The AACR Chemistry in Cancer Research (CICR) Working Group organizes three New Drugs on the Horizon sessions at the AACR Annual Meeting every year. “What we want to do is bring people together … from different aspects of drug discovery and development,” said Lori S. Friedman, PhD, chair of the CICR Working Group Steering Committee.

Applauding the immense collaborative spirit behind these efforts, she also acknowledged the crucial contributions of many people working behind the scenes to create new and hopefully better therapies.

“Cancer drug discovery has always been challenging,” said Friedman, of ORIC Pharmaceuticals, adding, “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

Therapies to stop aberrant RAS signaling were abundant, with three next-generation, orally available small molecule inhibitors.

Anne Edwards, PhD, of Revolution Medicines, introduced RMC-5127, a KRAS G12V-selective ON inhibitor—meaning it targets the activated form of KRAS—that achieved deep and durable tumor regressions in both cell-line and patient-derived xenograft models. The drug is advancing toward a first-in-human trial.

Carla P. Martins, PhD, of AstraZeneca, presented AZD0022, a KRAS G12D-selective ON/OFF inhibitor, meaning it targets both the activated and resting form of KRAS. Preclinical studies showed efficacy in KRAS G12D-driven tumor models, and it is currently being tested in patients with pancreatic, colorectal, and non-small cell lung cancers in the phase I/IIa ALAFOSS-01 trial that includes a combination cohort with EGFR inhibition.

Brian A. Lanman, PhD, of Amgen, shared AMG 410, a pan-KRAS ON/OFF inhibitor capable of targeting a wide array of KRAS mutations and amplifications, but not HRAS or NRAS. In pancreatic xenograft models, AMG 410 showed significant efficacy alone and in combination with EGFR and PD-1 therapies. The compound has an Investigational New Drug (IND) application and a clinical trial is planned.

Reprogramming the tumor immune microenvironment

Several presentations sought to not only target cancer cells but also create conditions in the tumor immune microenvironment that are more favorable to tumor rejection, by targeting the immune cells and stromal cells.

Adam Pelzek, PhD, of Abpro, highlighted ABP-102/CT-P72, a HER2 and CD3 bispecific T-cell engager designed to selectively activate T cells only in the presence of HER2-overexpressing tumor cells. It demonstrated strong preclinical activity in HER2-high and intermediate models, with low off-target toxicity in monkeys, paving the way for trials in patients.

Weixiao Sha, PhD, of Merck, presented M0324, an agonist antibody that only activates CD40 when MUC1 is highly expressed nearby. M0324 outperformed other CD40 antibodies in preclinical studies and showed a favorable safety profile in monkeys, supporting further clinical development.

Aaron Balog, PhD, of Bristol Myers Squibb, disclosed BMS-986449, a small molecule that selectively degrades transcription factors Helios (IKZF2) and Eos (IKZF4) to reprogram regulatory T cells (Tregs) into effector T cells. It is currently being tested in a phase I study both alone and in combination with nivolumab (Opdivo) PD-1 blockade in patients with advanced solid cancers.

Alexei Karpov, PhD, and Markus Reschke, PhD, both of Novartis, described FXX489, a fibroblast activation protein (FAP)-targeting radioligand therapy that induced tumor regressions in multiple cancer models, both as monotherapy and in combination with chemotherapy. FXX489 is now in a phase I trial in patients with breast, colorectal, lung, and pancreatic cancers.

Meher Majety, PhD, of Roche, showcased RO7567132, a bispecific antibody targeting FAP and lymphotoxin-beta receptor (LTBR)—which is expressed on a variety of cells in the microenvironment and the vasculature—that is designed to turn “cold” tumors “hot” and enhance response to immunotherapy. In mouse models of breast cancer, RO7567132 turned immunologically “cold” tumors “hot,” enhancing responses to PD-L1 and T-cell engager therapies. It is now in a phase I trial that includes a combination with atezolizumab (Tecentriq) PD-L1 blockade.

Dual-targeting strategies in prostate cancer

Two bispecific approaches targeting advanced prostate cancer were highlighted.

Ciara Metcalfe, PhD, of Genentech, presented GDC-2992, a bifunctional molecule that blocks both the wild-type and mutant forms of the androgen receptor that is often expressed aberrantly in prostate cancer. Preclinical data showed tumor regression and suppression of prostate specific antigen (PSA), and it is now 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 conjugate that binds both the PSMA and STEAP1 antigens often overexpressed in metastatic castration-resistant prostate cancer. After promising results in primates, a phase I study is ongoing in patients with metastatic castrate-resistant prostate cancer.

Novel approaches for liver cancer and microsatellite instability

Two presentations revealed therapies targeting molecularly distinct patient subsets.

Yanhua Rao, PhD, of GSK, presented GSK4418959 (IDE275), a reversible inhibitor of the Werner helicase (WRN) that selectively targets solid cancers characterized by high microsatellite instability. It demonstrated activity in xenograft models resistant to other WRN inhibitors, with minimal toxicity in microsatellite stable cells.

Jenny Karlsson, PhD, of Bayer, introduced BAY 3547926, a targeted alpha-emitting radiotherapeutic that delivers Actinium-225 to glypican-3 (GPC3)-positive liver cancer cells. Based on strong antitumor effects observed in preclinical models, the phase I BANTAM-01 trial is now enrolling patients with advanced hepatocellular carcinoma.

While wrapping up the third and final New Drugs on the Horizon sessions, Mary Mader, PhD, former chair of the CICR Steering Committee, presented a slide showing the chemical structures of the 12 new agents “all aiming to make a difference for patients by providing more options for treatment of this family of diseases that we call cancer.”

Mader, now at MM Molecular Pharma Consulting, ended on a solemn personal note about her own father, who was treated with a lung cancer drug first introduced at a New Drugs on the Horizon session in the past. This poignant anecdote underscored the real-world impact of these innovations and the hope they offer to patients.

The full recording of each of these sessions is available for registered Annual Meeting attendees through October 2025 on the virtual meeting platform.