Background: Carboplatin, etoposide, and atezolizumab (PEA) is the most widely used combination for first-line treatment of extensive-stage small cell lung cancer (ES-SCLC). Chemotherapy-induced myelosuppression is a common sequalae that is traditionally managed with lineage-specific supportive care modalities. Studies that evaluated trilaciclib versus placebo in combination with chemotherapy demonstrated statistically significant improvements in the duration of severe neutropenia (SN), defined as ANC < 500 cells/μL, in cycle 1 and incidence of SN as a result of its transient myeloprotective effects. There remains considerable controversy in the adoption of trilaciclib as a supportive medication in clinical practice. The objective of this quality assessment study was to assess utility of trilaciclib in real-world ES-SCLC patients. Methods: This was a single center study with quasi-experimental design comparing patients with confirmed ES-SCLC who received trilaciclib + PEA (PEAT) from April 2021 to July 2022 versus those who received PEA without trilaciclib (PEA) from February 2020 to February 2021. Patients with limited-stage SCLC, prior treatment with immunotherapies, carboplatin dose AUC < 3.5 with cycle 1, and active clinical trial enrollment were excluded. The primary endpoint evaluated was incidence of SN after cycle 1 and during treatment period. Additional measures related to myelopreservation and patient outcomes were assessed as secondary endpoints. Demographic data was analyzed using descriptive statistics. Dichotomous and continuous variables were compared by Mann-Whitney U or one-sided Fisher's exact test. Progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier (KM) estimate. Results: 34 patients received PEAT and 44 patients received PEA. Demographic and baseline clinical characteristics were similar between both cohorts except for older median age of patients (69 years old vs 64 years old) and higher proportion of male patients (65% vs 39%) in the trilaciclib cohort. Even though there was a numerically lower rate of SN (3%) and hospitalization due to febrile neutropenia (FN) or infection (6%) in the PEAT versus the PEA (18%;11%) cohort, statistical significance was not met (p = 0.07;p = 0.065). Likewise, incidence of FN, platelet transfusion requirements, all-cause chemotherapy reductions, and treatment delays were not statistically different. However, the PEAT cohort as compared to PEA experienced a statistically significant reduction in red blood cell transfusion requirements (3% vs 23%; p = 0.02) and grade 3-4 anemia (6% vs 25%; p = 0.03). PFS and OS between the two cohorts were not statistically different. Conclusions: Based on this single center retrospective study, use of trilaciclib appears to confer improvement in the safety profile of PEA without negatively impacting survival outcomes. Therefore, results of this study support the integration of trilaciclib with PEA for ES-SCLC.

Trilaciclib indication: Trilaciclib, a CDK4/6 inhibitor, was used before chemotherapy to reduce the incidence of bone marrow suppression and approved by the FDA for small cell lung cancer patients in 2021.

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.

The study will include 3 study phases: Screening Phase, Treatment Phase, and Survival Follow-up Phase. The Treatment Phase begins on the day of the first dose of study treatment and completes at the Safety Follow-up Visit. Trilaciclib and sacituzumab govitecan-hziy will be administered intravenously (IV) in 21-day cycles. Study drug administration will continue until progressive disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or clinical progression as determined by the Investigator, unacceptable toxicity, withdrawal of consent, Investigator decision, or the end of the study, whichever occurs first. The first Survival Follow-up assessment should occur approximately 3 months after the Safety Follow-Up Visit and will continue every 3 months until the end of the study (or death).

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.

The purpose of this expanded access protocol is to provide access to trilaciclib for chemotherapy-induced myelosuppression in patients receiving chemotherapy as a treatment for small cell lung cancer (SCLC). Patients will receive trilaciclib intravenously as a 30-minute infusion prior to chemotherapy dosing and on each day that chemotherapy is administered. Supplementary to providing access to trilaciclib, this expanded access program will also capture Real World Data to help inform subsequent trilaciclib development. Requests for access to trilaciclib will be managed by Bionical Emas. G1 Therapeutics will review eligibility of, as well as complete a medical review of, each patient access request.

Trilaciclib indication: Trilaciclib, a CDK4/6 inhibitor, was used before chemotherapy to reduce the incidence of bone marrow suppression, approved by FDA and NMPA for small cell lung cancer in 2021 and in 2022. Envafolimab indication: Envafolimab, a PD‐L1 inhibitor, was used for unresectable or metastatic, MSI‐H or dMMR, Adult patients with advanced solid tumors, approved by NMPA in 2021.

The purpose of this study is to evaluate the mechanism of action, as well as the safety and efficacy of trilaciclib in combination with standard of care treatment in the neoadjuvant setting of early-stage triple negative breast cancer (TNBC). This study will have four phases: 1) Screening Phase, 2) Trilaciclib Lead-In Phase, 3) Treatment Phase, and 4) Surgery and Follow-Up Phase. After a screening phase of up to 21 day, each participant will receive trilaciclib single-dose monotherapy during the lead-in phase, followed by a tumor biopsy. During the treatment phase, each participant will receive trilaciclib with standard of care chemotherapy. Immunotherapy may be included during the treatment phase, per standard of care. 3-5 weeks following conclusion of the treatment phase, each participant will undergo definitive surgery. A 30-day Safety Follow-up Visit will occur 30 days after the last dose of trilaciclib and an End of Study Visit will occur within 14 days after definitive surgery.

Overall, up to 130 patients were planned to be enrolled in the study. In Part 1, approximately 40 patients were planned to be enrolled, assuming 9 to 10 cohorts. Part 1 was open-label, and no randomization or blinding was required. In Part 2A, approximately 45 patients were to be enrolled and randomly assigned (2:1) to trilaciclib (240 mg/m2) and topotecan (0.75 mg/m2) or placebo and topotecan (1.5 mg/m2). In Part 2B, approximately 45 patients were to be enrolled and randomly assigned (2:1) to trilaciclib (240 mg/mg2) and topotecan (1.5 mg/m2) or placebo and topotecan (1.5 mg/m2). Patients who received placebo in Part 2A and Part 2B were to be combined into a single placebo group for the analysis to compare with trilaciclib+topotecan 1.5 mg/m2 with placebo + topotecan 1.5 mg/m2 (proximately 30 per treatment group). The sample size calculation was to demonstrate the superiority of trilaciclib + topotecan 1.5 mg/m2 over placebo + topotecan 1.5 mg/m2 with respect to at least 1 of the primary endpoints. The overall type I error rate was 1-sided 0.10. Using the most conservative Bonferroni procedure for the 2 primary endpoints, a 1-sided individual type I error rate 0.10/2=0.05 was assigned to each outcome variable (DSN in Cycle 1 and occurrence of SN) in the sample size calculation. Assuming a common standard deviation of 2.5, a difference in the duration of SN in Cycle 1 of at least 2 days between the treatment groups, a sample size of 28 per arm was required to have 90% power to detect the assumed treatment effect. For occurrence of SN, assuming the event rate was 45% for placebo group, to detect an absolute reduction of 37% by trilaciclib group with 90% power would require a sample size of at least 29 per arm. Thus, 30 per arm was needed to ensure 90% power to detect assumed treatment effect for DSN in Cycle 1 and occurrence of SN. All calculations were carried out using the POWER procedure in SAS®, Version 9.4 procedure in SAS®, Version 9.4 or higher. The results from endpoints that were commonly collected at Part 1 and part 2 are presented together in this report. The posted results represent the final results of Study G1T28-03, a Phase 1b/2a safety and pharmacokinetic (PK) study of trilaciclib (G1T28) in patients with previously treated extensive-stage small cell lung cancer (SCLC) receiving topotecan chemotherapy in the second/third-line (2/3L) setting. The final myelopreservation efficacy results for both parts and exposure for Part 1 are from database lock 1 (data cut-off \[DCO\] for Primary Completion Date \[PCD\] 28 September 2018). The final anti-tumor efficacy (BOR, DOR, PFS) for both parts, final overall survival for Part 1 and exposure data from Part 2 are from a second database lock 2 (DCO 31 May 2019) and the final overall survival for Part 2 and safety (adverse events) are through the end of the study on October 4, 2021 which resulted in the final database lock (DCO 01 Nov 2021). The maximum time frames provided reflect the time from when the first patient could be evaluated for an endpoint (ie. date of first dose of first patient) to the time when the data from both parts presented for that endpoint was considered final.

Patients will be randomly assigned (1:1) to receive placebo or trilaciclib on Days 1 and 2 administered intravenously (IV) prior to FOLFOXIRI/bevacizumab in 14-day cycles for up to 12 cycles (Induction). Following completion of Induction, patients will continue in Maintenance, where they will receive trilaciclib or placebo per randomization allocation at study entry. Trilaciclib/placebo will be administered prior to infusional-5FU/leucovorin/bevacizumab at the same dose and schedule used during Induction. The patient may continue to receive treatment on study until disease progression, unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the trial, whichever occurs first. Treatment cycles will occur consecutively without interruption, except when necessary to manage toxicities or for administrative reasons.