RMC-9805 (HY-156819)

Revolution Medicines reported on RMC-9805 and RMC-6236, both in Phase 1 studies. RMC-6236 is a non-covalent RAS^MULTI (ON) inhibitor, and RMC-9805 is highly selective covalent inhibitor of KRAS^G12D (ON), both of which have oral activity. As a "first in class" inhibitor, RMC-9805 has the potential for use as a monotherapy and in combination therapies for cancer patients. It has demonstrated durable tumor regressions in various KRAS^G12D tumor models, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC)^[1][2].

ORIC-944 (HY-158102)

PRC2 dysregulation occurs in multiple tumor types and is associated with poor prognosis in patients with prostate cancer. Inhibition of PRC2 complex may overcome prostate cancer plasticity. The first-generation PRC2 inhibitors developed by ORIC, which target EZH2, exhibit poor pharmacologic properties, posing a risk of drug interactions and having a short half-life. Patients need to take high doses of the medication twice daily. The "best in class" PRC2 inhibitor ORIC-944 , currently in Phase 1/1b, is an allosteric inhibitor of PRC2 that binds to the EED subunit. ORIC-944 demonstrated single agent tumor growth inhibition in a spectrum of in vivo prostate cancer models, including AR-positive, AR-mutant, ARv7, ARPI-responsive and ARPI-resistant models^[3].

BBO-8520 (HY-158107)

BridgeBio Pharma has a broad pipeline with more than 30 projects, and BBO-8520, presented at the conference, is a small molecule direct inhibitor of KRAS^G12C (ON) state with high oral bioavailability. BBO-8520 covalently binds to Switch II pockets in the GTP-bound (ON) and GDP-bound (OFF) state conformations of KRAS^G12C, thereby rapidly and powerfully inhibiting KRAS^G12C activity. BBO-8520 is currently in a Phase 1a/1b study designed to evaluate the safety, tolerability, initial antitumor activity, and PK of BBO-8520 as a single agent and in combination with pembrolizumab in patients with KRAS^G12C mutated non-small cell lung cancer^[4].

BMS-986365 (HY-158101)

BMS reported the "first-in-class" androgen receptor ligand-directed degrader (AR-LDD), BMS-986365, which is currently in Phase 1 for the treatment of metastatic castration-resistant prostate cancer (mCRPC). BMS-986365 has a dual mechanism-of-action: AR degradation and receptor antagonism, and can effectively degrade AR by CRL4CRBN E3 ligase and proteasoma-dependent manner. BMS-986365 induces effective and durable AR signaling inhibition, overcoming resistance to existing AR pathway inhibitor (ARPI) therapies^[5].

ABBV-303 (HY-P990306)

AbbVie is one of the earliest pharmaceutical giants to enter the ADC track. AbbVie reported ABBV-303, a c-Met targeted multispecific NK cell engager in Phase 1 studies. ABBV-303 includes three functional arms: (1) a c-Met binding scFv based on ABT-700, common to c-Met-targeting antibody-drug conjugates ABBV-400 and Teliso-V; (2) a Fab arm that binds NKG2D, a stimulatory receptor expressed by NK cells and activated CD8⁺ T cells; and (3) a heterodimeric IgG1 Fc which binds CD16a on NK cells and links the other two binding moieties. ABBV-303 exhibits sub-nanomolar redirected killing potency against tumor cells expressing a wide range of c-Met. ABBV-303 tends to immune recruitment and has the potential to reshape the tumor immune microenvironment. In addition, ABBV-303 demonstrates good tolerability in preclinical multi-dose safety studies in non-human primates at the highest dose^[6][7].

M3554 (HY-158109)

At this conference, Merck reported M3554, a novel anti-GD2 antibody-drug conjugate. Merck disclosed preclinical data on M3554, which demonstrated strong antitumor activity in PDX models of neuroblastoma, osteosarcoma, and glioma, with a dose range of 3-10 mg/kg. M3554 exhibited good pharmacokinetics in rats and monkeys, with a very stable linker-payload and good safety profile^[8].

Actinium-225-PSMA-Trillium (BAY 3563254)

Radiopharmaceuticals are traditionally used in diagnostic imaging. In recent years, therapeutic radiopharmaceuticals have gained traction, especially radionuclide drug conjugates (RDCs) as a promising avenue for tumor treatment. Novartis has already introduced two RDCs to the market, and Bayer has ramped up its investment in radionuclide drugs. Actinium-225-PSMA-Trillium (BAY 3563254), disclosed by Bayer at the conference, is a radionuclide drug for the treatment of advanced metastatic castration-resistant prostate cancer. The drug binds to PSMA and emits radiation to damage cancer cells and impede their growth^[9]. Currently, BAY 3563254 is undergoing Phase 1 clinical study and for the evaluation of safety and imaging in humans^[10].

AZD8421 (HY-158106)

AZD8421 is a highly selective CDK2 inhibitor reported by AstraZeneca with an IC₅₀ of 9 nM against CDK2. AZD8421 forms a hydrogen bonding interaction with CDK2-specific residue Lys89 (K89) near the solvent region of the ATP-binding pocket, with selectivity 300 times higher than that of CDK9. The study of kinetic properties revealed that AZD8421 had a longer residence time (2 h) on CDK2. AZD8421 demonstrated significant tumor suppressor activity in a CDK4/6 inhibitor-resistant breast cancer PDX model with monotherapy and in combination with palbociclib (CDK4/6 inhibitor)^[11]. AZD8421 is currently under Phase1/2 studies^[12].

ARV-393 (HY-158105)

ARV-393 is an orally effective BCL6-targeted PROTAC reported by Arvinas for the treatment of non-Hodgkin’s lymphoma. ARV393 shows DC₅₀ and GI₅₀ values < 1 nM in numerous DLBCL and BL cell lines, and has demonstrated deep BCL6 degradation both in vitro and in vivo. ARV393 produces excellent tumor volume suppression (TGI) in multiple tumor xenotransplantation models^[13]. ARV-393 is expected to begin human trials in the first half of 2024.

NST-628 (HY-158115)

NST-628 is a novel, potent, and brain-penetrant Pan-RAF-MEK nondegrading molecular glue introduced by Nested Therapeutics, which can inhibit RAS and RAF-driven cancers. NST-628 exhibits strong and durable inhibition of the RAF-MEK signaling complex, and it has high intrinsic permeability into the brain, thus demonstrating broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models^[14].

NST-628 oral tablets have been tested in Phase 1 in March 2024 for the treatment of patients with solid solid tumors with mutated RAS-MAPK signaling pathway^[15].

VVD-214 (HY-158116)

At the conference, Vividion Pharmaceuticals revealed for the first time VVD-214/R07589831, an ATP-WRN helicase covalent allosteric inhibitor. VVD-214/R07589831 stabilizes WRN in a closed state and inhibits ATP hydrolysis and helicase activity. VVD-214/R07589831 covalently engages cysteine 727 of WRN, triggering widespread double-stranded DNA breaks, nuclear swelling, and cell death in MSI-high, but not microsatellite stable cells.

In addition, VVD-214/R07589831 drives in vivo antitumor activity in an MSI model of immune checkpoint resistance. VVD-214/R07589831 provided robust tumor regression in multiple MSI-high colorectal cancer cell lines and patient derived xenograft models, including models from patients progressing on immune checkpoint therapies^[16]. VVD-214 was exceptionally well tolerated, and constitutes a promising oral drug candidate for patients with MSI-high cancers, currently in Phase 1 trials^[17].

PF-07220060 (HY-139450)

PF-07220060 is a selective CDK4 inhibitor reported by Pfizer. The selectivity of PF-07220060 reduces the effect on myeloid precursor cells in vitro and neutrophils in vivo. Among human CDK4/6 inhibitors, PF-07220060 has the highest expected CDK4 coverage (~90%).

In xenograft models of HR⁺HER2^- breast cancer, the increase in CDK4 coverage led to stronger tumor growth inhibition. PF-07220060 also demonstrated superior efficacy compared to Palbociclib in prostate cancer xenografts at clinically relevant doses^[18]. Partial Phase 1/2a data for PF-07220060 in the treatment of patients with advanced solid tumors of HR⁺/HER2^- mBC were disclosed at the conference.