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Cyclin-dependent kinase (CDK)4/6 inhibitors regulate the cell cycle by binding to CDK4/6, thus exerting an inhibitory effect, and they have a notable impact on tumor immunity. CDK4/6 inhibitors have been demonstrated to modulate the immune microenvironment by affecting immune cells and immune escape phenomena in the tumor microenvironment. T cells, natural killer cells and macrophages are all regulated by CDK4/6 inhibitors, thereby acting on cancer cells. In addition, these inhibitors modulate immune checkpoints, enhancing antitumor immune responses when combined with immune checkpoint inhibitors, such as programmed death-ligand 1 and programmed death-1. However, these inhibitors are not without limitations, as they can enhance tumor immune evasion. Therefore, combination therapies to improve efficacy are being investigated, including immunotherapy, targeted therapy, chemotherapy and radiation therapy. In addition, challenges associated with the widespread use of CDK4/6 inhibitors, such as the emergence of tumor resistance, underscore the necessity for further research to enhance the clinical applicability of these inhibitors.

The current standard treatment for hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (BC) involves the use of anti-HER2 monoclonal antibodies combined with chemotherapy, followed by sequential endocrine therapy. However, crosstalk between the HR and HER2 pathways may cause drug resistance. Combining therapies targeting both the HR and HER2 pathways may be a rational approach for patients with HR+/HER2+ tumors, as this strategy could counteract resistance by blocking crosstalk in the receptor pathway. However, clinical data in this field remain limited. The present report describes the case of a patient with HR+/HER2+ late-stage BC who achieved a long-term partial response rate after receiving anti-HER2 combination chemotherapy followed by sequential treatment with endocrine therapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. The present case provides additional evidence suggesting that incorporating CDK4/6 inhibitors into standard targeted chemotherapy regimens may be an effective treatment option for patients with HR+/HER2+ BC.

Background The emergence of cyclin‐dependent kinases 4/6 inhibitors (CDK4/6i) represented a major breakthrough in the treatment of breast cancer over the past decade. In both clinical trials and real‐world settings, it was observed that patients using CDK4/6i might experience psychiatric adverse events (PAEs). Herein, we conducted a pharmacovigilance study to comprehensively assess the correlation between CDK4/6i and PAEs. Method We obtained individual case safety reports submitted to the FDA Adverse Events Reporting System (FAERS) during the period from January 2015 to December 2023. In disproportionality analysis, the reporting odds ratio (ROR) and information component (IC) values were calculated for each adverse event‐drug combination. Univariate logistic regression analysis was utilized to explore factors associated with PAEs following CDK4/6i treatment. Results A total of 95,591 reports related to CDK4/6i were identified, with 6.72% reporting PAEs, and this proportion exhibited an annual upward trend. Based on the ROR and IC values, 17 categories of PAEs were defined as CDK4/6i‐related PAEs. Among these PAEs, insomnia, stress, eating disorder, depressed mood, and sleep disorder were very common, each accounting for over 10% of CDK4/6i reports. Ribociclib showed the highest risk signal of CDK4/6i‐related PAEs (ROR = 1.89[1.75–2.04], IC025 = 0.79), followed by palbociclib (ROR = 1.47[1.41–1.53], IC025 = 0.49), while abemaciclib did not exhibit a significant signal (ROR = 0.52[0.44–0.62], IC025 = −1.13). Female sex, younger age and weight exceeding 80 kg were significant risk factors for the incidence of CDK4/6i‐related PAEs. Conclusions Using data from a real‐world, large‐scale spontaneous reporting system for adverse drug reactions, our study delineated the spectrum of PAEs to CDK4/6i. This potentially offered valuable insights for healthcare professionals to manage the risk of PAEs in patients receiving CDK4/6i treatment, particularly those with psychiatric disorders. This is a pharmacovigilance study to comprehensively assess the correlation between cyclin‐dependent kinases 4/6 inhibitors (CDK4/6i) and psychiatric adverse events (PAEs). Our study identified 17 categories of PAEs highly associated with CDK4/6i through disproportionality analysis, and revealed differences in the profiles of PAEs among three CDK4/6i.

Background De novo stage IV breast cancer presents a significant challenge due to its advanced nature and poor prognosis. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have emerged as effective treatments for hormone receptor-positive HER2-negative breast cancers. However, predicting patient responses remains difficult. This study aimed to evaluate the prognostic value of FDG PET/CT in predicting therapeutic response and progression-free survival (PFS) in patients with de novo stage IV breast cancer undergoing CDK4/6i treatment. Methods A retrospective analysis was conducted on 106 patients with de novo stage IV breast cancer who were treated with CDK4/6i between 2016 and 2023. All patients underwent FDG PET/CT before treatment and 68 patients underwent follow-up FDG PET/CT. The relationship between SUVmax and clinicopathological factors was analyzed using t-test and ANOVA. PFS was assessed via Kaplan-Meier analysis and Cox proportional hazards models, with a focus on SUVmax parameters, including the SUVmax values of the primary tumor (SUVmax_primary), metastatic regional lymph node (SUVmax_LN), distant metastasis (SUVmax_distant), the highest SUVmax value along the entire body (SUVmax_whole), and their proportional responses during follow-up. Results Lower Ki-67 score (1+) was significantly associated with lower SUVmax_primary ( P  = 0.002) and SUVmax_whole ( P  = 0.007) scores than higher Ki-67 scores. SUVmax_whole was a significant predictor of PFS at baseline (hazard ratio, HR = 2.45, P  = 0.012) and follow-up (HR = 4.32, P  = 0.002). Patients with higher SUVmax reductions showed better PFS outcomes (HR = 0.22, P  < 0.001). Neither the initial SUVmax of the primary lesion (HR = 1.81, P  = 0.067) nor its response (HR = 0.49, P  = 0.063) on follow-up were significant predictors of PFS. Conclusions This study highlights the prognostic value of FDG PET/CT in evaluating the therapeutic response to CDK4/6i in de novo stage IV breast cancer. SUVmax_whole and its proportional response serve as important predictors of PFS, emphasizing the need to assess metabolic activity across the entire body rather than just in the primary tumor.

Abstract Background Preclinical models demonstrated promising anti-tumor activity of SPH4336, a novel oral, highly selective cyclin-dependent kinase (CDK) 4/6 inhibitor. Methods This phase I study enrolled patients who received SPH4336 orally in 6 dose-escalation cohorts (50-600 mg) in a 3 + 3 design. Based on tolerability, pharmacokinetics (PK) and activity data from the dose-escalation phase, 2-3 dose cohorts were expanded. Dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase II dose (RP2D), efficacy, safety, tolerability, and pharmacokinetics (PK) were investigated. Results A total of 29 patients with breast cancer (BC) (n = 14), sarcoma (n = 8), non-small cell lung cancer (n = 2) and others (n = 5) were enrolled. Neither DLT nor MTD were reached. All patients had at least one treatment-related adverse events (TRAEs), most of which were grade 1/2. Grade ≥ 3 TRAEs occurred in 51.7% of patients. One patient died from disease progression and five reported serious adverse events. Plasma concentrations increased dose-dependently, except at 600 mg, and steady state was reached at 2 weeks for 400 mg. One BC patient in the 600-mg cohort had a confirmed partial response. The disease control rate was 59.3% (95% CI, 38.8-77.6). Conclusion SPH4336 demonstrated an acceptable safety profile and dose-dependent plasma exposure in patients with various advanced solid tumors. (ClinicalTrials.gov Identifier: NCT05905614; IRB Approved.)

Purpose To assess real-world treatment patterns in patients diagnosed with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (mBC) who received cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with an aromatase inhibitor (AI) or fulvestrant at first line. Methods Patient characteristics, treatment history, and outcomes data were extracted from the French ‘Système National des Données de Santé’ (SNDS) database for patients diagnosed with HR+/HER2- mBC between January 2014 and June 2019 and who received combination therapy with a CDK4/6 inhibitor and endocrine therapy. Kaplan-Meier methodology was used to assess time to next treatment (TTNT) and time to treatment discontinuation (TTTD). Results The cohort comprised 6061 patients including 4032 patients who received CDK4/6 inhibitors + AIs and 2029 patients who received CDK4/6 inhibitors + fulvestrant. Median follow-up was 13.5 months (IQR 9.5–18.1). The median TTTD of first line treatment with CDK4/6 inhibitors + AIs and CDK4/6 inhibitors + fulvestrant was 17.3 months (95% CI 16.8–17.9) and 9.7 months (95% CI 9.0–10.2), respectively. Chemotherapy was the most common second line therapy. Median TTTD of subsequent treatment lines was progressively shorter following first line treatment with CDK4/6 inhibitors + AIs (2nd line: 4.6 months (95% CI 4.4–4.9) and with CDK4/6 inhibitors + fulvestrant (2nd line: 4.7 months (95% CI 4.3–5.1). TTNT was longer than TTTD across lines of therapy. Conclusion This real-world analysis confirms the effectiveness of CDK4/6 inhibitor-based regimens in French patients and highlights the frequent use of chemotherapy as second line therapy.

Breast cancer remains a major global health challenge. In 2022, there were an estimated 2.3 million new cases and 670,000 deaths among women worldwide. Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer accounts for approximately 70% of breast cancer diagnoses. The treatment landscape for advanced HR+)/HER2− breast cancer has been transformed by the introduction of CDK4/6 inhibitors in the first-line setting. However, therapeutic strategies following progression on CDK4/6 inhibitors remain heterogeneous and uncertainty exists in their optimal integration in clinical practice. This review aims to systematically examine available second-line and subsequent treatment options for HR+/HER2− metastatic breast cancer after progression on CDK4/6 inhibitors, with a focus on biomarker-driven strategies and emerging therapies. The therapeutic landscape beyond CDK4/6 inhibitors includes targeted agents guided by actionable biomarkers as well as novel selective estrogen receptor degraders (SERDs). In biomarker-unselected populations, options include CDK4/6 continuation strategies, endocrine monotherapy in selected cases, and cytotoxic therapy. The integration of molecular testing via next-generation sequencing has become standard of care in guiding these decisions. However, overlapping molecular alterations and a lack of consensus on treatment sequencing pose significant challenges. Prognostic factors such as circulating tumor DNA dynamics may further refine treatment personalization. Post-CDK4/6 therapy in HR+/HER2− metastatic breast cancer is an evolving and increasingly complex area of practice. Optimal treatment selection should be tailored to both tumor biology and patient-specific factors, supported by molecular testing and high-quality evidence.

PurposeAdding cyclin-dependent kinase (CDK) 4/6 inhibitor to endocrine therapy improves progression-free survival (PFS) in advanced breast cancer but the impact of ethnicity on efficacy and toxicity is unclear. We aimed to estimate the relative treatment efficacy and toxicity of endocrine therapy with and without CDK4/6 inhibitors, and compare between Asian/non-Asian subgroups.MethodThis meta-analysis included published first-line randomized trials comparing CDK4/6 inhibitor-endocrine therapy versus endocrine monotherapy. Hazard ratios (HR) and 95% confidence intervals (CI) for the overall population and Asian/non-Asian subgroups were extracted. The inverse-variance-weighted method was used to pool treatment estimates of PFS.ResultsFour trials (N = 2499) were included. Patients received combination CDK4/6 inhibitor-endocrine therapy (N = 1441; ribociclib, [46.4%]; palbociclib, [30.8%]; or abemaciclib, [22.8%]) versus endocrine monotherapy (N = 1058). CDK4/6 inhibitor-endocrine therapy was associated with prolonged PFS compared with endocrine monotherapy (HR 0.56; 95% CI 0.50–0.62). In Asians (N = 492), PFS HR was 0.39 (95% CI 0.29–0.51, P < 0.0001). In non-Asians (N = 2007), PFS HR was 0.62 (95% CI 0.54–0.71, P < 0.0001). There was a significant treatment-by-ethnicity interaction (P = 0.002). Toxicity data by ethnic subgroup were only available from two trials (n = 1334) with no convincing evidence that the risk of toxicity between CDK4/6 inhibitor-endocrine therapy and endocrine monotherapy varied by ethnicity.ConclusionAdding CDK4/6 inhibitor to endocrine therapy prolongs PFS compared to endocrine therapy alone as first-line treatment in advanced breast cancer. The magnitude of PFS benefit is ethnicity-dependent but there is no interethnic differences in relative treatment-related toxicities. These findings may assist in the design and interpretation of trials, inform economic analyses, and stimulate pharmacogenomic research.

PurposeWe assessed pulmonary toxicity of cyclin-dependent kinase (CDK)4/6 inhibitors by analyzing the publicly available FDA Adverse Event Reporting System (FAERS).MethodsReports of interstitial lung disease (ILD) were characterized in terms of demographic information, including daily dose, latency, concomitant drugs known to be associated with ILD, and causality assessment (adapted WHO system). Disproportionality analyses were carried out by calculating reporting odds ratios (RORs) with 95% confidence interval (CI), accounting for major confounders, including notoriety and competition biases.ResultsILD reports (N = 161) represented 2.1% and 0.3% of all reports for abemaciclib and palbocilcib/ribociclib, respectively, with negligible proportion of concomitant pneumotoxic drugs. Increased reporting was found for CDK4/6 inhibitors when compared to other drugs (ROR = 1.50; 95%CI = 1.28–1.74), and abemaciclib vs other anticancer agents (4.70; 3.62–5.98). Sensitivity analyses confirmed a strong and consistent disproportionality for abemaciclib. Higher-than-expected reporting emerged for palbociclib (1.38; 1.07–1.77) and ribociclib (2.39; 1.34–3.92) only when removing Japan reports. ILD occurred at recommended daily doses, with median latency ranging from 50 (abemaciclib) to 253 (ribociclib) days. Causality was highly probable in 55% of abemaciclib cases, probable in 68% of palbociclib cases.ConclusionsIncreased reporting of ILD with CDK4/6 inhibitors calls for further comparative population-based studies to characterize and quantify the actual risk, taking into account drug- and patient-related risk factors. These findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals through FAERS and other real-world data, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of CDK4/6 inhibitors when diagnosing a lung injury.

HER2-positive breast cancer represents a biologically aggressive subtype associate with poor prognosis, despite advances in targeted therapies. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), initially approved for hormone-receptor-positive, HER2-negative disease, are now being explored in HER2-positive settings due to their mechanistic synergy with the HER2 signaling pathway. This review synthesizes evolving clinical evidence from trials and highlights further research into biomarker discovery. CDK4/6i may redefine treatment paradigms in HER2-positive breast cancer, offering a potential, non-chemotherapy option with durable benefit in select patient populations.