7%) resulted from new lesions (NL), or non-target lesion (NTL) increases, even while target lesions were shrinking or stable. Pts with this mixed response pattern showed increased overall survival. Specifically, enhanced OS was evident in pts showing a reduction in 1) any of their target lesions (HR 0.27; p=0.01), 2) in total tumor burden \u003e10% at 12 wks (HR 0.05, p=0.004); or, 3) total tumor burden below baseline at any time (HR 0.26; p=0.02) independent of NL/NTL status. Analyses of biopsies and peripheral blood indicated profound infiltration of activated myeloid and T cells into tumor tissue after 6 wks of therapy. Pts at baseline were largely devoid of activated T cells. However, a significant fraction of pts (16/44) showed activated T cells as early as 3 wks on therapy which correlated with significantly greater OS (HR 0.15; p=0.01). Conclusion: The combination of Imprime and Pembro provides promising response rates and overall survival in chemo-refractory metastatic TNBC. Biopsy analyses consistently showed activation of both myeloid and T cells with extensive infiltration into tumor tissue. Examination of response patterns and clinical benefit revealed extended OS even in pts not classified as responders by RECIST. Indeed, extended OS was most evident in pts with any reduction in TL, regardless of NL/NTLs. These data suggest that clinical benefit from the combination of Imprime and ICI therapy may not be adequately scored using standard RECIST v1.1 and suggest a modified RECIST criteria might better score clinical benefit of such a combination. Citation Format: Mark T Uhlik, Nandita Bose, Joanna Cox, Paulette Mattson, Michele Gargano, Stephen O9Day, Virginia Borges, Bartosz Chmielowski, Ruta Rao, Maysa Abu-Khalaf, Alison Stopeck, Michael Chisamore, Bruno Osterwalder, Jeremy Graff. Response and clinical benefit assessment of the combination of the dectin-1 agonist imprime PGG and anti-PD-1 pembrolizumab in chemotherapy-resistant metastatic triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD1-02.