Trilaciclib Prior to Chemotherapy in Patients with Metastatic Triple-Negative Breast Cancer: Final Efficacy and Subgroup Analysis from a Randomized Phase II Study

Tan, Antoinette R.; Wright, Gail S.; Thummala, Anu; Danso, Michael A.; Popović, Lazar; Pluard, Timothy; Han, Hyo S.; Vojnović, Željko; Vasev, Nikola; Ma, Ling; Richards, Donald A.; Wilks, Sharon; Milenković, Dušan; Xiao, Jie; Sorrentino, Jessica A.; Horton, Janet K.; O’Shaughnessy, Joyce

doi:10.1158/1078-0432.ccr-21-2272

Cited by 26 publications

(18 citation statements)

References 40 publications

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“…CDK4/6 inhibition may not drive cell cycle exit directly in these cells, but if the tumour cells become enlarged and damaged following treatment then this could produce vulnerabilities to secondary agents, such as chemotherapeutics that either enhance DNA damage or inhibit DNA damage repair. This may help to explain the surprising finding that the CDK4/6 inhibitor trilaciclib improves overall survival in triple-negative breast cancer when given prior to chemotherapy with the genotoxic combination of gemcitabine and carboplatin (Tan et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Oncogenic signals prime cancer cells for toxic cell growth during a G1 cell cycle arrest

Foy

Crozier

Pareri

et al. 2022

Preprint

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A long-term goal in cancer research has been to inhibit the cell cycle in tumour cells without causing toxicity in proliferative healthy tissues. The best evidence that this is achievable is provided by CDK4/6 inhibitors, which arrest the cell cycle in G1, are well-tolerated in patients, and are effective in treating ER+/HER2- breast cancer. CDK4/6 inhibitors are effective because they arrest tumour cells more efficiently than some healthy cell types and, in addition, they affect the tumour microenvironment to enhance anti-tumour immunity. We demonstrate here another reason to explain their efficacy. Tumour cells are specifically vulnerable to CDK4/6 inhibition because during the G1 arrest, oncogenic signals drive toxic cell overgrowth. This overgrowth causes permanent cell cycle withdrawal by either preventing exit from G1 or by inducing replication stress and genotoxic damage during the subsequent S-phase and mitosis. Inhibiting or reverting oncogenic signals that converge onto mTOR can rescue this excessive growth, DNA damage and cell cycle exit in cancer cells. Conversely, inducing oncogenic signals in non-transformed cells can drive these toxic phenotypes and sensitize cells to CDK4/6 inhibition. Together, this demonstrates how oncogenic signals that have evolved to stimulate constitutive tumour growth and proliferation can be driven to cause toxic cell growth and irreversible cell cycle exit when proliferation is halted in G1.

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Section: Discussionmentioning

confidence: 99%

Oncogenic signals prime cancer cells for toxic cell growth during a G1 cell cycle arrest

Foy

Crozier

Pareri

et al. 2022

Preprint

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“…In a phase II trial of patients with metastatic TNBC, trilaciclib given prior to chemotherapy improved OS. 27,28,48 As this was a relatively small study and OS was a secondary endpoint, this is being further evaluated in the phase III PRESERVE 2 trial. 55 The other PRESERVE studies (1, 3 and 4) are evaluating trilaciclib in combination with chemotherapy (one with chemoimmunotherapy) in metastatic colorectal cancer, metastatic urothelial carcinoma and metastatic non-small cell lung cancer, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Details of the trials are summarized in Table 1. [24][25][26][27][28] A pooled analysis of these three studies was presented at the Virtual Scientific Program of the 2020 American Society of Clinical Oncology Annual Meeting and later published by Weiss et al 21,29 Of the 242 total randomized patients, 123 received trilaciclib in conjunction with chemotherapy. Patient demographics and disease characteristics were relatively well balanced between the two groups; however, the trilaciclib group had more men (72.4%) and current smokers (39.8%).…”

Section: Trilaciclib In Lung Cancermentioning

confidence: 99%

Trilaciclib: A First-in-class Therapy to Reduce Chemotherapy-induced Myelosuppression

Young¹,

Tan²

2022

Oncology &Amp; Haematology

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Oral cyclin-dependent kinase (CDK) 4/6 inhibitors are routinely used to treat metastatic hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer in combination with endocrine therapy; however, they have not been widely used for other tumour types. Trilaciclib is an intravenous CDK 4/6 inhibitor that causes reversible cell cycle arrest in the G1 phase and transient haematopoietic stem and progenitor cell arrest. Ultimately, this protects the bone marrow and immune system from the cytotoxic impact of chemotherapy. Trilaciclib has been evaluated in extensive-stage small cell lung cancer in combination with chemotherapy as a myeloprotective agent and was approved by the US Food and Drug Administration for this use in February 2021. In metastatic triple-negative breast cancer, trilaciclib plus chemotherapy had a survival benefit over chemotherapy alone. This is being further investigated in a phase III trial. This review outlines the mechanism of this novel agent and describes preclinical and clinical data, characterizing its use in extensive-stage small cell lung cancer and advanced triple-negative breast cancer.

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“…Multiple clinical trials about palbociclib treated in various tumors such as breast cancer, ovarian cancer, Pancreatic Ductal Adenocarcinoma. Besides, other CDK4/6 inhibitors such as Abemaciclib [ 170 ], Ribociclib [ 171 ], Lerociclib [ 172 ], Trilaciclib [ 173 ], Dinaciclib [ 174 ], and SHR6390 [ 175 ] are also being adopted in clinical testing.…”

Section: Cdk4/6 Inhibitorsmentioning

confidence: 99%

Role of HOXA9 in solid tumors: mechanistic insights and therapeutic potential

et al. 2022

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HOXA9 functioning as a transcription factor is one of the members of HOX gene family, which governs multiple cellular activities by facilitating cellular signal transduction. In addition to be a driver in AML which has been widely studied, the role of HOXA9 in solid tumor progression has also received increasing attention in recent years, where the aberrant expression of HOXA9 is closely associated with the prognosis of patient. This review details the signaling pathways, binding partners, post-transcriptional regulation of HOXA9, and possible inhibitors of HOXA9 in solid tumors, which provides a reference basis for further study on the role of HOXA9 in solid tumors.

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Trilaciclib Prior to Chemotherapy in Patients with Metastatic Triple-Negative Breast Cancer: Final Efficacy and Subgroup Analysis from a Randomized Phase II Study

Abstract: Genetics, and Zymeworks; a grant from the Department of Defense; and is a member of the speaker bureau for Lilly. JX and JH are paid employees and shareowners of G1 Therapeutics, Inc. JS was a paid employee and shareowner Cancer Research.

Cited by 26 publications

References 40 publications

Oncogenic signals prime cancer cells for toxic cell growth during a G1 cell cycle arrest

Oncogenic signals prime cancer cells for toxic cell growth during a G1 cell cycle arrest

Trilaciclib: A First-in-class Therapy to Reduce Chemotherapy-induced Myelosuppression

Role of HOXA9 in solid tumors: mechanistic insights and therapeutic potential

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