2021 EORTC: Treatment with the dual mechanism ERK inhibitor, ASTX029, alters myeloid cell differentiation

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Treatment with the dual mechanism ERK inhibitor, ASTX029, alters myeloid cell differentiation

Abstract:

The inhibition of aberrant MAPK pathway activity is a clinically validated approach which has resulted in the approval of agents targeting tumors driven by activating mutations in BRAF and KRAS. Although the overall response rate to MAPK-targeting agents is high, duration of response is often limited by the emergence of acquired resistance. In contrast, immune checkpoint inhibitors (ICI) such as the anti-PD1 therapy, pembrolizumab, have a lower response rate but induce more durable responses. It has been demonstrated that inhibition of aberrant MAPK pathway activity enhances immune activation. For example, preclinical studies show that treatment with the BRAFV600E inhibitor dabrafenib or the KRASG12C inhibitor sotorasib induces a pro-inflammatory tumor microenvironment (TME), which is associated with increased anti-tumor immunity. Further, studies using syngeneic, MAPK-activated in vivo models have demonstrated that the combination of MAPK-targeting agents and ICI results in synergistic inhibition of tumor growth.

ASTX029 is a dual-mechanism ERK1/2 (ERK) inhibitor, inhibiting both the catalytic activity and phosphorylation of ERK, which is currently undergoing clinical development as part of a Phase 1/2 trial in advanced solid tumors (NCT03520075). ASTX029 has good oral bioavailability and shows potent inhibition of tumor growth in preclinical models bearing activating mutations in the MAPK pathway.

We have previously investigated the immunomodulatory effects of ASTX029 using an in vivo syngeneic tumor model and observed that treatment with ASTX029 resulted in a pro-inflammatory TME, with increased interferon signaling consistent with published data describing the effects of treatment with dual-mechanism ERK inhibitors (Kidger et al., Mol Cancer Ther, 2020). We also observed an increased expression of antigen presentation genes. Using digital spatial profiling, we evaluated the expression of 31 proteins in immune infiltrates and observed a significant decrease in CD14 and a significant increase in MHC class II in ASTX029-treated tumors compared to untreated tumors. We therefore investigated the immunomodulatory effects of ASTX029 using primary human monocytes under conditions that induce macrophage differentiation and polarisation. Treatment with ASTX029 induced a decrease in CD14 and an increase in MHC class II cell surface expression, consistent with our previous in vivo mouse model data. In addition, we observed changes in cell surface expression of phenotypic markers, such as CD206, following treatment with ASTX029.

These data support our previous observations and demonstrate that ERK inhibition by ASTX029 leads to phenotypic changes during monocyte to macrophage differentiation. Our data provide a strong rationale for the combination of ASTX029 with agents which aim to modulate the myeloid compartment or response to myeloid signaling.

Heightman et al., “Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2”

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https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.1c00905

Abstract

Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 (15) through structure-guided optimization of our previously published isoindolinone lead (7). The medicinal chemistry campaign focused on addressing CYP3A4-mediated metabolism and maintaining favorable physicochemical properties. These efforts led to the identification of ASTX029, which showed the desired pharmacological profile combining ERK1/2 inhibition with suppression of phospho-ERK1/2 (pERK) levels, and in addition, it possesses suitable preclinical pharmacokinetic properties predictive of once daily dosing in humans. ASTX029 is currently in a phase I–II clinical trial in patients with advanced solid tumors.

Munck et al., “ASTX029, a Novel Dual-Mechanism ERK Inhibitor, Modulates Both the Phosphorylation and Catalytic Activity of ERK”

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https://mct.aacrjournals.org/content/early/2021/07/30/1535-7163.MCT-20-0909#:~:text=ASTX029%20is%20a%20highly%20potent,not%20directly%20inhibiting%20MEK%20activity

Abstract

The MAPK signaling pathway is commonly upregulated in human cancers. As the primary downstream effector of the MAPK pathway, ERK is an attractive therapeutic target for the treatment of MAPK-activated cancers and for overcoming resistance to upstream inhibition. ASTX029 is a highly potent and selective dual-mechanism ERK inhibitor, discovered using fragment-based drug design. Due to its distinctive ERK binding mode, ASTX029 inhibits both ERK catalytic activity and the phosphorylation of ERK itself by MEK, despite not directly inhibiting MEK activity. This dual-mechanism was demonstrated in cell-free systems, as well as cell lines and xenograft tumor tissue, where the phosphorylation of both ERK and its substrate, RSK, were modulated on treatment with ASTX029. Markers of sensitivity were highlighted in a large cell panel, where ASTX029 preferentially inhibited the proliferation of MAPK-activated cell lines, including those with BRAF or RAS mutations. In vivo, significant anti-tumor activity was observed in MAPK-activated tumor xenograft models following oral treatment. ASTX029 also demonstrated activity in both in vitro and in vivo models of acquired resistance to MAPK pathway inhibitors. Overall, these findings highlight the therapeutic potential of a dual-mechanism ERK inhibitor such as ASTX029 for the treatment of MAPK-activated cancers, including those which have acquired resistance to inhibitors of upstream components of the MAPK pathway. ASTX029 is currently being evaluated in a first in human Phase I-II clinical trial in patients with advanced solid tumors (NCT03520075).

2021 AACR: A first-in-human, Phase 1 study of ASTX029, a dual-mechanism inhibitor of ERK1/2, in relapsed/refractory solid tumors

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View Poster: A first-in-human, Phase 1 study of ASTX029, a dual-mechanism inhibitor of ERK1/2, in relapsed/refractory solid tumors Abstract: Background: The RAS-RAF-MEK-ERK pathway is commonly upregulated in human cancers. This is an open-label Phase 1 study of ASTX029, a dual-mechanism extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor, in subjects with relapsed/refractory solid tumors (NCT03520075). Methods: The primary objectives are to identify a maximum tolerated dose and/or recommended Phase 2 dose. ASTX029 was administered orally daily of 21-day cycles as powder-in-bottle (PiB, Cohort 1/10mg) and tablet formulation (beginning with Cohort 6/80 mg) under fed conditions, and as tablet formulation under fasting conditions (beginning with Cohort 8/40 mg). Dose escalation occurred according to a “3+3 design” based on dose-limiting toxicity (DLT) events. Disease response was evaluated according to RECIST v1.1 and exploratory indicators, including tumor variant allele frequency changes detected by cell-free DNA (cfDNA) quantitation. Results: 56 subjects were treated with at least one dose of ASTX029 in Phase 1A (dose escalation). Of 46 subjects with data, 35 (76%) had any RAS mutations and 3 (9%) had BRAF mutations; 1 subject had both. At the 200 mg dose level (Cohort 5, PiB/fed), one of six evaluable subjects developed a DLT (grade 3 maculopapular rash). At the 280 mg dose level (Cohort 12, tablet/fasting), two subjects experienced grade 2 central serous retinopathy adverse events (CSR AEs) within a few days of dosing. These were the only CSR AEs noted and one event was declared a DLT. Both subjects recovered to baseline within days of dose interruption. One cohort level below this dose was expanded (Cohort 11/200 mg, tablet/fasting); this dose level was deemed safe (without a DLT or grade ≥2 visual AE in 7 subjects) and was selected for Phase 1B dose expansion. Mean pharmacokinetic (PK) exposure was 151% of target exposure, which is defined as the level expected to have biological activity based on animal studies. The most frequent grade ≥2 AEs assessed as drug-related included nausea (4 subjects, grade 2) and transaminitis (4 subjects: 3 grade 2, 1 grade 3). The grade 3 transaminitis occurred in a subject with metastatic sarcoma involving the liver. There was one serious AE of malaise considered related to study drug. Two subjects, one with KRAS-G12A and BRAF-D549N non-small cell lung cancer (120 mg) and one with KRAS-G12D metastatic pancreatic cancer (200 mg), achieved partial responses (cycle 15/ongoing and cycle 3/ongoing, respectively). In 2 subjects with stable disease as the best response, longitudinal cfDNA sequencing showed a decrease of tumor variant allele frequencies after 2 cycles of ASTX029, followed by a return to baseline levels before disease progression. The most common reason for ASTX029 discontinuation was disease progression. Conclusions: This Phase 1A study of the ERK1/2 inhibitor ASTX029 has identified a dose level of 200 mg daily of a 21-day cycle for investigation in the Phase 1B portion of the study. Pharmacokinetic and pharmacodynamic data suggest target exposures are achieved with preliminary clinical activity.