AACR San Diego 2024: New Drugs on the Horizon + RMC-6236
The New Drugs on the Horizon sessions at the AACR Annual Meeting 2024 in San Diego, were held in collaboration with the AACR Chemistry in Cancer Research Working Group and revealed twelve innovative oncology agents, covering both small molecules and large molecules. As in previous years, these sessions offered attendees a first look at the structures and preliminary data of novel cancer treatments that are entering, or progressing through the clinic. This three-part series took place on April 7th and 8th and was co-chaired by Mary Mader, Lori Friedman, Ingo Hartung, Michelle Arkin, Hong Shen, and Ben Ebert. In case you missed any of these exciting compounds –including several highly selective inhibitors, two molecular glues, a bifunctional degrader, a radiopharmaceutical, a bifunctional antibody, and one ADC – this article provides the structures and targets disclosed during the three sessions. As a bonus, slipped into the “KRAS: Broadening the Attack Beyond G12C…” session chaired by Kevin Shokat was the first disclosure of RMC-6326, a pan-RAS isoform inhibitor that shows remarkable activity in the clinic.
The newly disclosed oncology agents included:
ABBV-303 (AbbVie, North Chicago, IL/South San Francisco, CA/ Dragonfly Therapeutics, Waltham, MA; presented by Jennifer Stone): A c-Met targeted multispecific NK cell engager antibody based on Dragonfly Therapeutics’ TriNKET® technology that includes three functional arms: a c-Met binding scFv, a Fab arm that binds NKG2D, and a heterodimeric IgG1 Fc which binds CD16a on NK cells and links the other two binding moieties. A Ph. I trial of ABBV-303 will begin in H1 2024 for patients with solid tumors as a monotherapy and in combination with AbbVie’s anti-PD-1 checkpoint inhibitor, budigalimab (NCT06158958).
BMS-986365 (CC-94676) (BMS, San Diego, CA/Duke University, Durham, NC; presented by Shuichan Xu): A heterobifunctional degrader that induces cereblon (CRBN) E3 ligase-dependent ubiquitination and degradation of the androgen receptor (AR), as well as a broad range of clinically relevant AR mutants. BMS-986365 has advanced to a Ph. I trial in subjects with metastatic, castration-resistant prostate cancer (NCT04428788).
RMC-9805 (Revolution Medicines, Redwood City, CA; presented by John E. Knox): A first-in-class, orally bioavailable, CNS-penetrant covalent inhibitor of KRAS G12D(ON) that uses an aziridine warhead to covalently engage the oncogenic aspartate. RMC-9805 forms a tri-complex between the intracellular chaperone cyclophilin A (CypA) and the “ON” state of KRAS G12D, blocking its ability to signal through the MAPK pathway. RMC-9805 is currently in a Ph. I trial in adults with KRAS G12D-mutant solid tumors (NCT06040541).
ORIC-944 (ORIC Pharmaceuticals, South San Francisco, CA; presented by Lori Friedman): An orally bioavailable, second-generation PRC2 (polycomb repressive complex 2) inhibitor that selectively binds at the allosteric EED (embryonic ectoderm development) subunit and exhibits potential best-in-class properties. Remarkably, initial data shows that ORIC-944 may have the ability to “reprogram” refractory, AR-independent prostate tumors to a previous AR-dependent state. ORIC-944 is being evaluated in an ongoing Ph. Ib trial in patients with metastatic prostate cancer (NCT05413421).
ARV-393 (Arvinas, New Haven, CT; presented by Dan Sherman): An orally bioavailable PROTAC® that degrades B-cell lymphoma 6 (BCL6) via CRBN-mediated ubiquitination and proteasomal degradation. The rapid and sustained BCL6 degradation seen in vitro and in vivo is expected to propel ARV-393 into the clinic in H1 2024, having completed IND-enabling studies.
AZD8421 (AstraZeneca, Waltham, MA; presented by Christopher Denz): A highly selective CDK2 inhibitor with the potential to address resistance to standard-of-care CDK4/6 inhibitors. Compared to other CDK2 modulators, AZD8421 has an improved therapeutic index and combination potential. A Ph. I/IIa trial of AZD8421, alone and in combination with targeted anti-cancer drugs in patients with ER+/HER2- advanced breast cancer, and patients with metastatic high-grade serous ovarian cancer has been initiated (NCT06188520).
BBO-8520 (Frederick National Laboratory, Frederick, MD/BridgeBio Pharma, San Francisco, CA/Lawrence Livermore National Laboratory, Livermore, CA; presented by Pedro Beltran): A first-in-class, orally bioavailable covalent inhibitor of both the GTP-bound (ON)- and GDP-bound (OFF)-state conformations of KRAS G12C. This ability to target the KRAS (ON) state, gives BBO-8520 significant advantages over the competition in both in vitro and in vivo assays, including driving deep tumor regressions in mouse xenograft studies. BBO-8520 has advanced into a Ph. I trial to evaluate its safety, tolerability, and PK as a single agent and in combination with pembrolizumab in patients with advanced non-small cell lung cancer (NCT06343402).
M3554 (Merck KGaA, Darmstadt, DE/EMD Serono, Billerica, MA/Inter-Lab Ltd., Yavne, Israel; presented by Christiane Amendt): An anti-GD2 ADC based on the humanized ch14.18 anti-GD2 antibody that carries the topoisomerase I inhibitor (TOP1i), exatecan, as the payload, connected via a cleavable beta-glucuronide linker. M3554 exhibits in vivo antitumor activity with tumor regressions in the CHP134 xenograft model and patient-derived xenografts models. In addition, M3554 showed favorable PK in rats and monkeys, and a favorable safety profile.
Actinium-225 -PSMA-Trillium (BAY 3563254) (Bayer AG, AS, US/Ratio Therapeutics, Boston, MA; presented by Sabine Zitzmann-Kolbe): A novel prostate-specific membrane antigen (PSMA)-targeting radioligand consisting of a high-affinity PSMA inhibitor for specific tumor-targeting, an albumin-binding domain designed to prolong plasma residence time and increase the therapeutic index by improving tumor uptake while reducing salivary gland uptake, and a “macropa” chelator for robust radiolabeling with actinium-225. BAY 3563254 has advanced to a Ph. I trial to evaluate its antitumor activity in participants with advanced metastatic castration-resistant prostate cancer (NCT06217822).
NST-628 (Nested Therapeutics, Cambridge, MA/Memorial Sloan Kettering, New York, NY; presented by Klaus Hoeflich): An orally bioavailable, brain penetrant (pan-RAF)-MEK molecular glue that prevents RAF heterodimer formation, and subsequent MAPK signaling, through inducing a stable RAF-MEK glue complex. NST-628 exhibits best-in-class drug-like properties and has advanced to a two-part Ph. I trial to evaluate its preliminary efficacy in adult patients with MAPK pathway mutated/dependent advanced solid tumors who have exhausted standard treatment options (NCT06326411).
VVD-214 (RO7589831) (Vividion Therapeutics, San Diego, CA/Roche, Basel, CH; presented by Shota Kikuchi and Piergiorgio Pettazzoni): An oral, covalent, allosteric WRN helicase inhibitor discovered using Vividion’s chemoproteomics platform that engages Cys727 of WRN in a nucleotide-cooperative manner. VVD-214 provides robust tumor regression in colorectal cancer cell lines and patient-derived xenograft models, has completed IND-enabling studies, and, in collaboration with Roche, is being evaluated in a Ph. I trial in patients with microsatellite instability-high cancers (NCT06004245).
PF-07220060 (Pfizer, San Diego, CA; presented by Lars Anders and Gary Gallego): An oral aminopyrimidine-based selective CDK4 inhibitor that exhibits ~30-fold selectivity over CDK6, resulting in reduced preclinical hematological toxicity compared to the CDK4/6 inhibitor palbociclib. PF-07220060 is now in a Ph. III trial (NCT06105632) in combination with fulvestrant in patients with HR+/HER2- advanced or metastatic breast cancer.
RMC-6236 (Revolution Medicines, Redwood City, CA; presented by Elena Koltun and Wei Lin in the “KRAS: Broadening the Attack Beyond G12C…” session): An oral tri-complex glue that induces the formation of a complex between the intracellular chaperone cyclophilin A (CypA) and a broad range of RAS(ON) isoform mutants, inhibiting their activity. RMC-6236 is active against cell lines driven by G12C/D/V/A/S as well as NRAS G13X and Q61X mutations. Clinical data was presented showing remarkable activity against tumors driven by these specific mutations. The most advanced clinical trial is a Ph. I/II (NCT06162221) study of RMC-6236 in combination with standard of care.
Our team will cover these molecules in more depth in the coming weeks. Stay tuned!
