Targeted Therapy in HR+ HER2− Metastatic Breast Cancer: Current Clinical Trials and Their Implications for CDK4/6 Inhibitor Therapy and beyond Treatment Options

Elfgen, Constanze; Bjelic‐Radisic, Vesna

doi:10.3390/cancers13235994

Cited by 16 publications

(13 citation statements)

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“…Our study only suggested the tendency of CDK4/6 inhibitor-containing treatment regimens toward better OS from the view of SUCRA values. Currently, there are still challenges in differentiating the population that can acquire OS benefit from CDK4/6 inhibitors due to the profound heterogeneity of patients ( 63 ).…”

Section: Discussionmentioning

confidence: 99%

CDK4/6 inhibitors versus PI3K/AKT/mTOR inhibitors in women with hormone receptor-positive, HER2-negative metastatic breast cancer: An updated systematic review and network meta-analysis of 28 randomized controlled trials

Wang

et al. 2022

Front. Oncol.

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BackgroundUpdated evidence was required to compare the efficacy and safety of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors for patients with hormone receptor-positive and HER2-negative metastatic breast cancer.MethodsA systematic review and network meta-analysis was conducted utilizing data from randomized controlled trials (RCTs) that contained interventions of CDK4/6 inhibitors or PI3K/AKT/mTOR inhibitors. Progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were primary outcomes of interest. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% credible intervals (CrIs) were used to assess the survival outcomes and safety profiles, respectively.ResultsA total of 28 RCTs with 12,129 participants were included. Pooled analysis showed that CDK4/6 inhibitors significantly prolonged PFS than PI3K/AKT/mTOR inhibitors (HR, 0.81; 95% CrI, 0.69–0.94), whereas no significant differences were detected regarding OS. After balancing the treatment lines and metastatic sites, the superiority of CDK4/6 inhibitors only appeared in the visceral and non-visceral subgroups. Among CDK4/6 inhibitors, abemaciclib was significantly better than others in ≥3 grade neutropenia (OR, 0.04; 95% CrI, 0.01–0.15). The incidence of stomatitis and digestive disorders was different among diverse kinds of PI3K/AKT/mTOR inhibitors. Discrepancies appeared regarding TRAEs of hepatotoxicity, diarrhea, and hyperglycemia among different interventions.ConclusionsCDK4/6 inhibitors showed better efficacy in PFS, but the benefits disappeared when taking treatment line into consideration. Specific and discrepant safety profiles were found in two categories of agents.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO, identifier CRD42022321172.

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Section: Discussionmentioning

confidence: 99%

CDK4/6 inhibitors versus PI3K/AKT/mTOR inhibitors in women with hormone receptor-positive, HER2-negative metastatic breast cancer: An updated systematic review and network meta-analysis of 28 randomized controlled trials

Wang

et al. 2022

Front. Oncol.

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“… 396 Since 2015, three CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib have been approved for HR‐positive/HER2‐negative breast cancer in various settings and combination regimens. 397 , 398 The addition of the CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib to an aromatase inhibitor were studied in postmenopausal HR‐positive/HER2‐negative advanced breast cancer in the first‐line setting in PALOMA‐2, MONALEESA‐2, and MONARCH‐3 trials, respectively. The three combination regimens nearly doubled the duration of median PFS and improved ORR compared with the single‐use of an aromatase inhibitor, with or without prolonged OS.…”

Section: Selective Small Molecule Kinase Inhibitorsmentioning

confidence: 99%

“…Fortunately, neutropenia and leukopenia are relatively easy to manage in clinic. 398 In 2021, the newest CDK4/CDK6 inhibitor, trilaciclib, was permitted for patients with SCLC indicated to prevent chemotherapy‐induced myelosuppression. 407 SCLC is an ideal disease model to assess the myeloprotective effect of trilaciclib.…”

Section: Selective Small Molecule Kinase Inhibitorsmentioning

confidence: 99%

“…To date, the CDK4/6 inhibitors have been proved to interfere with the proliferation of breast cancer cells by decreasing pRb phosphorylation and arresting the cell cycle in the G1 phase 396 . Since 2015, three CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib have been approved for HR‐positive/HER2‐negative breast cancer in various settings and combination regimens 397,398 . The addition of the CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib to an aromatase inhibitor were studied in postmenopausal HR‐positive/HER2‐negative advanced breast cancer in the first‐line setting in PALOMA‐2, MONALEESA‐2, and MONARCH‐3 trials, respectively.…”

Section: Selective Small Molecule Kinase Inhibitorsmentioning

confidence: 99%

“…However, CDK4/6 inhibitors largely increased the rates of myelotoxic effects, especially for neutropenia and leukopenia. Fortunately, neutropenia and leukopenia are relatively easy to manage in clinic 398 . In 2021, the newest CDK4/CDK6 inhibitor, trilaciclib, was permitted for patients with SCLC indicated to prevent chemotherapy‐induced myelosuppression 407 .…”

Section: Selective Small Molecule Kinase Inhibitorsmentioning

confidence: 99%

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Small molecule inhibitors targeting the cancers

Liu

Chen

Zhang

et al. 2022

MedComm

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Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary targeted therapies for cancer. Due to their advantages in a wide range of targets, convenient medication, and the ability to penetrate into the central nervous system, many efforts have been devoted to developing more small molecule inhibitors. To date, 88 small molecule inhibitors have been approved by the United States Food and Drug Administration to treat cancers. Despite remarkable progress, small molecule inhibitors in cancer treatment still face many obstacles, such as low response rate, short duration of response, toxicity, biomarkers, and resistance. To better promote the development of small molecule inhibitors targeting cancers, we comprehensively reviewed small molecule inhibitors involved in all the approved agents and pivotal drug candidates in clinical trials arranged by the signaling pathways and the classification of small molecule inhibitors. We discussed lessons learned from the development of these agents, the proper strategies to overcome resistance arising from different mechanisms, and combination therapies concerned with small molecule inhibitors. Through our review, we hoped to provide insights and perspectives for the research and development of small molecule inhibitors in cancer treatment.

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Evaluation of Alisertib Alone or Combined With Fulvestrant in Patients With Endocrine-Resistant Advanced Breast Cancer

et al. 2023

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ImportanceAurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i–resistant MBC is unknown.ObjectiveTo assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC.Design, Setting, and ParticipantsThis phase 2 randomized clinical trial was conducted through the Translational Breast Cancer Research Consortium, which enrolled participants from July 2017 to November 2019. Postmenopausal women with endocrine-resistant, ERBB2 (formerly HER2)–negative MBC who were previously treated with fulvestrant were eligible. Stratification factors included prior treatment with CDK 4/6i, baseline metastatic tumor ERα level measurement (&lt;10%, ≥10%), and primary or secondary endocrine resistance. Among 114 preregistered patients, 96 (84.2%) registered and 91 (79.8%) were evaluable for the primary end point. Data analysis began after January 10, 2022.InterventionsAlisertib, 50 mg, oral, daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (arm 1) or alisertib same dose/schedule with standard-dose fulvestrant (arm 2).Main Outcomes and MeasuresImprovement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%.ResultsAll 91 evaluable patients (mean [SD] age, 58.5 [11.3] years; 1 American Indian/Alaskan Native [1.1%], 2 Asian [2.2%], 6 Black/African American [6.6%], 5 Hispanic [5.5%], and 79 [86.8%] White individuals; arm 1, 46 [50.5%]; arm 2, 45 [49.5%]) had received prior treatment with CDK 4/6i. The ORR was 19.6%; (90% CI, 10.6%-31.7%) for arm 1 and 20.0% (90% CI, 10.9%-32.3%) for arm 2. In arm 1, the 24-week clinical benefit rate and median progression-free survival time were 41.3% (90% CI, 29.0%-54.5%) and 5.6 months (95% CI, 3.9-10.0), respectively, and in arm 2 they were 28.9% (90% CI, 18.0%-42.0%) and 5.4 months (95% CI, 3.9-7.8), respectively. The most common grade 3 or higher adverse events attributed to alisertib were neutropenia (41.8%) and anemia (13.2%). Reasons for discontinuing treatment were disease progression (arm 1, 38 [82.6%]; arm 2, 31 [68.9%]) and toxic effects or refusal (arm 1, 5 [10.9%]; arm 2, 12 [26.7%]).Conclusions and RelevanceThis randomized clinical trial found that adding fulvestrant to treatment with alisertib did not increase ORR or PFS; however, promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and CDK 4/6i–resistant MBC. The overall safety profile was tolerable.Trial RegistrationClinicalTrials.gov Identifier: NCT02860000

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Targeted Therapy in HR+ HER2− Metastatic Breast Cancer: Current Clinical Trials and Their Implications for CDK4/6 Inhibitor Therapy and beyond Treatment Options

Cited by 16 publications

References 83 publications

CDK4/6 inhibitors versus PI3K/AKT/mTOR inhibitors in women with hormone receptor-positive, HER2-negative metastatic breast cancer: An updated systematic review and network meta-analysis of 28 randomized controlled trials

CDK4/6 inhibitors versus PI3K/AKT/mTOR inhibitors in women with hormone receptor-positive, HER2-negative metastatic breast cancer: An updated systematic review and network meta-analysis of 28 randomized controlled trials

Small molecule inhibitors targeting the cancers

Evaluation of Alisertib Alone or Combined With Fulvestrant in Patients With Endocrine-Resistant Advanced Breast Cancer

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