334P Lerociclib (G1T38), a continuously dosed oral CDK4/6 inhibitor, with fulvestrant in HR+/HER2- advanced breast cancer patients: Updated phase II results and dose selection

Bulat, Iurie; Maglakelidze, Marina; Krastev, Boris; Arkenau, Hendrick-Tobias; Murias, C.; Baird, Richard D.; Roylance, Rebecca; Wardley, Andrew M; Crijanovschi, Adrian; Gogiladze, Maia; Lu, Yujie; McCullough, Amy; Jain, Sarika; Wolfgang, Curt D.; Malik, Rajesh; Beelen, Andrew P.

doi:10.1016/j.annonc.2020.08.436

Cited by 4 publications

(3 citation statements)

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“…48 Clinical data generated for lerociclib in combination with fulvestrant in patients with hormone receptor-positive, HER2negative metastatic breast cancer showed strong clinical efficacy, with a progression-free survival of 28.6 months and a manageable toxicity profile. 49 This early clinical experience indicates potential clinical efficacy and safety.…”

Section: Cdk4/6 Inhibitors In Developmentmentioning

confidence: 97%

The promise of combining CDK4/6 inhibition with hormonal therapy in the first-line treatment setting for metastatic or recurrent endometrial adenocarcinoma

Ray-Coquard,

Monk,

Lorusso

et al. 2023

Int J Gynecol Cancer

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Metastatic or recurrent endometrioid adenocarcinoma of the uterine corpus is often incurable with limited treatment options. First-line treatment often includes cytotoxic chemotherapy, which incurs significant toxicities for many patients. Endometrial cancer, specifically endometrioid cancer, is a hormone-sensitive disease and, while single-agent hormonal therapies have demonstrated clinical benefit, resistance to these agents often leads to the use of chemotherapy. There is a lack of approved endocrine treatment options in the metastatic setting for most recurrent endometrial cancers, representing an unmet clinical need. Emerging evidence suggests that hormonal therapy in combination with other targeted treatments, such as cyclin dependent kinase (CDK)4/6 inhibitors, is well tolerated and effective in select patient populations. We discuss the clinical evidence suggesting that the combination of CDK4/6 inhibitors and hormonal therapy has the potential to represent an important addition to the first-line treatment options for patients with low-grade advanced or recurrent endometrial cancer.

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Section: Cdk4/6 Inhibitors In Developmentmentioning

confidence: 97%

The promise of combining CDK4/6 inhibition with hormonal therapy in the first-line treatment setting for metastatic or recurrent endometrial adenocarcinoma

Ray-Coquard,

Monk,

Lorusso

et al. 2023

Int J Gynecol Cancer

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“…Other CDK4/6i, such as lerociclib or trilaciclib, remain largely investigational at present. Lerociclib, a continuous oral CDK4/6i, has shown a safety profile and preliminary efficacy comparable to the approved agents in HR + /HER2 − –mBC 41 . The development of trilaciclib, which aims to maintain immune and bone marrow cells in G1 arrest and protect them from chemotherapy‐induced damage, has mostly focused on TNBC, where it has been granted an US FDA fast track designation, and is currently being evaluated in the phase 3 PRESERVE 2 study 42,43 …”

Section: G1/s Phase Transitionmentioning

confidence: 99%

Seize the engine: Emerging cell cycle targets in breast cancer

Fuentes‐Antrás,

Bedard,

Cescon

2024

Clinical & Translational Med

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Breast cancer arises from a series of molecular alterations that disrupt cell cycle checkpoints, leading to aberrant cell proliferation and genomic instability. Targeted pharmacological inhibition of cell cycle regulators has long been considered a promising anti‐cancer strategy. Initial attempts to drug critical cell cycle drivers were hampered by poor selectivity, modest efficacy and haematological toxicity. Advances in our understanding of the molecular basis of cell cycle disruption and the mechanisms of resistance to CDK4/6 inhibitors have reignited interest in blocking specific components of the cell cycle machinery, such as CDK2, CDK4, CDK7, PLK4, WEE1, PKMYT1, AURKA and TTK. These targets play critical roles in regulating quiescence, DNA replication and chromosome segregation. Extensive preclinical data support their potential to overcome CDK4/6 inhibitor resistance, induce synthetic lethality or sensitise tumours to immune checkpoint inhibitors. This review provides a biological and drug development perspective on emerging cell cycle targets and novel inhibitors, many of which exhibit favourable safety profiles and promising activity in clinical trials.

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“…Other newer CDK4/6 inhibitor agents include dalpiciclib, which has demonstrated a positive progression free survival (PFS) readout in combination with fulvestrant in the second- or third-line setting in the phase III DAWNA-1 trial ( Xu et al, 2021 ), and in combination with an AI in the first-line setting in the phase III DAWNA-2 trial ( Xu et al, 2022 ). Lerociclib had favorable signals of efficacy and tolerability in a dose escalation and expansion trial in combination with fulvestrant ( Bulat et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

CDK4/6 inhibitor resistance in estrogen receptor positive breast cancer, a 2023 perspective

Zhou

Downton

Freelander

et al. 2023

Front. Cell Dev. Biol.

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CDK4/6 inhibitors have become game-changers in the treatment of estrogen receptor-positive (ER+) breast cancer, and in combination with endocrine therapy are the standard of care first-line treatment for ER+/HER2-negative advanced breast cancer. Although CDK4/6 inhibitors prolong survival for these patients, resistance is inevitable and there is currently no clear standard next-line treatment. There is an urgent unmet need to dissect the mechanisms which drive intrinsic and acquired resistance to CDK4/6 inhibitors and endocrine therapy to guide the subsequent therapeutic decisions. We will review the insights gained from preclinical studies and clinical cohorts into the diverse mechanisms of CDK4/6 inhibitor action and resistance, and highlight potential therapeutic strategies in the context of CDK4/6 inhibitor resistance.

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334P Lerociclib (G1T38), a continuously dosed oral CDK4/6 inhibitor, with fulvestrant in HR+/HER2- advanced breast cancer patients: Updated phase II results and dose selection

Cited by 4 publications

References 0 publications

The promise of combining CDK4/6 inhibition with hormonal therapy in the first-line treatment setting for metastatic or recurrent endometrial adenocarcinoma

The promise of combining CDK4/6 inhibition with hormonal therapy in the first-line treatment setting for metastatic or recurrent endometrial adenocarcinoma

Seize the engine: Emerging cell cycle targets in breast cancer

CDK4/6 inhibitor resistance in estrogen receptor positive breast cancer, a 2023 perspective

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