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Cyclin-dependent kinases (CDKs) play a major role in regulating transitions within the cell cycle. Given the roles of CDK4/6 in promoting oncogenesis, selective inhibition of CDK4/6 has emerged as a novel approach for the treatment of breast cancer and various other tumors. While first and second generation CDK4/6 inhibitors were instrumental in targeting cell cycle pathways, they had numerous drawbacks such as limited selectivity and off-target effects. For that reason, a third generation of inhibitors was introduced and provided improved selectivity towards CDK4/6 leading to fewer side effects. To date, four compounds have been approved by the FDA as selective inhibitors of CDK4/6: palbociclib, ribociclib, abemaciclib, and trilaciclib. In this mini review, we summarize the biological, clinical, and chemical aspects of trilaciclib, a first-in-class CDK4/6 inhibitor notable for its dual role in cell cycle regulation and myelopreservation. Trilaciclib was granted FDA approval on February 2021, to improve the outcome of patients with metastatic-stage small cell lung cancer (SCLC) by protecting bone marrow suppression during chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Trilaciclib, in comparison to placebo plus carboplatin, etoposide, ± atezolizumab (PEA), has shown significant reductions in incidence of severe neutropenia (SN) among patients with extensive-stage small cell lung cancer (ES-SCLC). Despite these findings, real-world utility remains limited. Methods: A single-center quasi-experimental study compared trilaciclib + PEA (PEAT) versus PEA in ES-SCLC patients. The study period ranged from April 1, 2021 to July 31, 2022, for the PEAT recipients and February 1, 2020, to February 28, 2021, for PEA recipients. The primary endpoint evaluated was incidence of SN after cycle 1 and during the treatment period. Secondary endpoints included measures related to myelopreservation and patient outcomes. Results: Among 34 PEAT and 44 PEA patients, baseline characteristics were similar, except for a higher median age (69 vs 64 years) and more males (64.7% vs 38.6%) in the PEAT cohort. The PEAT cohort exhibited a lower SN rate (3%) versus the PEA cohort (18%), with statistical significance demonstrated on multivariate analysis (p = 0.015). Additionally, the PEAT cohort also demonstrated significant reductions in red blood cell transfusion requirements (3% vs 23%; p = 0.02), grade 3–4 anemia (6% vs 25%; p = 0.03), and grade 3–4 thrombocytopenia (0% vs 11%, p = 0.045). Conclusion: Trilaciclib, in combination with PEA, demonstrated an improvement in the safety profile without compromising survival outcomes in ES-SCLC patients. These findings underscore the potential benefits of incorporating trilaciclib in real-world clinical settings for enhanced patient care. [ABSTRACT FROM AUTHOR]

Trilaciclib is a first‐in‐class, intravenous cyclin‐dependent kinase 4 and 6 inhibitor approved for reducing the incidence of chemotherapy‐induced myelosuppression in adult patients with extensive‐stage small cell lung cancer receiving a platinum/etoposide‐containing or topotecan‐containing regimen. No dose adjustment is recommended for participants with mild hepatic impairment (HI) based on previous population pharmacokinetic (PK) analysis. This open‐label, parallel‐group study examined the impact of moderate and severe HI on the PK of trilaciclib. The study employed a reduced study design. Participants with moderate (Child–Pugh B, n = 8) and severe (Child–Pugh C, n = 5) HI and matched healthy controls (n = 11) received a single intravenous dose of trilaciclib 100 mg/m2. The unbound fraction of trilaciclib was comparable between the HI groups and the matched healthy control group. The unbound trilaciclib extent of exposure (i.e., area under the concentration‐time curve) in participants with moderate and severe HI was ∼40% and ∼60% higher, respectively, compared with healthy matched controls based on Child–Pugh classification. Ad hoc analysis using National Cancer Institute classification showed similar results. The US Food and Drug Administration‐approved trilaciclib dose of 240 mg/m2 should be reduced by ∼30%, to 170 mg/m2, for patients with moderate or severe HI. [ABSTRACT FROM AUTHOR]

Side effects from chemotherapy-induced myelosuppression can negatively affect patients' quality of life (QoL). Neutropenia increases infection risk, and anemia frequently results in debilitating fatigue. Additionally, the bleeding risk associated with thrombocytopenia can lead to fear and anxiety. However, traditional interventions for myelosuppression fall short of the ideal. Granulocyte colony-stimulating factors reduce the risk of severe neutropenia but commonly lead to bone pain. Erythropoiesis-stimulating agents are not always effective and may cause thromboembolic events, while transfusions to correct anemia/thrombocytopenia are associated with transfusion reactions and volume overload. Trilaciclib, which is approved for reducing myelosuppression in patients with extensive-stage small cell lung cancer, together with several investigational agents in development for managing myelosuppression have the potential to improve QoL for patients on chemotherapy. Plain Language Summary Chemotherapy can cause side effects by killing blood-forming cells in the bone marrow. This is known as myelosuppression and leads to neutropenia (decreased neutrophils [white blood cells]), anemia (decreased red blood cells) and thrombocytopenia (decreased platelets). Neutropenia can increase the risk of getting an infection, and severe cases might result in patients being hospitalized. Both neutropenia and anemia can cause fatigue, which is often reported by patients as being the most draining symptom of chemotherapy. Thrombocytopenia increases the risk of bleeding and can cause patients with cancer to become even more scared and anxious. Myelosuppression due to chemotherapy is usually managed with delays or reductions in the amount of chemotherapy that patients receive, but this may worsen the disease. Other treatments, known as supportive care interventions, include growth factors, which stimulate the production of blood cells and red blood cell or platelet transfusions. However, having these treatments in addition to chemotherapy can be a burden to patients, and they can cause side effects such as bone pain and blood clots. A treatment called trilaciclib is approved by the US Food and Drug Administration for patients receiving certain types of chemotherapy for advanced small-cell lung cancer. Trilaciclib has been shown to reduce neutropenia, anemia and thrombocytopenia in these patients and improve their quality of life. Other drugs are also being assessed in clinical trials for preventing or treating myelosuppression in patients with different cancer types. In the future, these drugs may improve quality of life for patients on chemotherapy. Tweetable Abstract The burden of chemotherapy-induced myelosuppression on patients with cancer is substantial. We provide insights on the impact of this side effect on the lives of patients and review management strategies aimed at improving outcomes. Executive summary Chemotherapy-induced damage of hematopoietic stem and progenitor cells in the bone marrow can result in myelosuppression (neutropenia, anemia and/or thrombocytopenia), which adversely affects patients' quality of life. Chemotherapy-induced myelosuppression is commonly managed with chemotherapy dose reductions or delays, which can negatively impact treatment outcomes, or supportive care interventions that are each associated with risks and limitations. Chemotherapy-induced neutropenia Neutropenia symptoms such as fatigue and concerns over the risk of infection negatively affect patients' daily activities and relationships. Granulocyte colony-stimulating factors reduce the risk of severe or febrile neutropenia but commonly lead to bone pain, which may result in chemotherapy dose delays or discontinuation. Chemotherapy-induced anemia Lower hemoglobin levels among patients with chemotherapy-induced anemia are correlated with poorer quality of life, and the most common symptom, fatigue, can be extremely debilitating for patients. Erythropoiesis-stimulating agents are associated with thromboembolic events, hypertension and potential increased mortality and tumor progression, while red blood cell transfusions carry the risk of transfusion-related reactions, volume overload or iron overload. Chemotherapy-induced thrombocytopenia Symptoms of a low platelet count include bruising and bleeding, and a diagnosis of thrombocytopenia can worsen patients' feelings of anxiety and fear beyond those associated with the cancer diagnosis. Platelet transfusions may be used in severe cases of thrombocytopenia but offer only a temporary solution and may cause infections, and febrile or allergic reactions. Conclusions & future perspectives Unlike conventional supportive care options, trilaciclib is used proactively to reduce myelosuppression and its symptoms across multiple blood cell lineages, which translates into improvements in patients' quality of life. In addition, several pipeline drugs have shown encouraging results in clinical trials and have the potential to improve quality of life for patients on chemotherapy. [ABSTRACT FROM AUTHOR]

Ovarian cancer is a prevalent malignant tumor of the female reproductive system, often remaining concealed until it reaches an advanced stage. The standard treatment protocol includes cytoreductive surgery for ovarian cancer plus postoperative consolidation chemotherapy and maintenance therapy, although it carries a high recurrence rate. During the treatment period, chemotherapy can lead to bone marrow suppression, a condition known as Chemotherapy-Induced Myelosuppression (CIM). This suppression may necessitate dose reduction or chemotherapy treatment cycle delay. In severe cases, CIM can result in infection, fever, and potential harm to the patient's life. Here, we report a case of a female patient with ovarian malignant tumor of biochemical recurrence who treated with chemotherapy combined with Trilaciclib, following previous perioperative chemotherapy with occurrence of severe CIM. It involves an intravenous injection of Trilaciclib before chemotherapy, which significantly abates the side effects of chemotherapy, reduces the occurrence of severe CIM, improves the patients' quality of life, and decreases the economic burden of hospitalization. We hope that this retrospective analysis of the case may serve as a reference in preventing and treating severe CIM during chemotherapy in some patients with malignant tumors, ultimately benefiting more patients with tumors. [ABSTRACT FROM AUTHOR]

Trilaciclib, a novel cyclin-dependent kinase 4/6 inhibitor, has demonstrated the ability to protect bone marrow from chemotherapy toxicity, improving patients' quality of life (QoL). This review describes the mechanism of action, efficacy, and toxicity profile of trilaciclib. Trilaciclib halts retinoblastoma protein phosphorylation during the early G1 phase, preventing the transition from the G1/S phase and inducing the cell cycle arrest in the G1 phase, which protects the hematopoietic cell lineages. Trilaciclib is indicated by the United States Food and Drug Administration and National Comprehensive Cancer Network to decrease the incidence of chemotherapy-induced myelosuppression in adult patients before a platinum/etoposide or topotecan containing regimen for extensive stage small cell lung cancer. Its ease of administration as an intravenous infusion, given before starting chemotherapy, and the favorable side effect profile make it a better-tolerated drug, improving patient QoL. [ABSTRACT FROM AUTHOR]

Introduction: Trilaciclib was recently approved in the USA for reducing chemotherapy-induced myelosuppression (CIM) among adults with extensive-stage small cell lung cancer (ES-SCLC) when administered prior to chemotherapy. There is limited understanding of real-world outcomes of trilaciclib. Methods: A comprehensive literature review was conducted using a keyword search in the MEDLINE, Embase, and conference abstracts. Additional studies were identified through communications with the authors of relevant studies. Published and unpublished real-world studies of trilaciclib- and comparable non-trilaciclib-treated patients with ES-SCLC were included. Evidence on myelosuppressive hematologic adverse events (HAEs), cytopenia-related healthcare utilization, and other reported outcomes (e.g., hospitalizations, dose reduction, and treatment delay) were synthesized. If feasible, outcomes were compared qualitatively between the trilaciclib and historical reference groups, and between first-line trilaciclib initiators and the overall trilaciclib population. Weighted averages were estimated for selected outcomes using sample size as the weight. Results: The literature search identified five unique studies based on eight records—two included trilaciclib only, two non-trilaciclib only, and one both. In trilaciclib cohorts, the weighted average prevalence of grade ≥ 3 myelosuppressive HAEs in ≥ 1 lineage, ≥ 2 lineages, and all three lineages was 40.5%, 14.5%, and 7.5%, respectively. All rates were numerically lower compared to the historical non-trilaciclib cohorts (58.8%, 28.0%, 13.0% respectively). Cytopenia-related healthcare utilization was also lower in the trilaciclib cohorts. In general, first-line trilaciclib initiators had numerically lower myelosuppressive HAEs and cytopenia-related healthcare utilization than the overall trilaciclib patients. Conclusions: The existing evidence suggests that trilaciclib may reduce single and multilineage grade ≥ 3 myelosuppressive HAEs and cytopenia-related healthcare utilization among patients with ES-SCLC in the real world. It is a promising new treatment for CIM prevention in ES-SCLC and may bring greater benefits to first-line trilaciclib initiators. Future studies are recommended to further evaluate the real-world effectiveness of trilaciclib. [ABSTRACT FROM AUTHOR]

Purpose: In a phase II trial in patients with metastatic triple-negative breast cancer (mTNBC; NCT02978716), administering trilaciclib prior to gemcitabine plus carboplatin (GCb) enhanced T-cell activation and improved overall survival versus GCb alone. The survival benefit was more pronounced in patients with higher immune-related gene expression. We assessed immune cell subsets and used molecular profiling to further elucidate effects on antitumor immunity. Methods: Patients with mTNBC and ≤ 2 prior chemotherapy regimens for locally recurrent TNBC or mTNBC were randomized 1:1:1 to GCb on days 1 and 8, trilaciclib prior to GCb on days 1 and 8, or trilaciclib alone on days 1 and 8, and prior to GCb on days 2 and 9. Gene expression, immune cell populations, and Tumor Inflammation Signature (TIS) scores were assessed in baseline tumor samples, with flow cytometric analysis and intracellular and surface cytokine staining used to assess immune cell populations and function. Results: After two cycles, the trilaciclib plus GCb group (n = 68) had fewer total T cells and significantly fewer CD8+ T cells and myeloid-derived suppressor cells compared with baseline, with enhanced T-cell effector function versus GCb alone. No significant differences were observed in patients who received GCb alone (n = 34). Of 58 patients in the trilaciclib plus GCb group with antitumor response data, 27 had an objective response. RNA sequencing revealed a trend toward higher baseline TIS scores among responders versus non‑responders. Conclusion: The results suggest that administering trilaciclib prior to GCb may modulate the composition and response of immune cell subsets to TNBC. [ABSTRACT FROM AUTHOR]

Background: Age is a major risk factor for the acute and chronic complications of cancer chemotherapy. The current approach to the prevention of these complications is reactive and involves the reduction of the doses and the delay of treatment which may compromise the outcome. There is a limited number of antidotes to chemotherapy toxicity and these have complications of their own. Oldest old and frail patients are mostly excluded from life saving cancer treatment due to the risk of severe and even lethal complications. Methods: molecular biology has revealed that different checkpoints control the proliferative cycle of normal and neoplastic cells. Two new drugs, Trilaciclib and ALRN‐6924 may cause a temporary cell cycle arrest (CCA) of normal cells without blocking the proliferation of the neoplastic ones and render the normal cells temporarily invulnerable to the toxicity of chemotherapy. We reviewed the publications related to these drugs on the Medline, the published drug information and the presentations to major medical conferences. Results: In three randomized controlled phase II trials Trilaciclib proved effective in preventing neutropenia, thrombocytopenia and anemia in patients with non small cell lung cancer with non proficient RB1 gene. Forty‐five percent of patients were 65 and older and age did not prevent the effectiveness of the drug. Trilaciclib was approved by the FDA for the management of these patients. ALRN‐6924 appeared promising in preventing myelotoxicity in patients whose cancer had deleted or mutated TP53, but failed to show any significant activity in a randomized controlled study. The development of this drug is now on hold Conclusions: CCA is a novel proactive approach to the toxicity of chemotherapy of special interest to older patients. At the very least it may prevent all forms of myelotoxicity with a single agent, obviating the risk and cost of polypharmacy. It allows to avoid the complications of myelopoietic growth factors which include severe pain, stem cell competition, bone marrow exhaustion, and hematological malignancies. It may allow the treatment of frail patients with full chemotherapy doses. It is also reasonable to expect that may complications other common and sometimes lethal complications of chemotherapy such as stomatitis, esophagitis, diarrhea and dehydration. [ABSTRACT FROM AUTHOR]

Background: This study aims to assess the clinical efficacy and safety of Trilaciclib in preventing chemotherapy-induced myelosuppression in adult patients through meta-analysis. Methods: The PubMed, Embase, Cochrane Library, Clinical Trials, EU Clinical Trials Register, and International Clinical Trials Registry Platform were searched up to 25 October 2022. Only randomized controlled trials (RCTs) comparing the clinical outcomes of Trilaciclib and Trilaciclib plus chemotherapy for treating malignant cancers in adult patients were included. The primary outcome included the incidence of SN, FN, the DSN, and administration of ESAs, G-CSFs, and RBC or platelet transfusions, while the secondary outcomes included the risk of adverse events (AEs) and severe adverse events (SAEs). Results: In total, four randomized controlled trials (RCTs) involving 345 patients with SCLC or breast cancer were included in this meta-analysis. Results showed that administration of Trilaciclib significantly reduced the occurrence of SN (19.3% vs. 42.2%, OR = 0.31), FN (3.22% vs. 6.72%, OR = 0.47), anemia (20.5% vs. 38.2%, OR = 0.38) and shortened the DSN during treatment. The proportion of patients receiving therapeutic use of ESAs (4.03% vs. 11.8%, OR = 0.31), G-CSF (37.0% vs. 53.5%, OR = 0.52), RBC transfusions (19.8% vs. 29.9%, OR = 0.56) was also statistically lower in the experimental group than in the control group. Meanwhile, the ORR, overall survival, and progress-free survival of the two groups were identical, and no negative impact of Trilaciclib on the clinical outcomes of chemotherapy treatments was found. Other chemotherapy-induced adverse events (AEs) and severe adverse events (SAEs) like diarrhea, fatigue, nausea, and vomiting were identical regardless of Trilaciclib usage. Conclusion: Trilaciclib demonstrated its efficacy in reducing the occurrence of chemotherapy-induced myelosuppression and utilization of supportive care interventions without undermining the clinical benefits of chemotherapy regimens during treatment with an acceptable safety profile. [ABSTRACT FROM AUTHOR]

Aims: Trilaciclib is a first‐in‐class, intravenous cyclin‐dependent kinase 4/6 inhibitor that provides multilineage protection from chemotherapy‐induced myelosuppression. This analysis aimed to characterize the population pharmacokinetics (PK) of trilaciclib, identify potential covariates influencing trilaciclib PK, and evaluate exposure–response relationships in extensive‐stage small cell lung cancer (ES‐SCLC) and triple‐negative breast cancer (TNBC) trials. Methods: Population PK analysis was performed using data from healthy volunteers (n = 72), patients with ES‐SCLC (n = 111) and patients with TNBC (n = 14). Exposure–response analyses were conducted to investigate the impact of trilaciclib exposure (AUC) on myeloprotective efficacy, antitumour efficacy and safety. Logistic regression and Cox regression models were used for binary and time‐to‐event endpoints, respectively. Results: Trilaciclib PK was described by a three‐compartment model. Sex, body surface area, baseline albumin concentration and age were identified as significant covariates on trilaciclib PK but did not have clinically relevant impact on exposure. Based on exposure–response analyses, lower and higher exposures of trilaciclib at clinical doses (200–280 mg/m2) were associated with similar myeloprotective effects. Trilaciclib exposure did not impact the antitumour effects of chemotherapy. Higher exposure to trilaciclib was associated with higher probabilities of headache, phlebitis/thrombophlebitis and injection site reactions. Conclusion: No dose adjustments are required based on the covariates tested. Trilaciclib resulted in optimal myeloprotective effects with no impact on antitumour effects of chemotherapy. However, higher exposure increased the probabilities of adverse events. The data further support selection of the recommended phase 2 dose (trilaciclib 240 mg/m2). [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is an aggressive malignancy for which cytotoxic chemotherapy remains the backbone of treatment. Trilaciclib is an intravenous cyclin-dependent kinase 4/6 inhibitor that induces transient cell cycle arrest of hematopoietic stem and progenitor cells and immune cells during chemotherapy exposure, protecting them from chemotherapy-induced damage and enhancing immune activity. Administration of trilaciclib prior to gemcitabine plus carboplatin (GCb) significantly improved overall survival (OS) compared with GCb alone in an open-label phase II trial in patients with metastatic TNBC, potentially through protection and direct activation of immune function. The randomized, double-blind, placebo-controlled, phase III PRESERVE 2 trial will evaluate the efficacy and safety of trilaciclib administered prior to GCb in patients with locally advanced unresectable or metastatic TNBC. Clinical Trial Registration: NCT04799249 (ClinicalTrials.gov) Recruiting! PRESERVE 2: a randomized, phase III placebo-controlled trial assessing trilaciclib prior to first-line chemotherapy in patients with advanced or metastatic triple-negative breast cancer. [ABSTRACT FROM AUTHOR]

Chemotherapy is the backbone of the treatment of several solid tumours and lymphomas. Myelotoxicity is often a dose-limiting toxicity and myeloprotection has always been investigated. In fact, over the years, several approaches have been studied in order to reduce the incidence of haematological toxicities and allow patients to receive effective, full-dose, chemotherapy. After the use of stimulating factors, such as granulocyte colony-stimulating factors and erythropoiesis-stimulating agents, in the very last years, a new approach has emerged. Trilaciclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, has been studied and it has been demonstrated in several clinical trials to reduce the incidence of myelotoxicity in small-cell lung cancer patients treated with chemotherapy or chemo-immunotherapy. Its potential role has not been fully studied yet, but it represents a highly effective tool to reduce myelotoxicity, widen the applicability of full-dose chemotherapy, even in frailer patients, and finally to increase the efficacy of chemotherapy in those tumours where relative dose intensity is a standard to achieve to get the best clinical results. [ABSTRACT FROM AUTHOR]

Abstract Background Supportive care interventions used to manage chemotherapy‐induced myelosuppression (CIM), including granulocyte colony‐stimulating factors (G‐CSFs), erythropoiesis‐stimulating agents (ESAs), and red blood cell (RBC) transfusions, are burdensome to patients and associated with greater costs to health care systems. We evaluated the utilization of supportive care interventions and their relationship with the myeloprotective agent, trilaciclib. Methods Data were pooled from three independent randomized phase 2 clinical trials of trilaciclib or placebo administered prior to chemotherapy in patients with extensive‐stage small cell lung cancer (ES‐SCLC). The impact of supportive care on the duration of severe neutropenia (DSN), occurrence of severe neutropenia (SN), and occurrence of RBC transfusions on/after week 5 was analyzed across cycles 1–4. Concordance and association between grade 3/4 anemia, RBC transfusions on/after week 5, and ESA administration was also evaluated. Results The use of G‐CSFs, ESAs, or RBC transfusions on/after week 5 was significantly lower among patients receiving trilaciclib versus placebo (28.5% vs. 56.3%, p

Maen Hussein,1 Marina Maglakelidze,2 Donald A Richards,3 Marielle Sabatini,4 Todd A Gersten,5 Keith Lerro,6 Ivan Sinielnikov,7 Alexander Spira,8,9 Yili Pritchett,10 Joyce M Antal,10 Rajesh Malik,10 J Thaddeus Beck11 1Florida Cancer Specialists, Leesburg, FL, USA; 2LLC Arensia Exploratory Medicine, Tbilisi, Georgia; 3Texas Oncology-Tyler, US Oncology Research, Tyler, TX, USA; 4Saint Leon Hospital, Bayonne, France; 5Florida Cancer Specialists, West Palm Beach, FL, USA; 6Regional Medical Oncology Center, Wilson, NC, USA; 7Volyn Regional Oncology Center, Lutsk, Ukraine; 8Virginia Cancer Specialists, Fairfax, VA, USA; 9US Oncology Research, The Woodlands, TX, USA; 10G1 Therapeutics, Inc., Research Triangle Park, NC, USA; 11Highlands Oncology Group, Fayetteville, AR, USACorrespondence: Maen HusseinFlorida Cancer Specialists, Leesburg, FL, USATel +1 352-787-9448Email mhussein@flcancer.comPurpose: Trilaciclib is an intravenous cyclin-dependent kinase 4/6 inhibitor indicated to decrease the incidence of chemotherapy-induced myelosuppression (CIM) by protecting hematopoietic stem and progenitor cells and immune system function from chemotherapy-induced damage (myeloprotection). Here, we investigated the myeloprotective effects of trilaciclib among patients at increased risk of CIM.Patients and Methods: Data were pooled from three randomized, double-blind, placebo-controlled, phase 2 clinical studies of trilaciclib administered prior to chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). Myeloprotective outcomes were evaluated in patient subgroups based on age (< 65 or ≥ 65 years), risk of chemotherapy-induced febrile neutropenia (FN), and risk of anemia or red blood cell (RBC) transfusions. For the FN and anemia analyses, risk factors were identified from published literature and used to classify patients into FN and anemia risk categories. Subgroup analysis based on age was also performed on patient reported outcome (PRO) measures.Results: In total, 123 patients received trilaciclib and 119 patients received placebo. Myeloprotective benefits of trilaciclib were observed regardless of age, with greater effects observed among patients aged ≥ 65 years. Across FN risk factors and categories, trilaciclib had beneficial effects on neutrophil-related endpoints vs placebo, with greater effects observed in patients at higher risk of FN. Effects on RBC-related endpoints favored trilaciclib vs placebo, regardless of anemia risk factors and categories. Improvements in PROs with trilaciclib were observed irrespective of age group, but with greater improvements and less deterioration from baseline observed in older patients.Conclusion: By both decreasing the incidence of CIM and improving quality of life, trilaciclib has the potential to allow patients receiving chemotherapy for ES-SCLC, including patients who are older or more vulnerable to CIM, to receive chemotherapy on schedule and at standard-of-care doses, and to improve the experience for patients receiving chemotherapy to treat ES-SCLC.Clinical Trial Numbers: NCT02499770; NCT03041311; NCT02514447.Keywords: trilaciclib, myelosuppression, myeloprotection, myelopreservation, chemotherapy, small cell lung cancer

Oral cyclin-dependent kinase (CDK) 4/6 inhibitors are routinely used to treat metastatic hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer in combination with endocrine therapy; however, they have not been widely used for other tumour types. Trilaciclib is an intravenous CDK 4/6 inhibitor that causes reversible cell cycle arrest in the G1 phase and transient haematopoietic stem and progenitor cell arrest. Ultimately, this protects the bone marrow and immune system from the cytotoxic impact of chemotherapy. Trilaciclib has been evaluated in extensive-stage small cell lung cancer in combination with chemotherapy as a myeloprotective agent and was approved by the US Food and Drug Administration for this use in February 2021. In metastatic triple-negative breast cancer, trilaciclib plus chemotherapy had a survival benefit over chemotherapy alone. This is being further investigated in a phase III trial. This review outlines the mechanism of this novel agent and describes preclinical and clinical data, characterizing its use in extensive-stage small cell lung cancer and advanced triple-negative breast cancer. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase 4/6 (CDK4/6) are key regulators of the cell cycle and are deemed as critical therapeutic targets of multiple cancers. Various approaches have been applied to silence CDK4/6 at different levels, i.e., CRISPR to knock out at the DNA level, siRNA to inhibit translation, and drugs that target the protein of interest. Here we summarize the current status in this field, highlighting the mechanisms of small molecular inhibitors treatment and drug resistance. We describe approaches to combat drug resistance, including combination therapy and PROTACs drugs that degrade the kinases. Finally, critical issues and perspectives in the field are outlined. [ABSTRACT FROM AUTHOR]

Background: Trilaciclib, an intravenous short acting cyclin-dependent kinase 4/6 inhibitor, has been approved for the prevention of chemotherapy-induced myelosuppression (CIM) in patients with extensive stage small cell lung cancer (ES-SCLC) receiving platinum/etoposide (EP) or topotecan (TPT)-based therapy in United States (US) since February 2021. Trilaciclib use received the priority review and approval in a real-world setting in China. This study thus aimed to collect real-world data and evaluate the protective effect of trilaciclib on CIM in Chinese patients with ES-SCLC., Methods: This single-arm, noninterventional real world study invited all patients with ES-SCLC who received trilaciclib with the platinum and etoposide ± anti-programmed cell death ligand-1 [anti-PD-(L)1] antibodies (EP group) or trilaciclib with TPT (TPT group) in Boao, Hainan China to participate in the study. The primary endpoint was the incidence of the severe (grade four) neutropenia (SN), and the secondary endpoints included other myeloprotection effects, safety and anti-tumor activity., Results: Between August 2021 and December 2022, a total of 30 patients who received trilaciclib with chemotherapy consented to participate in this real-world study. Among the enrolled patients, 26 patients were treated with EP regimen, of these, 18 patients were combined with anti-PD-(L)1 antibodies, and 4 patients were treated with TPT. The incidence of SN was 6.7%, with one patient each in EP group and TPT group. The incidence of grade three hematological toxicities was 30% (9/30), with 19.2% (5/26) in the EP group, and 100% (4/4) in the TPT group. The incidence of grade four hematological toxicities was 5/30 (16.7%), with 3/26 (11.5%) and 2/4 (50%) in EP and TPT group, respectively. Overall, the incidence of those who received intravenous or oral antibiotics was 6/30 (20%), with 4/26 (15.4%) in the EP group, and 2/4 (50%) in the TPT group. No ≥ grade three adverse events, serious adverse events (SAEs), and adverse events of special interest associated with trilaciclib were reported., Conclusions: Trilaciclib decreased the incidence of CIM in Chinese patients when administered prior to an EP-containing regimen [combined with or without PD-(L)1] or TPT for ES-SCLC. The effect of myeloprotection, anti-tumor and safety were all consistent with the studies conducted globally and data from the Chinese Phase three placebo-controlled study (TRACES)., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-893/coif). Y.C. is an employee of Hainan Simcere Zaiming Pharmaceutical Co., Ltd., and have stock and stock options of Simcere Pharmaceutical Group Limited. The other authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Trilaciclib is a CDK4/6 inhibitor, used to treat the bone marrow damage in chemotherapy patients. A series of thirteen novel structural trilaciclib analogs was obtained to evaluate their activity against acetylcholinesterase. An effective method for the synthesis of 4,7-substituted 8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine derivatives from a new methyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate was developed. Most of the synthesized pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine derivatives inhibited acetylcholinesterase in the micromolar range. The obtained data can be used for designing more potent acetylcholinesterase inhibitors with the pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine scaffold., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Proliferating hematopoietic stem and progenitor cells (HSPCs) are susceptible to chemotherapy-induced damage, resulting in myelosuppressive adverse events (AEs) such as neutropenia, anemia, and thrombocytopenia that are associated with high health care costs and decreased quality of life (QoL). In this study, a trial-based cost-effectiveness analysis was performed to help assess the economic impact of administering trilaciclib, a myeloprotective therapy that protects multilineage HSPCs from chemotherapy-induced damage, prior to standard first-line chemotherapy, using data from a pivotal Phase II study of trilaciclib in the setting of extensive-stage small cell lung cancer (ES-SCLC, NCT03041311). The aim of this study was to assess the cost-effectiveness of administering trilaciclib prior to chemotherapy versus chemotherapy alone among patients with ES-SCLC from a United States payer perspective. Data on the rate and frequency of myelosuppressive AEs and health utility were derived from the pivotal study of trilaciclib. Costs of managing myelosuppressive AEs and costs of chemotherapy treatment were sourced from published literature. Outcomes included the number of myelosuppressive AEs, costs (in 2021 US dollars), quality-adjusted life-years (QALYs), incremental cost, incremental QALY, and an incremental cost-effectiveness ratio. Administering trilaciclib prior to chemotherapy was associated with a reduction in neutropenia (82%), febrile neutropenia (75%), anemia (43%), and thrombocytopenia (96%) compared with chemotherapy alone. Additionally, trilaciclib prior to chemotherapy was cost-saving compared with chemotherapy alone ($99,919 vs $118,759, respectively) and associated with QALY improvement (0.150 vs 0.145, respectively). Probabilistic sensitivity analyses showed 58% of iterations projecting cost savings and QALY improvement with trilaciclib. The findings suggest that the use of trilaciclib prior to first-line chemotherapy in patients with ES-SCLC can be cost-beneficial owing to fewer myelosuppressive AEs and lower costs, together with a favorable QoL profile. [ABSTRACT FROM AUTHOR]

Chemotherapy‐induced myelosuppression is an acute, dose‐limiting toxicity of chemotherapy regimens used in the treatment of extensive‐stage small cell lung cancer (ES‐SCLC). Trilaciclib protects haematopoietic stem and progenitor cells from chemotherapy‐induced damage (myeloprotection). To assess the totality of the myeloprotective benefits of trilaciclib, including analysis of several clinically relevant but low‐frequency events, an exploratory composite endpoint comprising five major adverse haematological events (MAHE) was prospectively defined: all‐cause hospitalisations, all‐cause chemotherapy dose reductions, febrile neutropenia (FN), prolonged severe neutropenia (SN) and red blood cell (RBC) transfusions on/after Week 5. MAHE and its individual components were assessed in three randomised, double‐blind, placebo‐controlled Phase 2 trials in patients receiving a platinum/etoposide or topotecan‐containing chemotherapy regimen for ES‐SCLC and in data pooled from the three trials. A total of 242 patients were randomised across the three trials (trilaciclib, n = 123; placebo, n = 119). In the individual trials and the pooled analysis, administering trilaciclib prior to chemotherapy resulted in a statistically significant reduction in the cumulative incidence of MAHE compared to placebo. In the pooled analysis, the cumulative incidences of all‐cause chemotherapy dose reductions, FN, prolonged SN and RBC transfusions on/after Week 5 were significantly reduced with trilaciclib vs placebo; however, no significant difference was observed in rates of all‐cause hospitalisations. Additionally, compared to placebo, trilaciclib significantly extended the amount of time patients remained free of MAHE. These data support the myeloprotective benefits of trilaciclib and its ability to improve the overall safety profile of myelosuppressive chemotherapy regimens used to treat patients with ES‐SCLC. [ABSTRACT FROM AUTHOR]

Background: Supportive care interventions used to manage chemotherapy‐induced myelosuppression (CIM), including granulocyte colony‐stimulating factors (G‐CSFs), erythropoiesis‐stimulating agents (ESAs), and red blood cell (RBC) transfusions, are burdensome to patients and associated with greater costs to health care systems. We evaluated the utilization of supportive care interventions and their relationship with the myeloprotective agent, trilaciclib. Methods: Data were pooled from three independent randomized phase 2 clinical trials of trilaciclib or placebo administered prior to chemotherapy in patients with extensive‐stage small cell lung cancer (ES‐SCLC). The impact of supportive care on the duration of severe neutropenia (DSN), occurrence of severe neutropenia (SN), and occurrence of RBC transfusions on/after week 5 was analyzed across cycles 1–4. Concordance and association between grade 3/4 anemia, RBC transfusions on/after week 5, and ESA administration was also evaluated. Results: The use of G‐CSFs, ESAs, or RBC transfusions on/after week 5 was significantly lower among patients receiving trilaciclib versus placebo (28.5% vs. 56.3%, p < 0.0001; 3.3% vs. 11.8%, p = 0.0254; and 14.6% vs. 26.1%, p = 0.0252, respectively). Compared with placebo, trilaciclib significantly reduced DSN and SN, irrespective of G‐CSF administration. RBC transfusions and ESAs were most often administered in patients with grade 3/4 anemia; however, patients typically received RBC transfusions over ESA administration. Conclusions: By improving CIM and reducing the need for associated supportive care, trilaciclib has the potential to reduce the burden of myelosuppression on patients receiving myelosuppressive chemotherapy for the treatment of ES‐SCLC. Trial registration: ClinicalTrials.gov (NCT02499770; NCT03041311; NCT02514447). [ABSTRACT FROM AUTHOR]

Trilaciclib is an intravenous CDK4/6 inhibitor administered prior to chemotherapy to preserve haematopoietic stem and progenitor cells and immune system function from chemotherapy-induced damage (myelopreservation). The effects of administering trilaciclib prior to carboplatin, etoposide and atezolizumab (E/P/A) were evaluated in a randomised, double-blind, placebo-controlled Phase II study in patients with newly diagnosed extensive-stage small cell lung cancer (ES-SCLC) (NCT03041311). The primary endpoints were duration of severe neutropenia (SN; defined as absolute neutrophil count <0.5 × 109 cells per L) in Cycle 1 and occurrence of SN during the treatment period. Other endpoints were prespecified to assess the effects of trilaciclib on additional measures of myelopreservation, patient-reported outcomes, antitumour efficacy and safety. Fifty-two patients received trilaciclib prior to E/P/A and 53 patients received placebo. Compared to placebo, administration of trilaciclib resulted in statistically significant decreases in the mean duration of SN in Cycle 1 (0 vs 4 days; P < .0001) and occurrence of SN (1.9% vs 49.1%; P < .0001), with additional improvements in red blood cell and platelet measures and health-related quality of life (HRQoL). Trilaciclib was well tolerated, with fewer grade ≥3 adverse events compared with placebo, primarily due to less high-grade haematological toxicity. Antitumour efficacy outcomes were comparable. Administration of trilaciclib vs placebo generated more newly expanded peripheral T-cell clones (P = .019), with significantly greater expansion among patients with an antitumour response to E/P/A (P = .002). Compared with placebo, trilaciclib administered prior to E/P/A improved patients' experience of receiving treatment for ES-SCLC, as shown by reduced myelosuppression, and improved HRQoL and safety profiles [ABSTRACT FROM AUTHOR]

Purpose: Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle to preserve them from chemotherapy-induced damage (myelopreservation). We report integrated analyses of preclinical and clinical data that informed selection of the recommended Phase II dose (RP2D) used in trilaciclib trials in extensive-stage small cell lung cancer (ES-SCLC). Methods: A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed from preclinical data guided selection of an optimal dose for G1 bone marrow arrest in a first-in-human Phase I study (G1T28-1-01). PK, PD, safety, and efficacy data from G1T28-1-01 and two Phase Ib/IIa studies (G1T28-02/-03) in ES-SCLC were analyzed to support RP2D selection. Results: Model simulation of bone marrow arrest based on preclinical data predicted that a ≥ 192 mg/m2 dose would induce a 40–50% decrease in total bone marrow proliferation in humans and almost 100% cell cycle arrest of cycling HSPCs. Consistent with this model, analysis of bone marrow aspirates in healthy volunteers after trilaciclib 192 mg/m2 administration demonstrated almost 100% G1 arrest in HSPCs and 40% decrease in total bone marrow proliferation, with minimal toxicity. G1T28-02/-03 reported similar PK parameters with trilaciclib 200 mg/m2 but slightly lower exposures than expected compared with healthy volunteers; consequently, 240 and 280 mg/m2 doses were also tested to match healthy volunteer exposures. Based on PK and relevant safety data, 240 mg/m2 was selected as the RP2D, which was also favored by myelopreservation endpoints in G1T28-02/-03. Conclusion: Integrated PK/PD, safety, and efficacy data support 240 mg/m2 as the RP2D for trilaciclib. ClinicalTrials.gov Identifiers: NCT02243150; NCT02499770; NCT02514447. [ABSTRACT FROM AUTHOR]

Introduction: Multilineage myelosuppression is an acute toxicity of cytotoxic chemotherapy, resulting in serious complications and dose modifications. Current therapies are lineage specific and administered after chemotherapy damage has occurred. Trilaciclib is a cyclin-dependent kinase 4/6 inhibitor that is administered prior to chemotherapy to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy (myelopreservation).Methods: In this randomized, double-blind, placebo-controlled phase II trial, patients with previously treated extensive-stage small cell lung cancer (ES-SCLC) were randomized to receive intravenous trilaciclib 240 mg/m2 or placebo before topotecan 1.5 mg/m2 on days 1-5 of each 21-day cycle. Primary endpoints were duration of severe neutropenia (DSN) in cycle 1 and occurrence of severe neutropenia (SN). Additional endpoints were prespecified to further assess the effect of trilaciclib on myelopreservation, safety, patient-reported outcomes (PROs), and antitumor efficacy.Results: Thirty-two patients received trilaciclib, and 29 patients received placebo. Compared with placebo, administration of trilaciclib prior to topotecan resulted in statistically significant and clinically meaningful decreases in DSN in cycle 1 (mean [standard deviation] 2 [3.9] versus 7 [6.2] days; adjusted one-sided P < 0.0001) and occurrence of SN (40.6% versus 75.9%; adjusted one-sided P = 0.016), with numerical improvements in additional neutrophil, red blood cell, and platelet measures. Patients receiving trilaciclib had fewer grade ≥ 3 hematologic adverse events than patients receiving placebo, particularly neutropenia (75.0% versus 85.7%) and anemia (28.1% versus 60.7%). Myelopreservation benefits extended to improvements in PROs, specifically in those related to fatigue. Antitumor efficacy was comparable between treatment arms.Conclusions: Compared with placebo, the addition of trilaciclib prior to topotecan for the treatment of patients with previously treated ES-SCLC improves the patient experience of receiving chemotherapy, as demonstrated by a reduction in chemotherapy-induced myelosuppression, improved safety profile, improved quality of life and no detrimental effects on antitumor efficacy.Trial Registration: ClinicalTrials.gov: NCT02514447. [ABSTRACT FROM AUTHOR]

Background Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity. Patients and methods This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1–3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy. Results A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P  = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P  = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P  = 0.6107). Conclusion Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits. Clinical Trail number NCT02499770. [ABSTRACT FROM AUTHOR]

• TRACES study evaluated benefits of Trilaciclib in Chinese ES-SCLC patients. • Our study demonstrated myeloprotective benefits of trilaciclib prior chemotherapy. • Trilaciclib had a well-tolerated safety profile. Trilaciclib is a transient cyclin-dependent kinase 4/6 inhibitor that decreases the incidence of chemotherapy-induced myelosuppression in extensive-stage small cell lung cancer (ES-SCLC). TRACES study was designed to assess the safety, efficacy and pharmacokinetics (PK) of trilaciclib before chemotherapy in Chinese patients with ES-SCLC. The study included an open-label safety run-in part (Part 1) and double-blinded, placebo-controlled part (Part 2) where patients received trilaciclib or placebo before chemotherapy. Treatment-naïve or previously treated ES-SCLC patients received intravenous trilaciclib (240 mg/m2) or placebo before etoposide/carboplatin or topotecan, respectively. Primary endpoints were PK, safety and duration of severe neutropenia (DSN) in Cycle 1 in Part 1 and Part 2. Exploratory endpoints included the effect of trilaciclib on other myeloprotection endpoints, safety and antitumor efficacy. Overall, 95 Chinese patients were enrolled, of which 12 and 83 patients were in Part 1 and Part 2, respectively. In Part 1, trilaciclib was well tolerated. Non-compartmental analysis results revealed no substantial differences in the main exposure parameters. In Part 2, 41 patients received trilaciclib, and 42 received placebo. Patients in trilaciclib arm vs placebo arm had a clinically and statistically significant decrease in DSN (mean [SD]) in Cycle 1 (0 [1.7] vs 2 [3.0] days; P = 0.0003), with improvements in additional neutrophil, red blood cell, and platelet measures. After a median follow-up of 14.1 months, the median overall survival was 12.0 months in trilaciclib arm and 8.8 months in placebo arm (HR, 0.69; 95 % CI: 0.40–1.22). Median progression-free survival was 4.8 months and 4.3 months, respectively (HR, 0.86; 95 % CI: 0.53–1.39). Trilaciclib had a well-tolerated safety profile. Trilaciclib in the Chinese population demonstrated a similar PK and safety profile as seen in other global trials. There was significant reduction of DSN in Cycle 1, thereby substantiating the myeloprotective effects of trilaciclib in Chinese ES-SCLC patients. [ABSTRACT FROM AUTHOR]

Inhibition of cyclin-dependent kinases (CDKs) has evolved as an emerging anticancer strategy. In addition to the cell cycle-regulating CDKs, the transcriptional kinases Cdk12 and Cdk13 have become the focus of interest as they mediate a variety of functions, including the transition from transcription initiation to elongation and termination, precursor mRNA splicing, and intronic polyadenylation. Here, we determine the crystal structure of the small molecular inhibitor SR-4835 bound to the Cdk12/cyclin K complex at 2.68 Å resolution. The compound's benzimidazole moiety is embedded in a unique hydrogen bond network mediated by the kinase hinge region with flanking hydroxy groups of the Y815 and D819 side chains. Whereas the SR-4835 head group targets the adenine-binding pocket, the kinase's glycine-rich loop is shifted down toward the activation loop. Additionally, the αC-helix adopts an inward conformation, and the phosphorylated T-loop threonine interacts with all three canonical arginines, a hallmark of CDK activation that is altered in Cdk12 and Cdk13. Dose-response inhibition measurements with recombinant CMGC kinases show that SR-4835 is highly specific for Cdk12 and Cdk13 following a 10-fold lower potency for Cdk10. Whereas other CDK-targeting compounds exhibit tighter binding affinities and higher potencies for kinase inhibition, SR-4835 can be considered a selective transcription elongation antagonist. Our results provide the basis for a rational improvement of SR-4835 toward Cdk12 inhibition and a gain in selectivity over other transcription regulating CDKs., Competing Interests: Conflict of interest All authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cyclin-dependent kinase 4/6 inhibitors, which act by inhibiting progression from the G1 to S phases of the cell cycle, include palbociclib, ribociclib, abemaciclib, and trilaciclib. Palbociclib and ribociclib are currently food and drug administration-approved for use in combination with aromatase inhibitors in postmenopausal women with metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Palbociclib is also food and drug administration-approved for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy. Abemaciclib is the newest cyclin-dependent kinase 4/6 inhibitor to gain Food and Drug Administration (FDA) approval, specifically as monotherapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer previously treated with chemotherapy and endocrine therapy. Abemaciclib also shares a similar indication with palbociclib for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy. Trilaciclib use remains largely investigational at this time. However, despite FDA-approval for only metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, all four cyclin-dependent kinase 4/6 inhibitors have shown promise in hematologic malignancies and non-breast solid tumors. Although further research is needed, cyclin-dependent kinase 4/6 inhibitors represent intriguing developments in the treatment of various malignancies, including those with such poor prognoses as glioblastoma multiforme, mantle cell lymphoma, and metastatic melanoma. We discuss the approved indications, current research, and areas of future exploration for palbociclib, ribociclib, abemaciclib, and trilaciclib. [ABSTRACT FROM AUTHOR]

Cancer therapy is limited by toxicity in normal cells and drug-resistance in cancer cells. Paradoxically, cancer resistance to certain therapies can be exploited for protection of normal cells, simultaneously enabling the selective killing of resistant cancer cells by using antagonistic drug combinations, which include cytotoxic and protective drugs. Depending on the mechanisms of drug-resistance in cancer cells, the protection of normal cells can be achieved with inhibitors of CDK4/6, caspases, Mdm2, mTOR, and mitogenic kinases. When normal cells are protected, the selectivity and potency of multi-drug combinations can be further enhanced by adding synergistic drugs, in theory, eliminating the deadliest cancer clones with minimal side effects. I also discuss how the recent success of Trilaciclib may foster similar approaches into clinical practice, how to mitigate systemic side effects of chemotherapy in patients with brain tumors and how to ensure that protective drugs would only protect normal cells (not cancer cells) in a particular patient.

• Chemotherapy-induced neutropenia can lead to poor clinical outcomes. • CIN can lead to infections, hospitalizations, mortality, and lower chemotherapy dose intensity. • G-CSF agents have been the standard of care for the prevention of CIN for 30 years. • Emerging therapies will likely change the standard approach for CIN prevention. [ABSTRACT FROM AUTHOR]