Myeloprotection effects of trilaciclib in Chinese patients with extensive stage small cell lung cancer (ES-SCLC) receiving chemotherapy—a real-world study

Introduction

As of 2020, lung cancer accounted for 815,563 new cases and 714,699 deaths in China (1). Small cell lung cancer (SCLC), as a histological subtype of lung cancer, accounts for about 15% to 25% of patients with lung cancer, and extensive stage small cell lung cancer (ES-SCLC) accounts for about 70% at initial presentation. Standard therapies for treating naïve ES-SCLC consist of platinum-based chemotherapy, either alone or in combination with immune checkpoint inhibitors (e.g., atezolizumab or durvalumab, etc.) (2-4), while patients who no longer benefit from first line therapy are then treated with topotecan (TPT)-based therapy monotherapy (2023 guidelines of Chinese Society of Clinical Oncology-SCLC).

Chemotherapy-induced myelosuppression (CIM) is a common and major adverse event observed during anti-cancer treatment, leading to complications such as neutropenia, anemia, and thrombocytopenia. Patients with myelosuppression are more susceptible to infections, sepsis, bleeding, reductions in health-related quality of life, frequent hospitalizations, and even death (5-8). Published studies have shown that CIM (grade 3/4 neutropenia: 15.6–93.8%, anemia: 0–33.3%, and thrombocytopenia: 0–33.3%) (9-26) leads to dose reduction or delay of chemotherapeutic agents in patients with SCLC treated with carboplatin/cisplatin in combination with etoposide or TPT among Asian populations, including China, South Korea, and Japan. Limitation in the dose intensity of chemotherapeutic agents can influence the antitumor efficacy of chemotherapy. Therefore, CIM remains a major side effect in patients with SCLC requiring immediate attention. The current therapies can only provide symptomatic relief but do not mitigate or prevent CIM before chemotherapy. However, such therapies also result in undesirable adverse events. For instance, granulocyte colony-stimulating factor (G-CSF) can reduce neutropenia-related infections, but it increases the rate of bone pain (27). Red blood cell (RBC) transfusions carry risks of infections, whereas erythrocyte-stimulating agents (ESAs) can increase the risk of cardiovascular events, thus increasing the treatment burden. Therefore, there is an urgent need for other therapies to reduce the incidence of CIM after chemotherapy.

Trilaciclib is a highly selective and novel reversible cyclin dependent kinase 4/6 (CDK4/6) small molecule inhibitor that transiently maintains hematopoietic stem and progenitor cells in gap zero or one (G0/G1) phase in bone marrow (28). Therefore, for CDK4/6-independent tumors, such as SCLC, the combination of trilaciclib and chemotherapy can play a role in protecting the bone marrow without antagonizing the antitumor efficacy of concurrent chemotherapy. Based on the data from the G1T28-02 (phase 1b/2a) (29), G1T28-03 (phase 1b/2a) (30), G1T28-05 (phase 2) (31) trials, trilaciclib have been approved for the prophylactic use in patients with ES-SCLC receiving platinum/etoposide (EP) or TPT-based regimens (28). The administration of trilaciclib before EP or TPT regimen provides clinically meaningful protection in myelosuppression endpoints. Some experts recommend additional studies to confirm the clinical benefits of trilaciclib (32-36). There is lack of real-world data of trilaciclib in Chinese population. Therefore, to evaluate the safety and efficacy of trilaciclib in Chinese patients, a real-world study was carried out at the International Medical Tourism Advance Area of Hainan free trade port, Boao Hope city, Hainan Province. The State Council and Hainan provincial government has authorized medical institutions in the Le City Pilot Zone to treat patients with innovative drugs and medical devices that have been approved by either Food and Drug Administration or European Medical Agency but not approved by Center for Drug Evaluation (CDE), and subsequently utilize the real-world data generated to transform into one of the evidences for clinical evaluation, thus accelerating the list of foreign innovative products in China. The accelerated approval of pilot drugs by using Hainan free trade port, Boao Hope city clinical real-world data is significant to speed up the accessibility of global innovative drugs for clinical use in China. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-893/rc).

Methods

Study design

This was a single-arm, noninterventional study conducted between August 2021 and December 2022. The data were collected from 28 days before the first cycle of the intended chemotherapy regimen (EP or TPT systemic chemotherapy) until death, withdrawal, loss to follow-up, or termination of the study. The study was conducted in accordance with the ethical standards of the Declaration of Helsinki (as revised in 2013). This study was approved by the ethics committee of the main study center at Hainan General Hospital, Haikou city, China (ethical approval No. 2021 No 017) and informed consent was obtained from all individual participants.

Patients eligibility criteria

Eligible patients were aged ≥18 years and with a confirmed diagnosis of ES-SCLC. Patients were considered eligible if they were treated with either the combination of trilaciclib and EP regimen or trilaciclib and TPT. Patients with ES-SCLC who were on prior trilaciclib therapy or plan to use trilaciclib were included.

Treatment regimens

In all enrolled patients, trilaciclib was administered by intravenous (IV) infusion for 30 min at a dose of 240 mg/m², for 4 hours before chemotherapy, followed by the administration of either EP or TPT to the patient. The doses of EP or TPT were based on local practice of physicians. Patients were treated until progression, unacceptable toxicity, withdrawal of consent, or discontinuation by the patient or investigator. No dose modifications of trilaciclib were allowed. Additionally, 18 enrolled patients were treated with trilaciclib plus chemotherapy combined with anti-programmed cell death ligand-1 [anti-PD-(L)1] antibodies.

Procedure and endpoints

The primary endpoint was the incidence of severe neutropenia (SN), and the secondary endpoints included the incidence of grade 3/4 hematological toxicities, IV or oral antibiotics use, G-CSF use, platelet infusion, and RBC transfusion at week five or later. The tumor assessments were conducted by the investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria (37).

Sample size and statistical analysis

This study was a real-world study, and its sample size (30 enrolled patients) was not determined by the statistical hypothesis testing. Generally, a sample size of 30 provides a good asymptotic normality for continuous data. And for categorical data, such as incidence of SN, it also provided 79% probability of having at least one SN when receiving EP regimen [assuming 5.1% of incidence of SN as G1T28-02 (29) study reported] and provided 98% probability of having at most 17 SN when receiving TPT [assuming 40.6% of incidence of SN as G1T28-03 (30) study reported].

The full-analysis set included all 30 patients who received at least 1 dose of the study drug, which was used for myeloprotection and progression-free survival (PFS)/overall survival (OS) analysis. Safety analysis set included all patients who received at least one dose of the study drug. Response evaluable analysis set that was used for tumor response endpoints was conducted in patients who had measurable disease at the baseline tumor assessment and had at least one post-baseline tumor assessment.

Primary endpoint and other secondary myeloprotection endpoints were calculated as categorical variables. For duration of response (DOR), PFS and OS endpoints, the median time to event was estimated using the Kaplan-Meier method. All data analyses were conducted after the end of the study (database lock December 30, 2022). Statistical software SAS version 9.4 was used to conduct the data analyses.

Results

Patient disposition

Of the 30 patients enrolled, 26 received EP and 4 TPT. Twenty-four patients were treated with the first-line chemotherapy, and two patients were treated with ≥ two lines of therapy in the EP regimen group. All the patients in the TPT regimen group were previously treated with ≥ two lines of therapy. The mean age of the patients was 65±8.04 years, with 26 (86.7%) patients being male patients. Approximately, 93.3% (28/30) of patients had Eastern Cooperative Oncology Group performance score (38) of zero to two, and 22 (73.3%) patients had smoking history. Thirteen (46.4%) patients had IVB stage, 11 (39.3%) patients had IVA stage, 2 (7.1%) had IIIC stage, 1 (3.6%) patient had IIIB stage, and 1 (3.6%) patient had IIIA stage (Table 1).

Myeloprotective effect

The median cycles of trilaciclib treatment were six cycles in the EP group and three cycles in the TPT group.

The incidence of SN was 2/30 (6.7%) in the overall population, with 1/26 (3.8%) in the EP group and 1/4 (25%) in the TPT group.

The incidence of grade three hematological toxicities was 9/30 (30%), including 8/30 (26.7%) patients with decreased neutrophil count, 5/30 (16.7%) patients with anemia, 1/30 (3.3%) patients with decreased platelet count. The incidence of grade three hematological toxicities in the EP group was 5/26 (19.2%), including 5/26 (19.2%) patients with decreased neutrophil count and 2/26 (7.7%) patients with anemia. Similarly, the incidence of grade three hematological toxicities in the TPT group was 4/4 (100%), including 3/4 (75%) patients with decreased neutrophil count, 3/4 (75%) patients with anemia, and 1/4 (25%) patients with decreased platelet count. The incidence of grade 4 hematological toxicities was 5/30 (16.7%), including 2/30 (6.7%) patients with decreased neutrophil count, 2/30 (6.7%) patients with decreased platelet count. The incidence of grade 4 hematological toxicities in the EP group was 3/26 (11.5%), including 1/26 (3.8%) patients with decreased neutrophil count and 1/26 (3.8%) patients with decreased platelet count. The incidence of grade four hematological toxicities in the TPT group was 2/4 (50%), including 1/4 (25%) patients with a decreased neutrophil count and 1/4 (25%) patients with a decreased platelet count.

Twenty percent of patients received IV or oral antibiotics, with 4/26 (15.4%) in the EP group and 2/4 (50%) in the TPT group. G-CSF was administered in a total of 14/30 (46.7%) patients, with 11/26 (42.3%) patients in the EP group and 3/4 (75%) in the TPT group. Patients in the EP group had a reduced use of platelet transfusion (0/26, 0% vs. 1/4, 25%), interleukin-11 (0/26, 0% vs. 2/4, 50%), thrombopoietin (TPO) (1/26, 3.8% vs. 2/4, 50%), and ESA (3/26, 11.5% vs. 1/4, 25%) compared with the TPT group. Of the 30 patients, 1/30 (3.3%) received RBC transfusion in the EP group at week 5 or later (Table 2).

Adverse events

A total of 27 (90%) patients had at least one treatment-emergent adverse event (TEAE). Thirteen (43.3%) patients had ≥ grade three TEAEs, 9 (34.6%) patients in the EP group and 4 (100%) patients in the TPT group, and none of the event was related to trilaciclib. Four (13.3%) patients experienced TEAEs leading to permanent discontinuation of trilaciclib, and 3 (10%) patients experienced TEAEs leading to permanent discontinuation of chemotherapy (all not related to trilaciclib and related to chemotherapy). Thirteen (43.3%) patients experienced TEAEs leading to chemotherapy dose reduction, and no patients experienced TEAEs leading to dose reduction of trilaciclib. Nine (30%) patients had at least one serious adverse event (SAE) during the treatment, and none were related to trilaciclib. Four (13.3%) patients had treatment-emergent SAEs related to chemotherapy drugs, including 1 patient (3.8%) in the EP group and 3 patients (75%) in the TPT group. One (3.3%) patient had a TEAE leading to death (multiple organ dysfunction syndrome) in the TPT group and not related to either trilaciclib or chemotherapy (Table 3). No adverse events of special interest occurred. TEAEs with an incidence of ≥20% included increased neutrophil count (80%), increased white blood cell count (63.3%), decreased neutrophil count (56.7%), anemia (50%), decreased white blood cell count (46.7%), and decreased platelet count (26.7%).

Antitumor efficacy

The overall unconfirmed objective response rate (ORR) was 72.4% [21/29; 95% confidence interval (CI), 52.8–87.3%] and disease control response (DCR) was 96.6% (28/29; 95% CI, 82.2–99.9%). In the EP group, the unconfirmed ORR was 80.8% (21/26; 95% CI, 60.6–93.4%), DCR was 96.2% (25/26; 95% CI, 80.4–99.9%), and the median DOR was 6.8 months (95% CI, 5.1–9.2) with 83.3% (20/24; 95% CI, 62.6–95.3%), and the median DOR was 6.9 months (95% CI, 5.1–9.2) in the first-line patients. In the TPT group, the unconfirmed ORR was zero, as none of the patients had a response and DCR was 100% (3/3; 95% CI, 29.2–100%) (Table 4).

The median PFS was 7.9 months (95% CI, 5.1–9.4) in overall population. The median PFS was 8.2 months (95% CI, 7.0–10.5) and 3.5 months [95% CI, 0.7–not reached (NR)] in the EP group and TPT group, respectively. The median OS was 11.8 months (95% CI, 8.9–NR), with 12.3 months (95% CI, 9.4–NR) in the EP group and 4.2 months (95% CI, 0.7–NR) in the TPT group (Table 5 and Figure 1).

Figure 1 Kaplan-Meier curves for (A) PFS and (B) OS. EP, platinum/etoposide; LCL, lower confidence limit; OS, overall survival; PFS, progression-free survival; TPT, topotecan; UCL, upper confidence limit.

Discussion

In April 2022, an informal interim analysis (34) was conducted after 14 patients with ES-SCLC were enrolled in this study, and the occurrence of SN was 6.7%, the occurrence of TEAEs was 93.3%, there were no grade three or higher TEAE associated with trilaciclib, SAE, or TEAE resulting in death. In July 2022, CDE approved the conditional marketing of trilaciclib in China based on the clinical data of the global clinical trials that led to the approval by the United States Food and Drug Administration, the safety run-in data of the Chinese Phase three study (39), and the interim analysis data from this real-world study (40) conducted at Boao, Hainan Province. These data supported the priority review and approval of trilaciclib in China.

The results of this real-world study showed that trilaciclib decreased the incidence of CIM when administered in Chinese patients receiving chemotherapy regimens for ES-SCLC. To the best of our knowledge, this is the first real-world study of trilaciclib in Chinese patients with ES-SCLC. Previously, the Phase three TRACES study conducted in Chinese patients with ES-SCLC receiving either EP or TPT therapy reported that the administration of trilaciclib to patients before chemotherapy could significantly shorten the first cycle duration of SN after the treatment (0 vs. 2 days; P=0.0003) and the occurrence of SN [9.8% vs. 47.6%, adjusted relative risk (aRR): 0.188; 95% CI, 0.069–0.513]. At the same time, it reduced the incidence of febrile neutropenia (FN) event (per week) (0.001 vs. 0.01; aRR: 0.146; 95% CI, 0.018–1.188) and the incidence of grades 3 to 4 hematological toxicity event (per week) (0.29 vs. 0.42; aRR: 0.680; 95% CI, 0.467–0.990) (39). Approval of this drug was based on three randomized, Phase two, placebo-controlled studies (29-31). All of these three studies met their primary endpoints, which reported a reduction in the duration of SN and the rate of SN in patients receiving trilaciclib prior to the standard chemotherapy regimens in SCLC (29-31).

Daniel et al. (31) found that the myeloprotection endpoints with trilaciclib in the EP group were superior to the placebo group. As the frequency of follow up of hematological toxicities was lower in our study than in the studies conducted globally, the lowest levels of the neutrophil count, hemoglobin count, and platelet count may not be followed up, which may lead to a reduction of incidence of G-CSF, TPO, ESA, platelet transfusion, and blood transfusion. Similarly, the incidence of SN, grade 3/4 neutrophil count, grade 3/4 platelet count, and FN were lower (numerically) in the TPT group than in a study conducted by Hart et al. (30), however, the data of other myeloprotection endpoints in that study (30) were numerically better than our study, possibly due to the limited sample size and the lower frequency follow up of hematological parameters in our study (Tables S1,S2).

Furthermore, the 18 patients treated with trilaciclib and chemotherapy in combination with PD-(L)1 is the first study in China which involves treatment with PD-(L)1 among SCLC patients. The results showed a consistent trend in myeloprotection endpoints with published studies; therefore, it can be speculated that the addition of PD-(L)1 does not influence the protective effect of trilaciclib on CIM in Chinese patients with ES-SCLC, confirming that trilaciclib prevents CIM in Chinese patients with ES-SCLC, and the supporting indication is that the use of trilaciclib before PD-(L)1 combined with EP/TPT regimen for ES-SCLC can reduce the incidence of CIM.

A total of 27 (90%) patients had at least 1 TEAE, including ≥ grade 3 TEAEs, ≥ grade 3 hematological TEAEs, TEAEs leading to permanent discontinuation, and so on, which are consistent with the results of the TRACES study (39) and global studies (29-31). There were no TEAEs of ≥ grade 3, TEAEs of special interest, or FN associated with trilaciclib. Overall, no new safety signals were identified in patients with ES-SCLC treated with trilaciclib in combination with chemotherapy and PD-(L)1, and the results support the use of trilaciclib in combination with chemotherapy and PD-(L)1 in the Chinese ES-SCLC population.

Eighteen (60%) patients in the EP group of this study were also treated with PD-(L)1, and only numerically the data in this study were better than in the experimental and control groups of the G1T28-05 study (30), possibly because of the limited sample size, as well as the lower proportion of patients with brain metastases (15.4%) in the experimental group of the G1T28-05 study (27.8%) (30). In addition, the frequency of follow-up for the tumor assessment in this study is approximately every 2 months, with a longer interval, which may affect the median PFS. However, on the other hand, the median OS may be affected if no subsequent antitumor treatments are followed up. For patients in the TPT group, the median PFS and median OS were consistent with the trends from the experimental and control arms of the G1T28-05 study (30); however, due to smaller sample size, the antitumor tumor response results need to be further explored. Overall, the use of trilaciclib before chemotherapy did not reduce the antitumor efficacy of patients (29,30).

There are a few limitations which warrant mention. Firstly, as this is a non-interventional study, with lower prespecified follow-up frequency than the Phase two interventional study and some patients started the trilaciclib combination therapy in the middle of the chemotherapy cycle. As a result, the duration of severe neutropenia of cycle one, which was the primary endpoint in TRACES study, was not measurable and cannot be compared with other four interventional study results. Secondly, the sample size is small, with only 26 patients enrolled in EP group and four patients in TPT group, which might result in a higher incidence of AEs in this study compared with studies having larger sample sizes. Lastly, information about the subsequent antitumor therapies was not collected of the patients enrolled in this study, which may affect the median OS, thus the antitumor efficacy needs to be further explored.

Mecapegfilgrastim, a long-acting recombinant human granulocyte colony-stimulating factor, can lower the risk of chemotherapy induced neutropenia (CIN) in patients with cancer. As trilaciclib is not a neutrophil-specific agonist, there is no perspective head-to-head study specifically comparing these two agents. However, there is one real world study conducted in China that compared the effectiveness of trilaciclib and mecapegfilgrastim in reducing the incidence of CIM. This real-world study (41) relying on electronic medical record data from 57 hospital information systems at the National Cancer Center (NCC) covered the time period from January 2018 to December 2023. Patients with ES-SCLC undergoing EP therapy were selected from the NCC database. Patients using trilaciclib or mecapegfilgrastim were divided into two groups according to the real-world clinical practice. Propensity score matching was applied to balance demographic and clinical characteristics before comparison was done between the groups.

After matching, it was observed that each group consisted of 160 patients with no significant differences in matched variables. Compared to mecapegfilgrastim, trilaciclib reduced incidence of grade 1–4 CIM 33% (55.63% vs. 83.13%, P<0.001), grade 3–4 CIM 59% (6.88% vs. 16.88%, P=0.005), grade 1–4 CIN 38.5% (10% vs. 16.25%, P=0.09) and grade 3–4 CIN 75% (1.25% vs. 5.0%, P=0.10). Additionally, it was also observed that trilaciclib reduced grade 1–4 CRA 30.6% (50% vs. 80.63%, P<0.0001). Moreover, trilaciclib led to lower usage rates of recombinant human thrombopoietin (2.5% vs. 13.75%, P<0.001), recombinant interleukin-11 (1.25% vs. 15%, P<0.001), erythropoiesis-stimulating agents (4.4% vs. 8.9%, P=0.23), and transfusions (3.13% vs. 10%, P=0.02).

Overall, when compared with mecapegfilgrastim, trilaciclib reduced the incidence of multilineage CIM and the use of other CIM-related measures in patients receiving etoposide combined with platinum-based chemotherapy, showed a significant myeloprotective effect and reduction in the utilization of medical resources.

Conclusions

This was the first real-world study that evaluated the myeloprotection endpoints and antitumor efficacy of trilaciclib in China. The available data showed that the safety of trilaciclib in combination with chemotherapy and anti-PD-(L)1 antibodies was well tolerated in Chinese patients with ES-SCLC, and the effect of CIM prevention was consistent with that observed in the TRACES study data, global clinical studies, and Chinese phase three registration study. The study thus supports the use of trilaciclib at a dose of 240 mg/m² to reduce the incidence of myelosuppression in Chinese patients with ES-SCLC.

Acknowledgments

The authors would like to acknowledge Anwesha Mandal and Ramandeep Singh (PhD) of Indegene Limited, India for their editorial support.

Funding: This work was supported by Hainan Simcere Zaiming Pharmaceutical Co., Ltd., and State Key Laboratory of Neurology and Oncology Drug Development.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-893/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-893/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-893/prf

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.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the ethical standards of the Declaration of Helsinki (as revised in 2013). This study was approved by the ethics committee of the main study center at Hainan General Hospital, Haikou city, China (ethical approval No. 2021 No 017) and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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