Phase I/II trial of palbociclib, pembrolizumab and letrozole in patients with hormone receptor-positive metastatic breast cancer

Yuan, Yuan; Lee, Jin Sung; Yost, Susan E.; Frankel, Paul; Ruel, Christopher; Egelston, Colt; Guo, Weihua; Padam, Simran; Tang, Aileen; Martínez, Norma; Schmolze, Daniel; Presant, Cary A.; Ebrahimi, Behnam; Yeon, Christina; Sedrak, Mina S.; Patel, Niki; Portnow, Jana; Lee, Peter; Mortimer, Joanne

doi:10.1016/j.ejca.2021.05.035

Cited by 36 publications

(20 citation statements)

References 45 publications

(42 reference statements)

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“…These adverse events are unlikely due to the choice of ICI (i.e. a PD-1 versus a PD-L1 inhibitor), as a further phase I/II trial for HR + breast cancer, examining upfront combination treatment with the CDK4/6i, palbociclib (given on a 3 week on/1 week off schedule), with pembrolizumab and letrozole, was well tolerated and reportedly safe 37 . It is worth noting however, approximately 50% of patients in this trial required dose delays or dose reductions to manage toxicities associated with neutropenia 37 , which is a common side effect of CDK4/6i 38 – 40 .…”

Section: Boosting Response Rates To Icimentioning

confidence: 99%

“…a PD-1 versus a PD-L1 inhibitor), as a further phase I/II trial for HR + breast cancer, examining upfront combination treatment with the CDK4/6i, palbociclib (given on a 3 week on/1 week off schedule), with pembrolizumab and letrozole, was well tolerated and reportedly safe 37 . It is worth noting however, approximately 50% of patients in this trial required dose delays or dose reductions to manage toxicities associated with neutropenia 37 , which is a common side effect of CDK4/6i 38 – 40 . Indeed, the principal toxicity seen across all 3 approved CDK4/6 inhibitors (abemaciclib, ribociclib and palbociclib) is hematological, including neutropenia, anemia and thrombocytopenia 38 – 40 .…”

Section: Boosting Response Rates To Icimentioning

confidence: 99%

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Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?

2022

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CDK4/6 inhibitors (CDK4/6i) were developed as a cancer therapeutic on the basis of their tumor-intrinsic cytostatic potential, but have since demonstrated profound activity as immunomodulatory agents. While currently approved to treat hormone receptor-positive breast cancer, these inhibitors are under investigation in clinical trials as treatments for a range of cancer types, including melanoma. Melanoma is a highly immunogenic cancer, and has always been situated at the forefront of cancer immunotherapy development. Recent revelations into the immunotherapeutic activity of CDK4/6i, therefore, have significant implications for the utility of these agents as melanoma therapies. In recent studies, we and others have proven the immunomodulatory effects of CDK4/6i to be multifaceted and complex. Among the most notable effects, CDK4/6 inhibition induces transcriptional reprogramming in both tumor cells and immune cells to enhance tumor cell immunogenicity, promote an immune-rich tumor microenvironment, and skew T cell differentiation into a stem-like phenotype that is more amenable to immune checkpoint inhibition. However, in some contexts, the specific immunomodulatory effects of CDK4/6i may impinge on anti-tumor immunity. For example, CDK4/6 inhibition restricts optimal T cells expansion, and when used in combination with BRAF/MEK-targeted therapies, depletes immune-potentiating myeloid subsets from the tumor microenvironment. We propose that such effects, both positive and negative, may be mitigated or exacerbated by altering the CDK4/6i dosing regimen. Here, we discuss what the most recent insights mean for clinical trial design, and propose clinical considerations and strategies that may exploit the full immunotherapeutic potential of CDK4/6 inhibitors.

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Section: Boosting Response Rates To Icimentioning

confidence: 99%

Section: Boosting Response Rates To Icimentioning

confidence: 99%

Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?

2022

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“…In clinical trials, a Phase Ib trial (NCT02779751) aimed to assess the safety and antitumor activity of abemaciclib plus pembrolizumab in patients with endocrine-resistant, metastatic ER+ breast cancers reported an overall response rate (ORR) of 29%, a high disease control rate of 82%, and a clinical benefit rate of 46%, along with higher durations of PFS (8.9 months) and OS (26.3 months) compared to abemaciclib monotherapy. Another CDK4/6 inhibitor-based immunotherapy combination (palbociclib plus pembrolizumab) in a Phase II study in postmenopausal patients with metastatic ER+ breast cancer patients (NCT02778685) also demonstrated a prolonged median follow-up time of 13.7 months and increased partial response rate of 42.1% ( 62 ).…”

Section: Discussionmentioning

confidence: 99%

Cyclin-Dependent Kinase Inhibitors Function as Potential Immune Regulators via Inducing Pyroptosis in Triple Negative Breast Cancer

Wang

Zhou

et al. 2022

Front. Oncol.

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BackgroundImmunotherapy is the most promising treatment in triple-negative breast cancer (TNBC), and its efficiency is largely dependent on the intra-tumoral immune cells infiltrations. Thus, novel ways to assist immunotherapy by increasing immune cell infiltrations were highly desirable.MethodsTo find key immune-related genes and discover novel immune-evoking molecules, gene expression profiles of TNBC were downloaded from Gene Expression Omnibus (GEO). Single-sample gene set enrichment analysis (ssGSEA) and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identified hub genes. The CMap database was used subsequently to predicate potential drugs that can modulate the overall hub gene expression network. In vitro experiments were conducted to assess the anti-tumor activity and the pyroptosis phenotypes induced by GW-8510.ResultsGene expression profiles of 198 TNBC patients were downloaded from GEO dataset GSE76124, and ssGSEA was used to divide them into Immune Cell Proficiency (ICP) group and Immune Cell Deficiency (ICD) group. Hub differential expressed gene modules between two groups were identified by WGCNA and then annotated by Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. A cyclin-dependent kinase (CDK) 2 inhibitor, GW-8510 was then identified by the CMap database and further investigated. Treatment with GW-8510 resulted in potent inhibition of TNBC cell lines. More importantly, in vitro and in vivo studies confirmed that GW-8510 and other CDK inhibitors (Dinaciclib, and Palbociclib) can induce pyroptosis by activating caspase-3 and GSDME, which might be the mechanism for their immune regulation potentials.ConclusionGW-8510, as well as other CDK inhibitors, might serve as potential immune regulators and pyroptosis promotors in TNBC.

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“…CDK4/6i was also shown to increase tumor infiltration and activation of effector T cells and augment the response to PD-1 blockade in a novel ex vivo organotypic tumor spheroid culture system and in multiple in vivo murine syngeneic models by Deng et al [ 28 ]. In a recent phase I trial, we tested the combination of AI, palbociclib, and pembrolizumab in patients with ER + HER2 − MBC [ 29 ], with a CR of 31%. In our peripheral blood mononuclear cells (PBMCs) flow cytometry analysis, CDK4/6i showed immune-priming effect with significantly increased fractions of type 1 conventional dendritic cells (cDC1s) within circulating dendritic cells and decreased classical monocytes (cMO) within circulating monocytes only in patients treated with palbociclib [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Phase II Study Combining Pembrolizumab with Aromatase Inhibitor in Patients with Metastatic Hormone Receptor Positive Breast Cancer

Yost

Lee

et al. 2022

Cancers

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This study investigated the safety and antitumor activity of aromatase inhibitors (AI) with immune checkpoint inhibitor (ICI) pembrolizumab in patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC) in a phase II study with a safety lead-in (NCT 02648477). Patients received pembrolizumab plus AI up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria were HR+ HER2− MBC; RECIST v1.1 measurable disease; adequate organ function; and ECOG 0-1. Primary endpoints were safety and overall response rate. A 3-at-risk design was used for the safety lead-in with a targeted accrual of 20 patients. Grade 2 adverse events (AEs) included 35% fatigue, 20% rash, and 10% hot flashes. Grade 3 immune-related AEs (irAEs) related to pembrolizumab included 5% elevated AST/ALT, 5% rash, and 5% lymphopenia. Two (10%) patients had partial responses, three (15%) had stable disease, and 15 (75%) had progression of disease. Median progression-free survival was 1.8 months (95% CI 1.6, 2.6), median overall survival was 17.2 months (95% CI 9.4, NA), and median follow-up time was 40.1 months (range 31.3–46.8 months). The combination was well tolerated, but clinical activity was comparable to AI alone.

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Phase I/II trial of palbociclib, pembrolizumab and letrozole in patients with hormone receptor-positive metastatic breast cancer

Cited by 36 publications

References 45 publications

Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?

Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?

Cyclin-Dependent Kinase Inhibitors Function as Potential Immune Regulators via Inducing Pyroptosis in Triple Negative Breast Cancer

Phase II Study Combining Pembrolizumab with Aromatase Inhibitor in Patients with Metastatic Hormone Receptor Positive Breast Cancer

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