A key to the quest?

In this issue of Blood, Spencer et al report on the phase 1 study results of the novel AKT inhibitor afuresertib, which showed favorable safety and pharmacokinetics and appeared to be clinically active in multiple myeloma.¹ 

Multiple myeloma remains incurable despite the development of next-generation proteasome inhibitors and immunomodulatory compounds.²  Given the systematic development of mechanisms of resistance to any known therapeutic agent because of the genetic complexity of myeloma and its multiclonal character, future therapeutic approaches are likely to be based on combinatory treatments to produce long-term remissions or eliminate the diseased clones.^3,4  Therefore, new drugs with novel mechanisms of action and favorable safety profiles are needed to augment currently used combinations and to avoid cross-resistance in myeloma.

It has been shown that the phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) signaling pathway (identified almost 2 decades ago) is frequently disturbed in many human cancers and plays a major role not only in tumor development but also in the tumor’s potential response to cancer treatment.^5,6  Activated Akt modulates the function of numerous substrates involved in important functions such as the regulation of cell survival, cell cycle progression, cellular growth, and metabolism (see figure).^7,8  Thus, many of the newly targeted agents have been specifically designed to act on PI3K/AKT-related targets in recent years—an attractive target for drug development because such agents might inhibit proliferation and reverse repression of apoptosis and resistance to cytotoxic therapy in cancer cells.⁹  These include inhibitors (kinase inhibitors and monoclonal antibodies) that target upstream regulators of PI3K/AKT, such as PI3K and growth factor receptors, and also downstream effectors, such as the components of the mammalian target of rapamycin/AKT pathway, and finally those that target AKT itself, principally through its adenosine triphosphate (ATP) binding site of PI3K and phosphorylation sites.

As a consequence, several inhibitors of proteins that are involved in PI3K/AKT signaling pathways have been under development for some time for myeloma, and some have even entered phase 3 clinical trials.¹⁰  However, despite compelling evidence of the key role of this pathway in tumor cells, particularly in the context of the feeding bone marrow milieu and microenvironment for myeloma tumor cells, no drug used alone or in combination with existing therapies developed to exploit activation of the PI3K/AKT pathway within myeloma cells and/or enhance the efficacy of existing chemotherapeutic agents has been approved to date for myeloma—a marker of truth on whether a drug has been proved worthy of achieving better therapy for multiple myeloma.

This first-time-in-human study (PKB112835) was designed to evaluate the safety, pharmacokinetics, and initial clinical efficacy of afuresertib in patients with relapsed and/or refractory hematologic malignancies. Afuresertib is a reversible, ATP-competitive, oral pan-AKT kinase inhibitor. Once-daily oral administration to mice delayed the growth of various human tumor xenografts in a dose-dependent manner. The frequency of sensitivity was particularly high in T-cell acute lymphoblastic leukemia (ALL), B-cell ALL, chronic lymphocytic leukemia, and non-Hodgkin lymphoma cell lines, with the 50% effective dose <1 μM. The maximum-tolerated dose was established at 125 mg per day. Clinical activity of single-agent afuresertib was observed in patients with myeloma, with an overall response rate (partial response or better) of 8.8% and a clinical benefit rate (≥ minor response) of 17.6% although the majority of patients had very advanced and/or end-stage myeloma. Interestingly, it appeared that single-agent afuresertib had a favorable safety profile, whereas previous PI3K/AKT inhibitors were often hampered by toxicities, including myelosuppression (mostly thrombopenia) and also nonhematologic gastrointestinal toxicities, metabolic disturbances (hyperlipidemia and hyperglycemia) and, to a lesser extent, skin issues, dyspnea, and dry cough, among others.

Therefore, the promise is great that a PI3K/AKT pathway inhibitor might finally complete the armamentarium for treating myeloma that will enable several choices of combinations to enhance treatment and limit development of mechanisms of resistance, given the favorable safety profile.