Phase I trial of the CDK 4/6 inhibitor, P1446A-05 (voruciclib) in combination with the BRAF inhibitor (BRAFi), vemurafenib in advanced, BRAF-mutant melanoma.

Diab, Adi; Martin, Alison; Simpson, Lauren; Algazi, Alain P.; Chawla, Purvi; Kim, Dae Won; Santra, Sourav; Patel, Vruti; Jadhav, Nitin; Abhyankar, Dhiraj; Davies, Michael A.; Buch, Shama; Kim, Kevin; Daud, Adil

doi:10.1200/jco.2015.33.15_suppl.9076

Cited by 8 publications

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“…As single agents in melanoma, CDK4/6 inhibitors do not display dramatic clinical activity (42, 43, 45–48). However, combination therapies employing CDK4/6 inhibitors with drugs targeting MEK or BRAF look promising, showing improved disease control and prolonged progression-free survival (14, 15, 49, 50). Our data regarding the effects of CDK4/6 inhibition on normal cells raise two questions for the field: 1.…”

Section: Discussionmentioning

confidence: 99%

Stromal Senescence By Prolonged CDK4/6 Inhibition Potentiates Tumor Growth

Guan

LaPak

Hennessey

et al. 2017

Molecular Cancer Research

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Senescent cells within the tumor microenvironment (TME) adopt a pro-inflammatory, senescence-associated secretory phenotype (SASP) that promotes cancer initiation, progression and therapeutic resistance. Here, exposure to Palbociclib (PD-0332991), a CDK4/6 inhibitor, induces senescence and a robust SASP in normal fibroblasts. Senescence caused by prolonged CDK4/6 inhibition is DNA damage-independent and associated with Mdm2 downregulation, whereas the SASP elicited by these cells is largely reliant upon NF-κB activation. Based upon these observations, it was hypothesized that the exposure of non-transformed stromal cells to PD-0332991 would promote tumor growth. Ongoing clinical trials of CDK4/6 inhibitors in melanoma prompted a validation of this hypothesis using a suite of genetically defined melanoma cells (i.e. Ras mutant, Braf mutant, and Ras/Braf wild type). When cultured in the presence of CDK4/6i–induced senescent fibroblasts, melanoma cell lines exhibited genotype-dependent proliferative responses. However, in vivo, PD-0332991-treated fibroblasts enhanced the growth of all melanoma lines tested and promoted the recruitment of Gr-1-positive immune cells. These data indicate that prolonged CDK4/6 inhibitor treatment causes normal fibroblasts to enter senescence and adopt a robust SASP. Such senescent cells suppress the anti-tumor immune response and promote melanoma growth in immunocompetent, in vivo models. Implications The ability of prolonged CDK4/6 inhibitor treatment to induce cellular senescence and a robust SASP in primary cells may hinder therapeutic efficacy and promote long-term, gerontogenic consequences that should be considered in clinical trials aiming to treat melanoma and other cancer types.

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Section: Discussionmentioning

confidence: 99%

Stromal Senescence By Prolonged CDK4/6 Inhibition Potentiates Tumor Growth

Guan

LaPak

Hennessey

et al. 2017

Molecular Cancer Research

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“…Concerning BRAF-mutant melanoma, preclinical data showed the usefulness of CDK4/6 inhibitor LY2835219 in killing vemurafenib-resistant cells, being the right premise for the use of this class of anticancer drugs in such a clinical scenario [ 126 ]. Voruciclib (P1446A-05) has been tested in combination with vemurafenib in a Phase 1 trial (NCT01841463) with good tolerability and efficacy, also in treatment-naïve patients [ 127 ]; similar results were reported for ribociclib, a potent and selective CDK4/6 inhibitor, administered together with encorafenib in BRAF-mutant melanoma patients [ 128 ]. A preclinical study investigated the optimal timing of adding palbociclib to BRAF and MEK inhibitors, confirming that double inhibition with BRAF and CDK4/6 inhibitors suppresses tumour growth in treatment naïve BRAF-mutant models, whilst the triple inhibition is ineffective after the development of BRAF inhibitor resistance [ 129 ].…”

Section: From the Past To The Future Of Braf-mutant Melanoma Treatmentioning

confidence: 97%

BRAF Gene and Melanoma: Back to the Future

Ottaviano

Giunta

Tortora

et al. 2021

IJMS

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As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.

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Cell Cycle Regulation and Melanoma

McArthur

2016

Curr Oncol Rep

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Dysregulation of cell cycle control is a hallmark of melanomagenesis. Agents targeting the G1-S and G2-M checkpoints, as well as direct anti-mitotic agents, have all shown promising preclinical activity in melanoma. However, in vivo, standalone single agents targeting cell cycle regulation have only demonstrated modest efficacy in unselected patients. The advent of specific CDK 4/6 inhibitors targeting the G1-S transition, with an improved therapeutic index, is a significant step forward. Potential synergy exists with the combination of CDK4/6 inhibitors with existing therapies targeting the MAPK pathway, particularly in subsets of metastatic melanomas such as NRAS and BRAF mutants. This reviews summaries of the latest developments in both preclinical and clinical data with cell cycle-targeted therapies in melanoma.

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Phase I trial of the CDK 4/6 inhibitor, P1446A-05 (voruciclib) in combination with the BRAF inhibitor (BRAFi), vemurafenib in advanced, BRAF-mutant melanoma.

Cited by 8 publications

References 0 publications

Stromal Senescence By Prolonged CDK4/6 Inhibition Potentiates Tumor Growth

Stromal Senescence By Prolonged CDK4/6 Inhibition Potentiates Tumor Growth

BRAF Gene and Melanoma: Back to the Future

Cell Cycle Regulation and Melanoma

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