Oncology’s New Drugs on the Horizon (II): Radiotherapy, Radioligands & Other Therapeutic Agents

The journey of bringing new cancer drugs to market is both arduous and rewarding, demanding extensive time and resources across various developmental stages. At the AACR Annual Meeting 2024 in San Diego, the New Drugs on the Horizon sessions unveiled a collection of innovative oncology agents, representing a leap forward in cancer therapeutics. Here, we look at the following six pioneering treatments in the realm of radiotherapy, radioligands and other therapeutic oncological agents. From highly selective inhibitors to molecular glues, from bifunctional degraders to radiopharmaceuticals, and from bifunctional antibodies to antibody-drug conjugates (ADCs), all together these sessions provided a panoramic view of cutting-edge approaches shaping the future of cancer treatment.

Related article: Oncology’s New Drugs on the Horizon (I): Cancer Immunotherapy and Targeted Therapy

Radiotherapy and Radioligands

BBO-8520 (Frederick National Laboratory/BridgeBio Pharma): First-in-Class Direct Inhibitor of KRAS^G12C(ON)

BBO-8520, a first-in-class direct inhibitor of KRAS^G12C(ON), offers a promising strategy for overcoming resistance to existing KRAS^G12C inhibitors. By targeting both the active and inactive states of KRAS^G12C, BBO-8520 demonstrates potent anti-tumor activity and represents a significant advancement in the field of KRAS-targeted therapy. As an orally bioavailable covalent inhibitor, BBO-8520 targets both the GTP-bound (ON) and GDP-bound (OFF) state conformations of KRAS^G12C, distinguishing itself from existing competitors. Its unique ability to target the KRAS(ON) state has demonstrated remarkable efficacy in preclinical assays, including driving profound tumor regressions in murine xenograft models. BBO-8520 has progressed to Phase I clinical trials to assess its safety, tolerability, and pharmacokinetics as a monotherapy and in combination with pembrolizumab in patients with advanced non-small cell lung cancer (NCT06343402).

Actinium-225-PSMA-Trillium (BAY 3563254) (Bayer/Ratio Therapeutics): Novel Targeted Therapy for mCRPC

Actinium-225-PSMA-Trillium, a novel 225Ac-labeled PSMA-targeting small molecule triad, shows promise for the treatment of metastatic castration-resistant prostate cancer (mCRPC). With its unique design and preclinical efficacy, Actinium-225-PSMA-Trillium represents a potential breakthrough in the treatment of mCRPC.Targeting prostate-specific membrane antigen (PSMA) with high affinity, radioligand BAY 3563254 can ensure precise tumor targeting. Engineered with an albumin-binding domain to enhance plasma residence time and improve tumor uptake while minimizing uptake in salivary glands, this innovative compound employs a “macropa” chelator for robust actinium-225 radiolabeling. Advancing to Phase I clinical trials, BAY 3563254 aims to assess its antitumor efficacy in individuals with advanced mCRPC (NCT06217822).

Other Therapeutic Agents: New Drugs in Oncology

M3554 (Merck KGaA/EMD Serono/Inter-Lab Ltd): Novel Anti-GD2 Antibody Drug Conjugate

M3554, a novel anti-GD2 antibody drug conjugate, presents a new therapeutic approach for oncology indications with high GD2 prevalence. By leveraging a potent payload and modified antibody moiety, M3554 demonstrates strong anti-tumor activity with a favorable safety profile, with promising potential for patients with GD2-expressing tumors. It is an ADC targeting GD2, utilizing the humanized ch14.18 anti-GD2 antibody linked to the topoisomerase I inhibitor (TOP1i), exatecan, via a cleavable beta-glucuronide linker. Demonstrating potent in vivo antitumor effects, M3554 induces tumor regressions in both the CHP134 xenograft model and patient-derived xenografts. Moreover, M3554 exhibits favorable pharmacokinetics in rats and monkeys, alongside a promising safety profile.

NST-628 (Nested Therapeutics/Memorial Sloan Kettering): Potent Brain-Penetrant MAPK Pathway Molecular Glue

NST-628, a fully brain-penetrant MAPK pathway molecular glue, demonstrates potent and durable inhibition of the RAS-MAPK signaling cascade. With its broad efficacy and favorable safety profile, NST-628 holds promise for the treatment of RAS- and RAF-driven cancers, addressing a significant unmet need in oncology. Its function as a brain-penetrant, orally bioavailable molecular glue targeting the (pan-RAF)-MEK pathway inhibits RAF heterodimer formation, thereby disrupting MAPK signaling by promoting a stable RAF-MEK glue complex. NST-628, boasting best-in-class drug-like characteristics, progresses to a two-part Phase I trial, assessing its initial efficacy in adult patients with advanced solid tumors dependent on MAPK pathway mutations and who have exhausted standard treatment options (NCT06326411).

VVD-214 (Vividion Therapeutics/Roche): Synthetic Lethal Allosteric Inhibitor of WRN Helicase

VVD-214, a synthetic lethal allosteric inhibitor of WRN helicase, offers a promising strategy for treating cancers with microsatellite instability (MSI). By targeting WRN helicase, VVD-214 demonstrates robust anti-tumor activity in MSI-high cancers, providing new hope for patients with this challenging disease. Identified through Vividion’s chemoproteomics platform, VVD-214 interacts with Cys727 of WRN in a nucleotide-cooperative manner. Demonstrating significant tumor regression in colorectal cancer cell lines and patient-derived xenograft models, VVD-214 has successfully concluded IND-enabling studies. Currently, in collaboration with Roche, it undergoes evaluation in a Phase I trial targeting patients with microsatellite instability-high cancers (NCT06004245).

PF-07220060 (Pfizer): A potent and selective CDK4 inhibitor

PF-07220060, a potent and selective CDK4 inhibitor, represents a significant advancement in the field of breast cancer treatment. With its improved efficacy and safety profile compared to existing CDK4/6 inhibitors, PF-07220060 holds promise as a new treatment option for patients with HR+ HER2- breast cancer and other CDK4-dependent tumors. PF-07220060 is an oral selective CDK4 inhibitor based on aminopyrimidine, which demonstrates an approximate 30 fold increase in selectivity over CDK6, mitigating preclinical hematological toxicity observed with palbociclib, a CDK4/6 inhibitor. Currently, in a Phase III trial (NCT06105632), PF-07220060 is being evaluated in combination with fulvestrant for patients diagnosed with HR+/HER2- advanced or metastatic breast cancer.

A Glimpse into the Future of Oncology Therapeutics

The AACR Annual Meeting 2024’s New Drugs on the Horizon sessions revealed twelve groundbreaking oncology therapeutics, of which 6 in the field of radiotherapy, radioligands & other therapeutic agents are discussed here. BBO-8520 targets KRAS^G12C(ON) to overcome resistance, while Actinium-225-PSMA-Trillium offers promise for metastatic castration-resistant prostate cancer. M3554 introduces an anti-GD2 antibody drug conjugate, and NST-628 and VVD-214 show potent inhibition in the RAS-MAPK pathway and targeting WRN helicase, respectively. PF-07220060 emerges as a potent CDK4 inhibitor for HR+ HER2- breast cancer. These findings advance cancer treatment paradigms, fostering optimism for improved outcomes in oncology.

Author

Bernice Lottering