Myeloprotection with trilaciclib in Chinese patients with extensive-stage small cell lung cancer

Small cell lung cancer (SCLC) comprises about 15% of all lung cancers and is characterized by its highly aggressive nature with rapid doubling time and the development of early metastasis. At diagnosis, two-thirds of patients with SCLC have extensive stage disease (ES-SCLC), which is defined as tumors spread beyond an area that can be encompassed within a single radiation field or tumors with distant metastasis (1,2). Patients are generally old (age >65 years) with a prior history of smoking and multiple comorbidities. The mainstay of first-line therapy for ES-SCLC involves platinum-based chemotherapy and immunotherapy. Unfortunately, most patients do not have a durable response to treatment and most relapse within 5 to 6 months of treatment. Topotecan, lurbinectedin and more recently tarlatamab are systemic treatment options for second line treatment (2). Many patients only have a modest response in the relapsed setting and overall, prognosis is poor with a median survival duration of ~1 year for patients with extensive stage disease (3).

Unfortunately, even though treatment has been evolving for patients with ES-SCLC, current therapies are cytotoxic to hematopoietic stem and progenitor cells in the bone marrow and associated with chemotherapy-induced myelosuppression (CIM). This manifests as anemia, neutropenia and thrombocytopenia with an increased risk of fatigue, infection and bleeding. Patients with ES-SCLC are particularly vulnerable to these side effects given their advanced age and multiple comorbidities. A recent study reported that over 55% of patients with ES-SCLC experienced CTCAE (Common Terminology Criteria for Adverse Events) v5 grade ≥3 myelosuppressive hematologic adverse events (HAEs) after receiving chemotherapy in community practices (4). The toxicities of CIM cause major morbidity with a reduction in patient’s quality of life, mortality and cost among patients with ES-SCLC. CIM also leads to dose modifications and dose delays, which can compromise potential treatment outcomes in patients with ES-SCLC. Treatment for CIM is currently supportive care interventions that are individualized for single hematopoietic lineages. These interventions consist of granulocyte-colony-stimulating factors (G-CSFs), erythropoiesis-stimulating agents (ESAs), or red blood cell (RBC) and/or platelet transfusions, which are administered reactively and have their own risks of adverse reactions including bone pain, thrombosis and transfusion reactions (5).

Myeloprotective therapy with trilaciclib offers a novel approach to the management of CIM. Trilaciclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor that is administered intravenously prior to chemotherapy and transiently arrests hematopoietic stem cells and progenitor cells in the G1 phase of the cell cycle to help protect them during chemotherapy (6). Tumor cells in SCLC do not rely on CDK 4/6 for replication due to the obligate loss of the retinoblastoma protein and are not affected by trilaciclib (7). Trilaciclib has also been shown to enhance antitumor responses in preclinical models by enhancing the sensitivity to immune checkpoint inhibitors (8).

Trilaciclib was approved by the Food and Drug Administration (FDA) in 2021 to decrease the incidence of CIM in patients with ES-SCLC after its myeloprotective effects were demonstrated in three randomized phase 2 clinical trials (9-11). These multicenter global trials enrolled 242 patients with ES-SCLC in the United States and Europe (12). The majority of patients were White, with a median age of 64 years, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, prior smoking history and no presence of brain metastasis (12). The first trial was a proof-of-concept study to evaluate the administration of trilaciclib 240 mg/m² in treatment-naïve patients receiving etoposide and platinum (the standard of care at the time) and the second and third trials expanded this investigation to include treatment-naïve patients receiving etoposide, platinum and programmed death ligand-1 (PD-L1) inhibitors and previously treated patients receiving topotecan (9-11).

A pooled analysis of the three studies demonstrated that myeloprotection from trilaciclib decreased hematologic toxicity (CTCAE v4.03 ≥ grade 3 HAEs) with a reduction in the use of supportive care interventions and CIM-related hospitalizations (12). All three studies as their primary endpoint showed a decrease in the occurrence of severe neutropenia (SN) during the treatment period (defined as an absolute neutrophil count <0.5×10⁹ cells/L; 11.4% patients in trilaciclib group vs. 52.9% patients in placebo group; P<0.001) and an improvement in the mean duration of sustained neutropenia (DSN) in cycle 1 (0 days in trilaciclib group vs. 4 days in placebo group; P<0.001), an endpoint highly predictive of the occurrence of neutropenic fever and the risk of infection. There was also a notable decrease in the administration of G-CSF, febrile neutropenia, grade 3 or 4 anemia and RBC transfusions. Surveys assessing patient-reported outcomes (PROs) indicated that the reduction in hematologic toxicity led to significant improvements in health-related quality of life (HRQoL), particularly in patients’ physical and functional well-being. The most common side effects observed with the use of trilaciclib for a median duration of 4 cycles were fatigue (11.5% patients) and nausea (10.7% patients), which were low-grade and did not result in dose modification (12).

The current study investigated the effects of trilaciclib in 95 Chinese patients with ES-SCLC, including both treatment-naïve and previously treated individuals (13). Most patients were male with ECOG PS of 0–1 and prior smoking history; the median age of patients was 62 years. Almost a third of patients (34.9%) had brain metastases at baseline; 55.4% of patients were treatment-naïve and 44.6% of patients were previously treated. Similar to the first proof of concept study of trilaciclib, the safety of 240 mg/m² dose was first confirmed in an open-label safety run-in. Patients were then randomized to trilaciclib or placebo before chemotherapy (etoposide/carboplatin for treatment-naïve patients and topotecan for previously treated patients). The use of trilaciclib in this study similarly resulted in a statistically significant decrease in the mean DSN in cycle 1 (0 days in trilaciclib group vs. 2 days in placebo group; P=0.0003), the occurrence of SN [9.8% in trilaciclib group vs. 47.5% in placebo group; 95% confidence interval (CI): 0.069–0.513] and the occurrence of febrile neutropenia (2.4% in trilaciclib group vs. 16.7% in placebo group; 95% CI: 0.017–0.905). A trend for decreased incidence of CTCAE v5 grade 3 or 4 anemia and ESA use was also seen. No new side effects related to trilaciclib were observed (13).

Even though trilaciclib has uniformly shown effectiveness in reducing CIM in clinical trials, its incorporation into clinical practice has been precluded by the limited evaluation of its real-world effectiveness (14). The small sample size of prior clinical trials limits their generalizability to patients that are older, female and have an ECOG PS >1 (12). A cost-efficiency analysis comparing the cost of trilaciclib with individual lineage-specific interventions estimated mean cost savings ranging from $646.36 (average sales price) to $7,397.69 (whole acquisition cost) per patient with the use of trilaciclib, but these have yet to be validated in a real-world setting (15). Evaluation of the trilaciclib with larger sample sizes will be helpful to corroborate the existing evidence of its clinical efficacy and to better understand the impact of its use in reducing overall healthcare costs and improving HRQoL benefit for patients (14).

The limited sample size of prior clinical trials has also limited the evaluation of the antitumor effects of trilaciclib (9-11). Preclinical data has shown that the addition of trilaciclib to chemotherapy plus immunotherapy regimens enhanced antitumor responses by modulating T-cell activation and proliferation and the tumor immune microenvironment (8). In theory, trilaciclib also has the potential to improve antitumor efficacy by maintaining the dose intensity of chemotherapy (8). Clinical trials have not corroborated this benefit and have shown similar tumor response rates, progression-free survival and overall survival between patients treated with trilaciclib and patients treated with placebo (9-12,15). Although, this does show that the myeloprotective benefits of trilaciclib do not compromise the efficacy of standard-of-care treatment regimens, no additional antitumor benefit was seen with trilaciclib use in prior clinical trials (9-12,16). This may reflect that the highly aggressive nature of SCLC limits the responsiveness to increasing relative dose intensity (RDI) of chemotherapy or to immune modulation (17,18). Individual studies were also not powered to detect differences in antitumor efficacy. Larger studies are therefore necessary to better investigate this relationship.

The use of trilaciclib in clinical trials was also associated with protection of non-hematologic cell lines (9-11). A pooled analysis of the first three clinical trials evaluating trilaciclib showed that the rate of alopecia was almost halved with the use of trilaciclib (13.1% with trilaciclib vs. 25.4% vs. placebo) (12). A favorable trend was also seen with trilaciclib reducing some gastrointestinal adverse effects (12). These findings suggest further benefit of trilaciclib in improving patient-related outcomes during chemotherapy. Additional evaluation of these associations could lead to decreased emotional distress of patients that are otherwise limited by the aggressive nature of their cancer.

Overall, trilaciclib shows promise as a novel treatment for the prevention of CIM in patients with ES-SCLC. Clinical trials have shown that administering trilaciclib before chemotherapy provides myeloprotection, reducing the hematologic toxicity associated with chemotherapy, lowering the need for CIM-related supportive care interventions and hospitalizations, and improving patients’ HRQoL. However, data on the real-world effectiveness of trilaciclib, its antitumor efficacy and its potential to protect non-hematologic cell lines during chemotherapy remain limited. Further studies are therefore necessary to more extensively explore the potential clinical benefits of trilaciclib.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-114/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-114/coif). The authors have no conflicts of interest to declare.

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