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

The New Drugs on the Horizon sessions, held during the AACR Annual Meeting 2024 in San Diego, showcased twelve innovative oncology agents, encompassing a diverse range of small and large molecules, including small molecule inhibitors to bispecific antibodies and radioligands. In collaboration with the AACR Chemistry in Cancer Research Working Group, these sessions provided attendees with exclusive insights into the structures and preliminary data of emerging cancer treatments entering or advancing through clinical development. This summary provides valuable insights into the intricacies of target validation, preclinical assessment, and clinical trials, setting the stage for the next wave of cancer therapeutics. Part 1 focuses on cancer immunotherapy and targeted therapy drug developments.

Cancer Immunotherapy and Targeted Therapy

ABBV-303 (AbbVie): Novel NK and CD8 T Cell Engager for c-Met-Expressing Tumors

ABBV-303, a novel NK and CD8 T cell engager, targets c-Met-expressing tumors with remarkable potency. By harnessing both innate and adaptive immune responses, ABBV-303 demonstrates promising anti-tumor activity across various cancer types. Preclinical studies have shown encouraging results, leading to the initiation of phase I clinical trials in solid tumors as a monotherapy and in combination with an anti-PD-1 checkpoint inhibitor. Dragonfly Therapeutics’ TriNKET® technology has been utilized to develop this novel multispecific NK cell engager antibody targeting c-Met. This innovative antibody incorporates three functional arms: a c-Met binding scFv, a Fab arm binding NKG2D, and a heterodimeric IgG1 Fc, which binds CD16a on NK cells and links the other two binding moieties. A Phase I trial of this antibody, known as ABBV-303, is set to commence in the first half of 2024. The trial will focus on patients with solid tumors, investigating both monotherapy and combination therapy with AbbVie’s anti-PD-1 checkpoint inhibitor, budigalimab (NCT06158958).

BMS-986365 (BMS/Duke University): Ligand-Directed Androgen Receptor Degrader (AR LDD) for Advanced Prostate Cancer

With a dual heterobifunctional degrader design, BMS-986365, a ligand-directed androgen receptor degrader (AR LDD), holds promise for the treatment of advanced prostate cancer. Its ability to induce rapid and deep degradation of both wildtype and mutant forms of the androgen receptor, along with superior potency compared to existing therapies, positions it as a potential game-changer in the field.Specifically, it is aimed at initiating cereblon (CRBN) E3 ligase-mediated ubiquitination, leading to the degradation of the androgen receptor (AR) and addressing various clinically relevant AR mutations. This novel drug has advanced into a Phase I clinical trial focusing on individuals diagnosed with metastatic, castration-resistant prostate cancer (NCT04428788).

RMC-9805 (Revolution Medicines): Oral, Covalent Tri-Complex KRASG12D(ON) Inhibitor

RMC-9805 presents a novel approach to targeting RAS^G12D mutant cancers. By selectively engaging the active, GTP-bound state of RAS^G12D, RMC-9805 demonstrates potent anti-tumor activity and synergistic effects with other therapeutic modalities, offering new hope for patients with KRAS^G12D-driven tumors. As a orally available inhibitor targeting KRAS^G12D(ON), RMC-9805 utilizes an aziridine warhead to form a covalent bond with the oncogenic aspartate. Through this mechanism, it disrupts KRAS^G12D signaling via the MAPK pathway. In Phase I trials for adults with KRAS^G12D-mutant solid tumors, RMC-9805 demonstrates promising potential (NCT06040541).

ORIC-944 (Mirati Therapeutics/ORIC Pharmaceuticals): Novel Inhibitor of PRC2 for Prostate Cancer Treatment

ORIC-944, a second-generation inhibitor of PRC2 (polycomb repressive complex 2), shows significant promise in treating prostate cancer by targeting EZH2 (Enhancer of Zeste Homolog 2). Its superior properties compared to first-generation inhibitors include potent anti-tumor activity and synergistic effects when combined with existing therapies. Available as an oral PRC2 inhibitor, ORIC-944, selectively targets the allosteric EED (embryonic ectoderm development) subunit, showing potential as a best-in-class agent. Initial findings suggest its capacity to reverse refractory, AR-independent prostate tumors to an AR-dependent state. Ongoing Phase Ib trials in metastatic prostate cancer patients (NCT05413421) aim to further evaluate its therapeutic efficacy.

ARV-393 (Arvinas): Potent BCL6 Targeting PROTAC® for Non-Hodgkin’s Lymphoma

ARV-393 offers a novel approach to treating Non-Hodgkin’s Lymphoma (NHL) by leveraging the PROTAC® technology. With its potent anti-tumor activity and favorable safety profile, ARV-393 presents itself as a promising therapeutic option for patients with NHL. Its orally bioavailable nature further enhances its potential, designed to degrade B-cell lymphoma 6 (BCL6) via CRBN-mediated ubiquitination and subsequent proteasomal degradation. Through its unique mechanism of action, ARV-393 induces rapid and sustained BCL6 degradation both in vitro and in vivo. This promising profile has propelled ARV-393 into clinical development, with plans to initiate Phase I trials in the first half of 2024, following successful completion of IND-enabling studies.

AZD8421 (AstraZeneca): Highly Selective CDK2 Inhibitor for Breast and CCNE1-High Cancers

AZD8421 addresses resistance to CDK4/6 inhibitors in breast and CCNE1-high cancers through its highly selective CDK2 inhibition. With a unique mechanism of action and favorable pharmacokinetic properties, AZD8421 emerges as a promising treatment option for patients with CDK2-dependent tumors. Its potential as a highly selective CDK2 inhibitor to overcome resistance commonly observed with standard-of-care CDK4/6 inhibitors, marks a significant advancement in the field of cancer therapy. Offering an improved therapeutic index and combination potential compared to other CDK2 modulators, AZD8421 has entered Phase I/IIa trials. These trials, conducted both as monotherapy and in combination with targeted anti-cancer drugs, aim to evaluate its efficacy in patients with ER+/HER2- advanced breast cancer and metastatic high-grade serous ovarian cancer (NCT06188520).

Forging Ahead: Pioneering Paths in Oncology Therapeutics

The AACR Annual Meeting 2024 showcased a remarkable array of novel cancer immunotherapy and targeted therapy agents poised to revolutionize oncology treatment. ABBV-303 harnesses innate and adaptive immunity against c-Met-expressing tumors, while BMS-986365 presents a promising approach for advanced prostate cancer by inducing rapid and deep degradation of the androgen receptor. RMC-9805 offers hope for KRAS^G12D-driven tumors, targeting the active state of RAS^G12D, while ORIC-944 demonstrates potent inhibition of EZH2 in prostate cancer. ARV-393 utilizes PROTAC® technology to degrade BCL6, showing potential for Non-Hodgkin’s Lymphoma, and AZD8421 addresses resistance in breast and CCNE1-high cancers through highly selective CDK2 inhibition. These findings herald a new era in cancer therapy, promising improved outcomes for patients across diverse malignancies.

Author

Bernice Lottering