Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth

Smith, Michèle C.; Mader, Mary M.; Cook, James A.; Iversen, Philip W.; Ajamie, Rose T.; Perkins, E.J.; Bloem, Laura J.; Yip, Yvonne Y.; Barda, David A.; Waid, Philip P.; Zeckner, Douglas J.; Young, Debra A.; Sánchez-Félix, Manuel; Donoho, Gregory P.; Wacheck, Volker

doi:10.1158/1535-7163.mct-15-0996

Cited by 68 publications

(51 citation statements)

References 44 publications

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“…In parallel with the short half-life of LY3023414 of about 2 hours, dephosphorylation by !50% of 4EBP1 lasted for about 4 hours and returned to baseline after 6 hours postdose. While this pharmacodynamic data in PBMCs can be only considered as surrogate for the pharmacodynamic effects in patients tumor tissue, the target inhibition kinetics are consistent with data in tumor xenograft models showing intermittent target inhibition in tumors to be associated with singleagent activity of LY3023414 (7). Therefore, assessment of PBMCs was considered a scientifically acceptable and clinically feasible surrogate approach to reflect pharmacodynamic effects of LY3023414 in patient's tumors in this phase I study.…”

Section: Discussionsupporting

confidence: 65%

“…LY3023414 is a novel and selective inhibitor of class I PI3K isoforms, mTORC1/2 and DNA-PK, as demonstrated in biochemical testing against approximately 266 kinases, with high solubility across a wide pH range (7). LY3023414 shows dose-dependent inhibition of phosphorylation of PI3K/Akt/mTOR pathway downstream substrates for 4 to 6 hours in vivo, reflecting the drug's half-life of 2 hours, and leads to potent antitumor activity in tumor xenograft models (7).…”

Section: Introductionmentioning

confidence: 99%

“…LY3023414 shows dose-dependent inhibition of phosphorylation of PI3K/Akt/mTOR pathway downstream substrates for 4 to 6 hours in vivo, reflecting the drug's half-life of 2 hours, and leads to potent antitumor activity in tumor xenograft models (7). An intermittent, "quick-on/quickoff" target engagement mechanism has been suggested to enhance clinical tolerability of PI3K/mTOR inhibitors as well as potentially reduce the emergence of compensatory resistance mechanisms (7,8). The pharmacokinetic parameters of LY3023414 in rats and dogs suggest that the drug is extensively absorbed at relevant doses and subsequently cleared in part via oxidative metabolism by CYP enzymes (7).…”

Section: Introductionmentioning

confidence: 99%

“…An intermittent, "quick-on/quickoff" target engagement mechanism has been suggested to enhance clinical tolerability of PI3K/mTOR inhibitors as well as potentially reduce the emergence of compensatory resistance mechanisms (7,8). The pharmacokinetic parameters of LY3023414 in rats and dogs suggest that the drug is extensively absorbed at relevant doses and subsequently cleared in part via oxidative metabolism by CYP enzymes (7). CYP3A4 and CYP1A2 are responsible for 82% and 18% of the CYP-mediated LY3023414 clearance, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, in vitro data suggest that LY3023414 may be a timedependent inhibitor of CYP3A4 metabolism, which could lead to increased plasma concentration of CYP3A4 substrates (Eli Lilly and Company, data on file). The nonclinical toxicology profile of LY3023414 provided a favorable benefit-risk profile enabling clinical studies of LY3023414 (7).…”

Section: Introductionmentioning

confidence: 99%

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A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer

Bendell

Varghese

Hyman

et al. 2018

Clinical Cancer Research

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Purpose: The PI3K/mTOR pathway is frequently aberrated in cancer. LY3023414 is a potent and selective ATP-competitive inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Here we report the dose-escalation results of the first-in-human phase I study of LY3023414.Experimental Design: A 3þ3 dose escalation for once-daily and twice-daily oral dosing of LY3023414 was followed by an expansion cohort for CYP3A4 drug-drug interaction (DDI) assessment. The primary objective was to determine the recommended phase 2 dose (RP2D). Additional objectives included safety, pharmacokinetics/pharmacodynamics, and antitumor activity.Results: Forty-seven patients with solid tumors received LY3023414 at once-daily (20-450 mg) or twice-daily dosing (150-250 mg). Dose-limiting toxicities were observed at 450 mg once-daily (thrombocytopenia, hypotension, hyperkalemia) in three of three patients, 250-mg twice-daily dosing (hypophosphatemia, fatigue, mucositis) in three of four patients, and in one of 15 patients at 200 mg twice-daily (nausea). Common related AEs included nausea (38%), fatigue (34%), and vomiting (32%) and were mostly mild or moderate. LY3023414 pharmacokinetics demonstrated dose-dependent increase in exposure with ! 90% target inhibition at doses !150 mg. DDI analysis demonstrated LY3023414 to be a weak inhibitor of CYP3A4. Durable partial response was observed in a patient with endometrial cancer harboring PIK3R1 and PTEN truncating mutations, and 13 additional patients (28%) had a decrease in their target lesions by up to 30%.Conclusions: LY3023414 has a tolerable safety profile and single-agent activity in patients with advanced cancers. The RP2D of LY3023414 monotherapy is 200 mg twice daily based on safety, tolerability, and pharmacokinetic/pharmacodynamic data. Clin Cancer Res; 1-10. Ó2018 AACR.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer

Bendell

Varghese

Hyman

et al. 2018

Clinical Cancer Research

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Assessments of prostate cancer cell functions highlight differences between a pan‐PI3K/mTOR inhibitor, gedatolisib, and single‐node inhibitors of the PI3K/AKT/mTOR pathway

Sen,

Khan,

Rossetti

et al. 2024

Molecular Oncology

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Metastatic castration‐resistant prostate cancer (mCRPC) is characterized by loss of androgen receptor (AR) sensitivity and oncogenic activation of the PI3K/AKT/mTOR (PAM) pathway. Loss of the PI3K regulator PTEN is frequent during prostate cancer (PC) initiation, progression, and therapeutic resistance. Co‐targeting the PAM/AR pathways is a promising mCRPC treatment strategy but is hampered by reciprocal negative feedback inhibition or feedback relief. Most PAM inhibitors selectively spare (or weakly inhibit) one or more key nodes of the PAM pathway, potentiating drug resistance depending on the PAM pathway mutation status of patients. We posited that gedatolisib, a uniformly potent inhibitor of all class I PI3K isoforms, as well as mTORC1 and mTORC2, would be more effective than inhibitors targeting single PAM pathway nodes in PC cells. Using a combination of functional and metabolic assays, we evaluated a panel of PC cell lines with different PTEN/PIK3CA status for their sensitivity to multi‐node PAM inhibitors (PI3K/mTOR: gedatolisib, samotolisib) and single‐node PAM inhibitors (PI3Kα: alpelisib; AKT: capivasertib; mTOR: everolimus). Gedatolisib induced anti‐proliferative and cytotoxic effects with greater potency and efficacy relative to the other PAM inhibitors, independent of PTEN/PIK3CA status. The superior effects of gedatolisib were likely associated with more effective inhibition of critical PAM‐controlled cell functions, including cell cycle, survival, protein synthesis, oxygen consumption rate, and glycolysis. Our results indicate that potent and simultaneous blockade of all class I PI3K isoforms, mTORC1, and mTORC2 could circumvent PTEN‐dependent resistance. Gedatolisib, as a single agent and in combination with other therapies, reported promising preliminary efficacy and safety in various solid tumor types. Gedatolisib is currently being evaluated in a Phase 1/2 clinical trial in combination with darolutamide in patients with mCRPC previously treated with an AR inhibitor, and in a Phase 3 clinical trial in combination with palbociclib and fulvestrant in patients with HR+/HER2− advanced breast cancer.

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New prospectives on treatment opportunities in RASopathies

Gelb

Yohe

Wolf

et al. 2022

American J of Med Genetics Pt C

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The RASopathies are a group of clinically defined developmental syndromes caused by germline variants of the RAS/mitogen-activated protein (MAPK) cascade. The prototypic RASopathy is Noonan syndrome, which has phenotypic overlap with related disorders such as cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome with multiple lentigines, and others. In this state-of-the-art review, we summarize current knowledge on unmet therapeutic needs in these diseases and novel treatment approaches informed by insights from RAS/MAPK-associated cancer therapies, in particular through inhibition of MEK1/2 and mTOR in patients with severe disease manifestations. We explore the possibilities of integrating a larger arsenal of molecules currently under development into future care plans. Lastly, we describe both medical and ethical challenges and opportunities for future clinical trials in the field.

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Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth

Abstract: The PI3K/AKT/mTOR pathway is among the most frequently altered pathways in cancer cell growth and survival.

Cited by 68 publications

References 44 publications

A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer

A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer

Assessments of prostate cancer cell functions highlight differences between a pan‐PI3K/mTOR inhibitor, gedatolisib, and single‐node inhibitors of the PI3K/AKT/mTOR pathway

New prospectives on treatment opportunities in RASopathies

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