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Tumor Discovery Immunomodulatory effects of CDK4/6 inhibitors

neoadjuvant regimen of nivolumab in combination with This combination strategy simultaneously targets multiple
palbociclib and anastrozole, reported an impressive hallmarks of cancer, addressing both aberrant cellular
objective response rate of 71.4%. In addition, a phase II proliferation and enhancing antitumor immunity, while
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study (NCT02779751) that incorporated pembrolizumab also potentially overcoming resistance mechanisms that
with abemaciclib yielded an overall response rate of 23.1% limit the efficacy of monotherapies. 39,68,69 The interaction
and a disease control rate as high as 84.6%. Furthermore, between these agents occurs at multiple levels, creating a
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another trial (NCT02778685) that employed the comprehensive antitumor approach with the potential for
combination of pembrolizumab, palbociclib, and letrozole broader therapeutic efficacy.
achieved a notable 31% complete response rate, with a PFS
extending to 25.2 months. 61 At the cellular level, CDK4/6 inhibition fundamentally
alters cancer cell biology, rendering malignant cells more
It is important to highlight that a phase I trial evaluating susceptible to immune-mediated killing. The drug-induced
ribociclib in conjunction with spartalizumab (an anti-PD-1 G1 cell cycle arrest correlates with increased expression
antibody), with or without fulvestrant, in patients with of endogenous retroviral elements, stimulating viral
HR /HER2 MBC did not show significant additional mimicry responses and subsequent IFN-I/III production.
+
−
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benefit over ribociclib combined with fulvestrant alone. This process enhances tumor immunogenicity through
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Conversely, the phase II WJOG11418B NEWFLAME multiple mechanisms, including increased neoantigen
trial, which investigated the combination of nivolumab presentation, upregulation of MHC-I molecules,
with abemaciclib in HR /HER2 MBC, reported objective and chemokine-mediated recruitment of cytotoxic T
+
−
response rates of 54.5% and 40% in the fulvestrant and lymphocytes. Concurrently, CDK4/6 inhibitors suppress
letrozole treatment groups, respectively. Collectively, the expression of DNA methyltransferase 1, leading
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these results suggest that the combination of CDK4/6 to DNA hypomethylation and further activation of
inhibitors with immunotherapy holds promise as a viable immunostimulatory pathways. 71
treatment strategy for individuals with HR /HER2 breast
+
−
cancer. Moreover, CDK4/6 inhibitors remodel the TME to
promote enhanced immune cell infiltration, particularly
The criteria for identifying the most suitable CD8 T cells and B cells. This augmented immune
+
patients for combinations of CDK4/6 inhibitors with infiltration may potentiate the efficacy of PD-1/PD-L1
immunotherapy are still being explored. Numerous blockade therapies. In certain preclinical models,
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clinical trials are underway to assess this approach, such as the combination of CDK4/6 inhibitors with PD-L1
the ImmunoADAPT trial, which is investigating the use of blockade induced complete tumor regression in a
palbociclib in conjunction with avelumab for early-stage significant proportion of mice, even in cases where
estrogen receptor-positive breast cancer. 62,63 Preliminary PD-L1 monotherapy showed limited or no efficacy.
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findings from this trial suggest a trend toward better Notably, mice that achieved complete responses to either
PFS with the combination of fulvestrant, palbociclib, and combination therapy or CDK4/6 inhibitor monotherapy
avelumab, achieving a median PFS of 8.1 months. However, demonstrated resistance to tumor rechallenge, indicating
this enhancement did not reach statistical significance the establishment of durable immune memory. These
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when compared to fulvestrant monotherapy (hazard findings suggest that combining CDK4/6 inhibitors with
ratio = 0.75, 90% confidence interval: 0.50–1.12, p=0.23). ICIs may represent a promising strategy to enhance
In addition, the phase II PACE study (NCT03147287), antitumor immunity and improve therapeutic outcomes.
which evaluated palbociclib combined with avelumab in
HR /HER2 MBC patients who had progressed on prior 7.2. CDK4/6 inhibitors with ICIs tackle resistance
−
+
CDK4/6 inhibitor treatment, concluded that PD-1/PD-L1
inhibitors offer limited efficacy in this context without a The PALOMA, MONALEESA, and MONARCH trial
more refined patient selection process. 66 series have firmly established CDK4/6 inhibitors as a
fundamental therapeutic for HR /HER2 advanced breast
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7. Discussion cancer. 72-79 These pivotal studies evaluated three distinct
CDK4/6 inhibitors, including palbociclib, ribociclib, and
7.1. Synergistic mechanisms underlying the abemaciclib, in combination with endocrine therapy. Across
combination approach these studies, these agents consistently demonstrated
The scientific rationale for combining CDK4/6 significant improvements in median PFS, ranging from
inhibitors with ICIs stems from accumulating evidence 16 to 28 months in the first-line setting, 72,73,75,77,78 and
demonstrating that these drug classes act through 5 to 20 months in later line therapies. 74,76,77,79 Despite
complementary and potentially synergistic mechanisms. these advancements, therapeutic resistance typically

Volume 4 Issue 3 (2025) 24 doi: 10.36922/TD025190037