Cosela (trilaciclib)

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. 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.

P2, N=40, Not yet recruiting, Henan Cancer Hospital

P3, N=210, Not yet recruiting, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

P2, N=92, Terminated, G1 Therapeutics, Inc. | Active, not recruiting --> Terminated; Sponsor no longer pursuing trila for the indication.

P2, N=30, Active, not recruiting, G1 Therapeutics, Inc. | Trial primary completion date: Jun 2023 --> Nov 2023

P2, N=132, Not yet recruiting, Sun Yat-sen University

P2, N=30, Recruiting, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School | Not yet recruiting --> Recruiting

P2, N=36, Recruiting, Wake Forest University Health Sciences | Not yet recruiting --> Recruiting

Six drugs (abrocitinib, baricitinib, deucravacitinib, ritlecitinib, tofacitinib, upadacitinib) are used for the treatment of inflammatory diseases (atopic dermatitis, rheumatoid arthritis, psoriasis, alopecia areata, and ulcerative colitis)...The following seven drugs received FDA approval in 2023: capivasertib (HER2-positive breast cancer), fruquintinib (metastatic colorectal cancer), momelotinib (myelofibrosis), pirtobrutinib (mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma), quizartinib (Flt3-mutant acute myelogenous leukemia), repotrectinib (ROS1-positive lung cancer), and ritlecitinib (alopecia areata). All of the FDA-approved drugs are orally effective with the exception of netarsudil, temsirolimus, and trilaciclib. This review summarizes the physicochemical properties of all 80 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, polar surface area, potency, solubility, lipophilic efficiency, and ligand efficiency.

P2, N=30, Not yet recruiting, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

P2, N=116, Recruiting, wang shusen | Not yet recruiting --> Recruiting

Eligible patients met literature-based criteria for ES-SCLC using International Classification of Diseases, 10th Revision (ICD-10) diagnosis codes, received platinum/etoposide- or topotecan-based chemotherapy regimens after diagnosis, and were continuously enrolled ≥ 30 days preceding and following chemotherapy initiation. This real-world study demonstrated that receiving trilaciclib prior to chemotherapy treatment was associated with a lower rates of hospitalizations and cytopenia events, suggesting trilaciclib may prevent adverse events associated with treatment for ES-SCLC.

P4, N=30, Completed, Jiangsu Simcere Pharmaceutical Co., Ltd. | Active, not recruiting --> Completed | Trial completion date: Mar 2023 --> Nov 2022

P4, N=302, Recruiting, G1 Therapeutics, Inc. | Not yet recruiting --> Recruiting

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.

P2, N=36, Not yet recruiting, Wake Forest University Health Sciences

P2, N=116, Not yet recruiting, wang shusen

The results suggest that administering trilaciclib prior to GCb may modulate the composition and response of immune cell subsets to TNBC.

Five CDK4/6 inhibitors, palbociclib, ribociclib, abemaciclib, dalpiciclib, and trilaciclib have been approved for the treatment of this breast cancer subset at present. Possible approaches to overcome CDK4/6 inhibitors resistance were further discussed. For example, using another CDK4/6 inhibitor, PI3K inhibitor, mTOR inhibitor, or a novel drug.

P4, N=302, Not yet recruiting, G1 Therapeutics, Inc. | Initiation date: Jun 2023 --> Nov 2023

P2, N=132, Not yet recruiting, Fudan University

P2, N=132, Not yet recruiting, Sichuan University

Other chemotherapy-induced adverse events (AEs) and severe adverse events (SAEs) like diarrhea, fatigue, nausea, and vomiting were identical regardless of Trilaciclib usage. 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.

Multiple emerging agents show promise in decreasing the burden of CIN. Use of these therapies will reduce access disparities and will improve outcomes for patients with cancer receiving cytotoxic chemotherapy. Many ongoing trials are underway to evaluate the roles of these agents for more widespread use.

P4, N=302, Not yet recruiting, G1 Therapeutics, Inc.

P2, N=150, Not yet recruiting, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Patients (pts) with early-stage TNBC received single-dose trilaciclib followed by trilaciclib + dose-dense anthracycline/cyclophosphamide and taxane (AC/T)...4 serious TRAEs occurred in 2 (8%) pts: pembro-related colitis and hypertransaminasemia, trilaciclib/paclitaxel-related urosepsis, and AC-related febrile neutropenia... Safety and tolerability data are encouraging for trilaciclib in combination with AC/T ± pembrolizumab ± carboplatin in the neoadjuvant setting for early-stage TNBC. Preliminary efficacy data align with standard neoadjuvant chemotherapy regimens. Final pCR data from all pts and immune correlates from tumor and blood samples will be presented.

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. 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.

In an open-label, phase 2 trial in patients with metastatic triple-negative breast cancer (NCT02978716), administering trilaciclib prior to gemcitabine plus carboplatin improved overall survival, potentially through protection and direct activation of immune function. The increased generation of polyfunctional CD8+ T cells is associated with enhanced effector T-cell responses and memory T-cell differentiation. In combination with previous data showing increased differentiation of naïve T cells into memory T cells upon exposure to trilaciclib, these data support a beneficial role for trilaciclib in enhancing antitumor T-cell responses.

P3, N=326, Terminated, G1 Therapeutics, Inc. | Trial completion date: Jul 2025 --> Mar 2023 | Active, not recruiting --> Terminated; Despite achieving co-primary endpoints & other secondary measures of myeloprotection & tolerability, early anti-tumor efficacy data favor patients receiving placebo. Given the low likelihood of achieving PFS & OS endpoints, G1 decided to discontinue

P2, N=24, Completed, G1 Therapeutics, Inc. | Active, not recruiting --> Completed

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.

P2, N=30, Active, not recruiting, G1 Therapeutics, Inc. | Recruiting --> Active, not recruiting | N=45 --> 30

Currently, trilaciclib, palbociclib, ribociclib, and abemaciclib that bear dual specificities against CDK4 and CDK6 have been approved for clinical usage, and more CDK4/6 targeted agents are actively under clinical evaluations, among which, TY-302, a novel CDK4/6 inhibitor being developed by TYK Medicines, is under Phase II trial (NCT04433494)...Several CDK7 targeted agents, such as SY-5609 and Samuraciclib (CT7001), are under development...# Shengli Dong and Apeng Liang contributed equally to this work. * Jun Li, Shengli Dong and Apeng Liang are the correspondent authors.

P3, N=326, Active, not recruiting, G1 Therapeutics, Inc. | Trial completion date: Nov 2024 --> Jul 2025

The data indicate that 62 of these drugs are prescribed for the treatment of neoplasms (57 against solid tumors including breast, lung, and colon, ten against nonsolid tumors such as leukemia, and four against both solid and nonsolid tumors: acalabrutinib, ibrutinib, imatinib, and midostaurin). Four drugs (abrocitinib, baricitinib, tofacitinib, upadacitinib) are used for the treatment of inflammatory diseases (atopic dermatitis, psoriatic arthritis, rheumatoid arthritis, Crohn disease, and ulcerative colitis)...The following three drugs received FDA approval in 2022 for the treatment of these specified diseases: abrocitinib (atopic dermatitis), futibatinib (cholangiocarcinomas), pacritinib (myelofibrosis). All of the FDA-approved drugs are orally effective with the exception of netarsudil, temsirolimus, and trilaciclib. This review summarizes the physicochemical properties of all 72 FDA-approved small molecule protein kinase inhibitors including lipophilic efficiency and ligand efficiency.

P2, N=30, Recruiting, UNC Lineberger Comprehensive Cancer Center | Not yet recruiting --> Recruiting

P3, N=194, Active, not recruiting, G1 Therapeutics, Inc. | Recruiting --> Active, not recruiting

P2, N=30, Not yet recruiting, UNC Lineberger Comprehensive Cancer Center

In an open-label phase 2 trial in patients with metastatic triple-negative breast cancer, adding trilaciclib prior to gemcitabine plus carboplatin improved overall survival, potentially through protection and direct activation of immune function. The combination of trilaciclib plus α-PD-1 was consistently effective, irrespective of when treatment was initiated, or the tumor model used. The data suggest that trilaciclib provides complementary immune modulatory benefits that support the mechanism of IRI and provide a rationale for combining trilaciclib with IRI to enhance clinical efficacy, including in populations resistant to checkpoint blockade or who have received prior IRI treatment.

P3, N=326, Active, not recruiting, G1 Therapeutics, Inc. | Recruiting --> Active, not recruiting

To explore the effectiveness of trilaciclib and ALRN-6924 in the prevention of cancer chemotherapy-induced toxicity in older patients. They may also enable novel and more practical forms of clinical trials. By assessing the risk of chemotherapy-related toxicity with the Chemotherapy Risk Assessment Scale for High Age Patients (CRASH) or the Cancer and Aging Research Group (CARG) instruments, these agents may permit researchers to utilize patients as their own controls and endorse the approval of supportive care drugs based upon the risk profile of individual patients.