Breakthrough Treatments: A Sneak Peek at 12 Emerging Therapeutics

 Researchers presented 12 new cancer therapeutics, represented here by their chemical structures, during the New Drugs on the Horizon special series at the AACR Annual Meeting 2025.

The AACR Chemistry in Cancer Research (CICR) Working Group organizes three New Drugs on the Horizon symposia at the AACR Annual Meeting each year. The CICR Working Group Steering Committee, chaired by Lori S. Friedman, PhD, aims to bring together experts from many facets of drug discovery and development. 

She praised the great collaborative spirit that drove these efforts, as well as the critical contributions of many people working behind the scenes to develop new and hopefully better cures. 

"Cancer drug discovery has always been challenging," Friedman, of ORIC Pharmaceuticals, said. He said, "We learn a lot, we try to apply that knowledge to help patients, and we hope that by working together, we will continue to bring benefit to patients."

The three sessions showcased first disclosures of 12 novel therapeutics in or nearing early-stage clinical trials.

A new wave of precision KRAS inhibitors

There were three next-generation small molecule inhibitors that could be used orally to block abnormal RAS signaling. Revolution Medicines' Anne Edwards, PhD, unveiled RMC-5127, a KRAS G12V-selective ON inhibitor that targets the activated version of KRAS and achieves profound and long-lasting tumor regressions in both cell-line and patient-derived xenograft models. The medicine is getting ready for its first human study. 

Carla P. Martins, PhD, from AstraZeneca, presented AZD0022, a KRAS G12D-selective ON/OFF inhibitor that targets both the activated and resting forms of KRAS. Preclinical investigations in KRAS G12D-driven tumor models demonstrated efficacy, and it is now being investigated in patients with pancreatic, colorectal, and non-small cell lung malignancies in the phase I/IIa ALAFOSS-01 trial, which includes a combination cohort with EGFR inhibition.

Reprogramming the tumor immune microenvironment

Several presentations attempted to not only target cancer cells, but also to generate conditions in the tumor immunological microenvironment that are more conducive to tumor rejection by targeting immune and stromal cells.

Adam Pelzek, PhD, of Abpro, discussed ABP-102/CT-P72, a HER2 and CD3 bispecific T-cell engager that preferentially activates T cells in the presence of HER2-overexpressing tumor cells. It displayed good preclinical effectiveness in HER2-high and intermediate models in monkeys, with minimal off-target effects, opening the path for patient studies.

Weixiao Sha, PhD, of Merck, demonstrated M0324, an agonist antibody that only activates CD40 when MUC1 is abundant nearby. M0324 outperformed other CD40 antibodies in preclinical investigations and demonstrated a positive safety profile in monkeys, suggesting further clinical development.

Advancing Prostate Cancer Treatment: Dual-Targeting Approaches

Two bispecific techniques to treating advanced prostate cancer were highlighted.

Ciara Metcalfe, PhD, of Genentech, presented GDC-2992, a bifunctional molecule that inhibits both the wild-type and mutant variants of the androgen receptor, which is frequently aberrantly expressed in prostate cancer. Preclinical evidence demonstrated tumor regression and PSA lowering, and it is currently in a phase I trial in patients with advanced or metastatic prostate cancer.

Regina M. Reilly, PhD, of AbbVie, introduced ABBV-969, a dual-targeting antibody-drug combination that binds to both the PSMA and STEAP1 antigens, which are commonly overexpressed in metastatic castration-resistant prostate cancer. Following promising results in primates, a phase I trial is currently underway in patients with metastatic castrate-resistant prostate cancer.