Abstract LB-133: Correlative analysis of pharmacokinetics and pharmacodynamics of RGX-104, a first-in-class Liver-X-Receptor (LXR) agonist, and clinical outcomes in patients with advanced solid tumors

Abstract LB-133: Correlative analysis of pharmacokinetics and pharmacodynamics of RGX-104, a first-in-class Liver-X-Receptor (LXR) agonist, and clinical outcomes in patients with advanced solid tumors

RGX-104, a first-in-class small-molecule LXR agonist modulates innate immunity and cancer progression via transcriptional activation of ApoE. ApoE protein suppresses tumor cell invasion and angiogenesis, and also depletes circulating and tumoral myeloid derived suppressor cells (MDSC), leading to T...

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Published in:Cancer research (Chicago, Ill.) Vol. 80; no. 16_Supplement; p. LB-133
Main Authors: Mita, Monica, Mita, Alan, Hamilton, Erika, Falchook, Gerald S., Postow, Michael, Chmielowski, Bartosz, Schilder, Russell J., Strauss, James, Lim, Emerson, Pant, Shubham, Jain, Angela, Rixe, Oliver, Redman, Rebecca, Kim, Kevin B., Dragovich, Tomislav, Harvey, R. Donald, Puzanov, Igor, Schneider, Nimisha, Deehan, Renee, Guennel, Tobi, Lin, Joe, Tavazoie, Sohail, Waltzman, Roger, Rowinsky, Eric, Szarek, Michael, Sridhar, Subhasree, Busby, Robert, Lebaka, Narayan, Andreu, Celia, Kurth, Isabel, Darst, David, Tavazoie, Masoud, Raza, Syed, Wasserman, Robert, Gonsalves, Foster C.
Format: Journal Article
Language:English
Published: 15-08-2020
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Summary:RGX-104, a first-in-class small-molecule LXR agonist modulates innate immunity and cancer progression via transcriptional activation of ApoE. ApoE protein suppresses tumor cell invasion and angiogenesis, and also depletes circulating and tumoral myeloid derived suppressor cells (MDSC), leading to T cell activation.A multivariate approach was used to address pharmacokinetic (PK) and pharmacodynamic relationships of RGX-104 in a phase 1 dose escalation study in patients with relapsed/refractory solid tumors. The study entailed multiple escalation arms with RGX-104 as monotherapy and in combination with nivolumab, ipilimumab, or docetaxel. Various markers including intratumoral ApoE and its receptor LRP1 in biopsy specimens, gene expression of LXR-targets in whole blood, serum markers including cytokines and lipids, as well as immune cell types such as MDSC, CD8 T-cells, and neutrophils in peripheral blood from patients were monitored at several time points. PK metrics were tracked to assess dose response relationships. Clinical outcomes such as objective response, time to disease progression, and duration on therapy were used for exploratory correlative analyses. A generally dose dependent increase in steady state exposure to RGX-104 was observed among all cohorts; the lowest efficacious exposure among patients with partial response was ~14,000 ng*h/mL. Treatment with RGX-104 at doses ranging from 120 mg BID to 240 mg BID induced expression of LXR targets, ApoE [2.7X (p=0.008) to 7.1X (p=0.007)] and ABCA1 [ 6.3X (p=1.20E-03) to 7X (p=8.1E-04] over baseline in a generally dose-dependent manner as assessed in whole blood. Similarly, MDSC depletion, ranging from 70%-90% relative to baseline, was observed in patients treated with RGX-104 along with concomitant CD8 T-cell activation; similar effects were noted in patients in combination cohorts. A model to explore dose dependency of change in immune cell types suggested that baseline levels of MDSC were most predictive of the magnitude of MDSC reduction after treatment, and that favorable clinical outcomes correlate with the extent of MDSC reduction and T cell activation. Low baseline levels of tumoral ApoE were associated with greater clinical benefit, with almost all patients with stable disease or partial response exhibiting ApoE tumor positive score of ≤20%; these patients also exhibited low/negative PD-L1 (<1%) staining, revealing a target specific tumor biomarker and PD-L1 subset that could support prospective patient selection. These and additional markers will be tracked in expansion cohorts of RGX-104 in combination with pembrolizumab and carboplatin/pemetrexed for 1st line treatment of patients with metastatic non-small cell lung cancer (PD-L1 <1%) and in combination with docetaxel for 2nd line treatment of patients with small cell lung cancer. Citation Format: Monica Mita, Alan Mita, Erika Hamilton, Gerald S. Falchook, Michael Postow, Bartosz Chmielowski, Russell J. Schilder, James Strauss, Emerson Lim, Shubham Pant, Angela Jain, Oliver Rixe, Rebecca Redman, Kevin B. Kim, Tomislav Dragovich, R. Donald Harvey, Igor Puzanov, Nimisha Schneider, Renee Deehan, Tobi Guennel, Joe Lin, Sohail Tavazoie, Roger Waltzman, Eric Rowinsky, Michael Szarek, Subhasree Sridhar, Robert Busby, Narayan Lebaka, Celia Andreu, Isabel Kurth, David Darst, Masoud Tavazoie, Syed Raza, Robert Wasserman, Foster C. Gonsalves. Correlative analysis of pharmacokinetics and pharmacodynamics of RGX-104, a first-in-class Liver-X-Receptor (LXR) agonist, and clinical outcomes in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-133.
ISSN:0008-5472
1538-7445
DOI:10.1158/1538-7445.AM2020-LB-133