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Effects of Trilaciclib on Chemotherapy-Induced Myelosuppression and Patient-Reported Outcomes in Patients with Extensive-Stage Small Cell Lung Cancer: Pooled Results from Three Phase II Randomized, Double-Blind, Placebo-Controlled Studies
Address for correspondence: Jared Weiss, Division of Medical Oncology, Linebergery Cancer Center at the Univeristy of North Carolina, 101 Manning Drive, Chapel Hill, NC, 27514.
Chemotherapy-induced myelosuppression (CIM) and its sequalae cause significant side effects and harm to quality of life. Trilaciclib is an intravenous CDK4/6 inhibitor that is administered prior to chemotherapy to protect hematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection).
Patients and Methods
Data from three randomized, double-blind, placebo-controlled studies (NCT02499770, NCT03041311, and NCT02514447) were pooled to evaluate the effects of trilaciclib administered prior to standard-of-care chemotherapy (first-line etoposide plus carboplatin [E/P], first-line E/P plus atezolizumab, and second-/third-line topotecan) in patients with extensive-stage small cell lung cancer (ES-SCLC). The primary endpoints were duration of severe neutropenia (absolute neutrophil count < 0.5 × 109 cells/L) in cycle 1 and occurrence of severe neutropenia. Additional prespecified endpoints further assessed the effect of trilaciclib on myeloprotection, health-related quality of life (HRQoL), antitumor efficacy, and safety.
Results
Of 242 randomized patients, 123 received trilaciclib and 119 received placebo. Compared with placebo, administration of trilaciclib prior to chemotherapy resulted in significant decreases in most measures of multilineage CIM. The reduction in hematologic toxicity translated into the reduced need for supportive care interventions and hospitalizations due to CIM or sepsis and improvements in HRQoL domains related to the protected cell lineages, including fatigue, physical wellbeing, and functional wellbeing. Antitumor efficacy was similar for patients receiving trilaciclib or placebo.
Conclusion
Administering trilaciclib prior to chemotherapy resulted in clinically meaningful reductions in CIM and its consequences and improved patient HRQoL, with no impact on the antitumor efficacy of three individual chemotherapy regimens used in the first- or second-/third-line treatment of ES-SCLC.
Standard-of-care (SoC) treatments for patients with extensive-stage small cell lung cancer (ES-SCLC) cause significant side effects, with chemotherapy-induced myelosuppression (CIM) being one of the most common adverse events (AEs) associated with carboplatin plus etoposide (E/P), E/P plus atezolizumab (E/P/A), and second-line topotecan.
Although CIM may be culturally accepted as a consequence of cytotoxic therapy, it continues to cause real suffering. As patients with ES-SCLC are often elderly
National Cancer Institute. SEER Cancer Statistics Review (CSR) 1975-2016. Available at: https://seer.cancer.gov/csr/1975_2016/. Accessed: April 12, 2021.
they can be more vulnerable to the consequences of CIM, including infection, sepsis, bleeding, and fatigue, all of which have significant negative effects on health-related quality of life (HRQoL).
The need to refrain from social contact due to the high risk of infection can leave patients with chemotherapy-induced neutropenia feeling isolated and less active,
Despite fatigue, which can result from disease- and/or treatment-related factors, being one of the most common symptoms reported by oncology patients, it is frequently overlooked by physicians because no effective therapy currently exists, most likely due to its multifactorial etiology.
Currently, CIM is managed with dose delays and reductions, in addition to the supportive use of granulocyte-colony-stimulating factors (G-CSFs), erythropoiesis-stimulating agents (ESAs), or red blood cell (RBC) and/or platelet transfusions.
The wide application of dose modifications, dose delays, or treatment discontinuation contributes to a reduction in the relative dose intensity (RDI) of chemotherapy.
Furthermore, supportive care interventions are often administered reactively, are specific to single hematopoietic lineages (neutrophils, RBCs, or platelets), and impart their own set of risks for adverse reactions; these include bone pain with G-CSFs,
Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review.
Lessons from the past: long-term safety and survival outcomes of a prematurely terminated randomized controlled trial on prophylactic vs. hemoglobin-based administration of erythropoiesis-stimulating agents in patients with chemotherapy-induced anemia.
As a result, there is a need for additional interventions to augment the current SoC.
Trilaciclib (G1 Therapeutics, Inc., Research Triangle Park, NC) is an intravenous (IV) CDK4/6 inhibitor indicated to reduce the incidence of CIM in adult patients when administered prior to an E/P- or topotecan-containing regimen for ES-SCLC. When administered within 4 hours prior to the start of chemotherapy, trilaciclib transiently arrests hematopoietic stem and progenitor cells in the G1 phase of the cell cycle during chemotherapy exposure, simultaneously preserving or protecting multiple cell lineages from the cytotoxic effects of chemotherapy.
Because SCLC tumor cells replicate independently of CDK4/6 due to the obligate loss of the retinoblastoma protein, trilaciclib is expected to affect only CDK4/6-dependent host cells, not tumor cells.
The effects of administering trilaciclib prior to chemotherapy have been investigated in three randomized, placebo-controlled, double-blind, phase II clinical studies in patients with ES-SCLC.
Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.
Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: a multicentre, randomised, double-blind, placebo-controlled phase II trial [e-pub ahead of print].
Myelopreservation with trilaciclib in patients receiving topotecan for small cell lung cancer: results from a randomized, double-blind, placebo-controlled phase II study.
All three studies included clinically relevant endpoints across multiple hematopoietic lineages, including hematologic AEs, laboratory values, and use of supportive care interventions. Each clinical study included analyses of standard antitumor efficacy evaluations and validated patient-reported outcome (PRO) measures to evaluate whether trilaciclib could improve HRQoL during chemotherapy treatment. In this analysis, data from all three studies were pooled to evaluate the overall treatment effect of trilaciclib with regard to myeloprotection, safety, HRQoL, and antitumor efficacy.
Patients and Methods
Study Design
This was a retrospective, pooled analysis of data from the randomized, double-blind, placebo-controlled, phase II portions of three global, multicenter studies: G1T28-05 (NCT03041311), G1T28-02 (NCT02499770), and G1T28-03 (NCT02514447). In each study, eligible patients were enrolled from sites in the United States and Europe if they were ≥18 years of age and had confirmed ES-SCLC, measurable disease according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2, and adequate organ function. Details on the patient populations and treatment schedules of the three studies are provided in Table 1.
Table 1Overview of Trilaciclib Clinical Studies Included in Pooled Analysis
Study
Patient Population
Treatment Schedule
G1T28-05 (NCT03041311)
Newly diagnosed (first-line) ES-SCLC
Trilaciclib 240 mg/m2 IV QD prior to chemotherapy on days 1-3 of each 21-day E/P/A IV cycle
E/P/A therapy was comprised of standard-of-care etoposide (100 mg/m2) IV on days 1, 2, and 3 and carboplatin AUC 5 (calculated via the Calvert formula, maximum 750 mg) on day 1, with the addition of atezolizumab (1200 mg) IV on day 1 of each 21-day chemotherapy cycle. Maintenance treatment was comprised of atezolizumab (1200 mg) IV on day 1 of each 21-day cycle; trilaciclib and placebo were not administered during maintenance.
for up to four cycles followed by atezolizumab monotherapy (without trilaciclib) Q21D Placebo IV QD prior to chemotherapy on days 1-3 of each 21-day E/P/A IV cycle for up to four cycles followed by atezolizumab monotherapy (without placebo) Q21D
G1T28-02 (NCT02499770)
Newly diagnosed (first-line) ES-SCLC
Trilaciclib 240 mg/m2 IV QD prior to chemotherapy on days 1-3 of each 21-day E/P IV cycle
E/P therapy was comprised of standard-of-care etoposide (100 mg/m2) IV on days 1, 2, and 3 and carboplatin AUC 5 (calculated via the Calvert formula, maximum 750 mg) on day 1 of each 21-day cycle.
Placebo IV QD prior to chemotherapy on days 1-3 of each 21-day E/P IV cycle
G1T28-03 (NCT02514447)
Previously treated (second-/third-line) ES-SCLC
Trilaciclib 240 mg/m2 IV QD prior to topotecan 1.5 mg/m2 IV QD on days 1-5 of each 21-day cycle Placebo IV QD prior to topotecan 1.5 mg/m2 IV QD on days 1-5 of each 21-day cycle
Abbreviations: AUC = area under the plasma concentration-time curve; E/P = etoposide/carboplatin; E/P/A = etoposide/carboplatin plus atezolizumab; ES-SCLC = extensive-stage small cell lung cancer; IV = intravenous(ly); QD = once daily; Q21D = every 21 days.
a E/P/A therapy was comprised of standard-of-care etoposide (100 mg/m2) IV on days 1, 2, and 3 and carboplatin AUC 5 (calculated via the Calvert formula, maximum 750 mg) on day 1, with the addition of atezolizumab (1200 mg) IV on day 1 of each 21-day chemotherapy cycle. Maintenance treatment was comprised of atezolizumab (1200 mg) IV on day 1 of each 21-day cycle; trilaciclib and placebo were not administered during maintenance.
b E/P therapy was comprised of standard-of-care etoposide (100 mg/m2) IV on days 1, 2, and 3 and carboplatin AUC 5 (calculated via the Calvert formula, maximum 750 mg) on day 1 of each 21-day cycle.
In the G1T28-05 study, a maximum of four induction cycles with trilaciclib or placebo prior to E/P/A were given prior to initiation of maintenance therapy with atezolizumab monotherapy. Neither trilaciclib nor placebo was administered during maintenance. In G1T28-02 and G1T28-03, patients were treated with trilaciclib or placebo prior to chemotherapy until disease progression, unacceptable toxicity, withdrawal of consent, or discontinuation by investigator.
To ensure unconfounded assessment of the ability of trilaciclib to prevent CIM, administration of ESAs and primary prophylaxis with G-CSFs were prohibited in cycle 1, although therapeutic G-CSF was allowed. Following completion of cycle 1, both ESAs and G-CSFs (prophylactic or therapeutic), were permitted per SoC guidelines. RBC and platelet transfusions were allowed per investigator discretion throughout the entire treatment period.
All studies were designed and conducted in compliance with the tenets of the Declaration of Helsinki and the Good Clinical Practice guideline of the International Council for Harmonisation. Study protocols and study-related materials were approved by the institutional review board or independent ethics committee of each investigational site. Written informed consent was obtained from each patient before the initiation of study procedures.
Myelosuppression Endpoints
The primary myelosuppression endpoints were duration of severe neutropenia (DSN) in cycle 1 and percentage of patients with severe neutropenia (SN; occurrence) during the treatment period. SN was defined as absolute neutrophil count (ANC) < 0.5 × 109 cells/L. Secondary endpoints included evaluation of the effects of trilaciclib on other neutrophil measures, as well as RBC and platelet lineages. For neutrophils, the secondary endpoints included occurrence of febrile neutropenia (FN) AEs and occurrence and number of G-CSF administrations. RBC endpoints included occurrence of grade 3/4 anemia (defined as at least one hemoglobin value < 8.0 g/dL during the treatment period), occurrence of RBC transfusions on or after week 5 of the treatment period, total number of RBC transfusions on or after week 5 per 100 weeks, occurrence of ESA administrations during the treatment period, and total number of ESA administrations per 100 cycles. Platelet endpoints included occurrence of grade 3/4 thrombocytopenia (at least one platelet count < 50.0 × 109 cells/L), occurrence of platelet transfusions during the treatment period, and total number of platelet transfusions per 100 weeks.
Additional myelosuppression endpoints were occurrence of chemotherapy dose reductions for any reason across the treatment period and the total number of cycles with at least one chemotherapy dose reduction. The occurrence of infection serious AEs (SAEs) and IV antibiotic administrations were also assessed across the treatment period.
Safety was monitored continuously throughout each study and included assessments of AEs, SAEs, the occurrence and total number of hospitalizations due to CIM (neutropenia, anemia, thrombocytopenia) or sepsis, laboratory safety assessments, vital signs, physical examination, and electrocardiography.
PRO Endpoints
All three studies included PRO measures (Functional Assessment of Cancer Therapy [FACT]-General, FACT-Lung, and FACT-Anemia [FACT-An]) as exploratory endpoints. These validated PRO instruments were administered on day 1 of each 21-day cycle, with a 7-day recall period. Subscales and measures of the FACT-An questionnaire, considered most relevant to measure the impact of chemotherapy on patient HRQoL, were selected a priori for the pooled analysis. These included physical wellbeing (PWB), functional wellbeing (FWB), fatigue subscale (fatigue), anemia trial outcome index (anemia-TOI), and FACT-An total scores.
Antitumor Efficacy Endpoints
Antitumor activity endpoints were comprised of the objective response rate (ORR), defined as the proportion of patients who achieved a confirmed complete or partial response as per RECIST 1.1; duration of response (DOR), calculated from the date of the first confirmed complete response or partial response to the earliest date of radiologic disease progression or death; progression-free survival (PFS), calculated from the date of randomization to the earliest date of radiologic disease progression or death; and overall survival (OS), calculated as the time from the date of randomization to the date of death. For each of the time-to-event endpoints, censored time was calculated for patients without an event during the study following prespecified censoring rules.
Statistical Analysis
Each study had two planned and executed database locks (DBLs); myelosuppression and PRO data were pooled from the first DBL of each study, and antitumor efficacy data from the second (or final for study G1T28-02) DBL. Each DBL included the same intention-to-treat population. All analyses were conducted using SAS 9.4 software (SAS Institute, Inc., Cary, NC). To test data consistency and the statistical validity of efficacy data pooling, a Breslow–Day test was conducted to evaluate representative myelosuppression endpoints within each lineage (occurrence of SN, grade 3/4 anemia, RBC transfusions on/after week 5, and grade 3/4 thrombocytopenia).
To adjust for potential variability among patients and studies, ECOG PS (0/1 or 2), presence of brain metastases (yes or no), and study (G1T28-05, G1T28-02, or G1T28-03) were identified as common factors when evaluating treatment effects. A nonparametric analysis of covariance was used to assess treatment group differences for DSN in cycle 1 using the three factors as the fixed effects and baseline ANC as a covariate. For binary endpoints, treatment effect was evaluated using a modified Poisson regression model.
A negative binomial regression model was used to assess treatment effect for incidence endpoints, whereby incidence was calculated by dividing the total number of events by the total number of cycles or weeks, and reported per 100 units. Both models contained the three factors with corresponding baseline laboratory values as covariates and included duration of exposure as the offset variable. The estimated relative risk for trilaciclib over placebo and its 95% confidence interval (CI) were generated, along with a two-sided P value.
Change from baseline to the end of a cycle (1-4) was analyzed for PRO endpoints using a mixed-effect, maximum likelihood-based, repeated measures analysis model, with treatment, ECOG PS, presence of brain metastases, study, time, and baseline value as effects. Time-by-treatment and baseline-by-treatment interactions were also included. Literature-derived thresholds of meaningful within-patient change (FWB, PWB, and fatigue [3 points], anemia-TOI [6 points], and FACT-An total score [7 points])
What is a clinically meaningful change on the Functional Assessment of Cancer Therapy–Lung (FACT-L) Questionnaire?: results from Eastern Cooperative Oncology Group (ECOG) Study 5592.
Combining anchor and distribution-based methods to derive minimal clinically important differences on the Functional Assessment of Cancer Therapy (FACT) Anemia and Fatigue Scales.
were used to classify changes as improvement (increase from baseline exceeded threshold), deterioration (decrease from baseline exceeded threshold), or stable (change from baseline neither exceeded improvement nor deterioration threshold). The Kaplan–Meier method was used to estimate median duration of time to confirmed deterioration (TTCD), which was observed at two consecutive visits.
The ORR was reported by treatment group together with its 95% CI, calculated using the Clopper–Pearson method. Treatment group difference in ORR was analyzed using a stratified Cochran–Mantel–Haenszel method. Median DOR, PFS, and OS were estimated using the Kaplan–Meier method, with corresponding 95% CIs calculated from the Brookmeyer and Crowley method. Treatment group differences for TTCD, PFS, and OS were tested using a stratified log-rank test, and each hazard ratio (HR) and its associated 95% CI were calculated from a Cox proportional hazards model with treatment and the three factors as fixed effects.
The safety dataset (pooled from the second DBL of each study) included patients who were randomized and received at least one dose of the study drug and served as the basis for analyzing AEs and hospitalizations. AEs were coded using MedDRA 20.1 and summarized by Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE 4.03) grade and study drug-relatedness, as determined by the investigator.
Results
Patient Demographics and Baseline Characteristics
Overall, the pooled datasets included 242 patients randomized between October 12, 2016, and June 1, 2018. Patient demographics and baseline disease characteristics were generally comparable across treatment groups (Table 2). Median age in both treatment groups was 64 years; most patients were white, had an ECOG PS of 0 or 1, and were without brain metastases. There were slightly more male patients and current smokers in the trilaciclib group compared with placebo. More than half of the patients were enrolled from study sites outside the United States.
Table 2Demographic and Baseline Disease Characteristics
Characteristic
Trilaciclib Prior to Chemotherapy (n = 123)
Placebo Prior to Chemotherapy (n = 119)
Age (y), median (min, max)
64 (45, 82)
64 (39, 86)
Age group, n (%)
<65 y
66 (53.7)
61 (51.3)
≥65 y
57 (46.3)
58 (48.7)
Male, n (%)
89 (72.4)
73 (61.3)
Race, n (%)
White
120 (97.6)
110 (92.4)
Other
3 (2.4)
9 (7.6)
Country, n (%)
United States
53 (43.1)
57 (47.9)
Not United States
70 (56.9)
62 (52.1)
ECOG PS, n (%)
0/1
108 (87.8)
107 (89.9)
2
15 (12.2)
12 (10.1)
Presence of brain metastases, n (%)
Yes
27 (22.0)
28 (23.5)
No
95 (77.2)
90 (75.6)
Missing
1 (0.8)
1 (0.8)
Smoking history, n (%)
Never smoked
7 (5.7)
8 (6.7)
Former smoker
66 (53.7)
74 (62.2)
Current smoker
49 (39.8)
36 (30.3)
Missing
1 (0.8)
1 (0.8)
Baseline LDH, n (%)
≤ULN
55 (44.7)
61 (51.3)
>ULN
62 (50.4)
54 (45.4)
Missing
6 (4.9)
4 (3.4)
Abbreviations: ECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase; max = maximum; min = minimum; ULN = upper limit of normal.
The administration of trilaciclib prior to chemotherapy significantly decreased most measures of CIM and the need for supportive care interventions (Figure 1). Statistically significant improvements in the primary endpoints of DSN in cycle 1 and occurrence of SN were observed in the trilaciclib group versus the placebo group. Mean (standard deviation) DSN in cycle 1 was 0 days (1.8) with trilaciclib versus 4 days (5.1) with placebo (P < .0001); throughout the treatment period, 14 patients (11.4%) in the trilaciclib group had SN versus 63 patients (52.9%) in the placebo group (P < .0001).
Figure 1Myelopreservation Benefits with Trilaciclib Administered Prior to Chemotherapy.
Abbreviations: ESA = erythropoiesis-stimulating agent; G-CSF = granulocyte-colony-stimulating factor; RBC = red blood cell.
aBecause results from the Breslow–Day test indicated inconsistent treatment effects on platelet endpoints across the three studies, statistical testing was not supported.
Most secondary myelosuppression endpoints, including the percentage of patients with G-CSF administration, grade 3/4 anemia, RBC transfusions on or after week 5 of study treatment, ESA administrations, and grade 3/4 thrombocytopenia also significantly favored trilaciclib over placebo (Figure 1). The percentage of patients with FN AEs was numerically lower in the trilaciclib group than in the placebo group, although the difference was not statistically significant (P = .0889) (Figure 1). A similar proportion of patients in the trilaciclib and placebo groups received platelet transfusions (8.1% vs. 9.2%). The incidence of G-CSF administration was 16.4/100 cycles among patients receiving trilaciclib versus 40.6/100 cycles among patients receiving placebo (P < .0001). The incidences of RBC transfusions per 100 weeks and ESA administrations per 100 cycles for patients receiving trilaciclib versus placebo were 1.5 versus 3.1 (P = .0027) and 1.6 versus 6.4 (P = .0359), respectively. Fewer patients receiving trilaciclib had infection SAEs or received IV antibiotics compared with those receiving placebo (6.5% vs. 10.1%, and 19.5% vs. 23.5%, respectively).
Treatment effects were consistent across the three individual studies for neutrophil- and RBC-related endpoints, as indicated by the results of the Breslow–Day test that assessed the homogeneity of odds ratios across studies (P = .1049 for occurrence of SN; P = .9241 for occurrence of grade 3/4 anemia; P = .3547 for occurrence of RBC transfusions on or after week 5). However, results from the Breslow–Day test indicated inconsistent treatment effects on platelets across the three studies, as P = .0018 for occurrence of grade 3/4 thrombocytopenia.
Exposure and Safety
Median duration of treatment was four cycles for patients receiving trilaciclib or placebo. Among patients who continued after cycle 1, 11 patients (8.9%) receiving trilaciclib required more than one chemotherapy dose reduction versus 36 patients (30.3%) receiving placebo, with an incidence of 2.8 versus 9.3 per 100 cycles (P < .0001). In the G1T28-05 and G1T28-02 studies, mean RDI up to cycle 4 was numerically higher in the trilaciclib group than in the placebo group for both carboplatin and etoposide (95.7% vs. 90.2% for carboplatin and 93.4% vs. 89.0% for etoposide). Because patients in the G1T28-03 study were randomized to one of two doses of topotecan, dose intensity could not be calculated for topotecan, as this would have broken the blind.
In the pooled safety dataset, of 122 patients in the trilaciclib group and 118 patients in the placebo group, 94.3% and 96.6% of patients had at least one AE and 29.5% and 25.4% of patients had an SAE, respectively (Table 3). The only trilaciclib-related AEs occurring in ≥10% of patients were fatigue (11.5%) and nausea (10.7%); these were all low grade with the exception of two patients with grade 3 fatigue. Two patients had SAEs that were considered related to trilaciclib (grade 2 deep vein thrombosis and grade 3 thrombophlebitis). Fatal AEs were observed in six patients (4.9%) receiving trilaciclib: pneumonia (n = 2), (acute) respiratory failure (n = 2), pneumonia and respiratory failure (n = 1), hemoptysis (n = 1), and cerebrovascular accident (n = 1). Three patients (2.5%) in the placebo group had fatal AEs: pneumonia (n = 1) and sepsis (n = 2). No fatal AEs were considered related to trilaciclib.
Table 3Summary of Adverse Events in the Pooled Safety Population
Event
n (%)
Trilaciclib Prior to Chemotherapy (n = 122)
Placebo Prior to Chemotherapy (n = 118)
Any AE
115 (94.3)
114 (96.6)
Any placebo-/trilaciclib-related AE
45 (36.9)
49 (41.5)
Any serious AE
36 (29.5)
30 (25.4)
Any placebo-/trilaciclib-related serious AE
2 (1.6)
1 (0.8)
Any AE of grade ≥3
73 (59.8)
98 (83.1)
Any AE of grade ≥4
30 (24.6)
62 (52.5)
Any placebo-/trilaciclib-related AE of grade ≥3
10 (8.2)
18 (15.3)
Any hematologic AE
82 (67.2)
106 (89.8)
Any hematologic AE of grade ≥3
54 (44.3)
91 (77.1)
Any hematologic AE of grade ≥4
19 (15.6)
62 (52.5)
AESIs for trilaciclib
23 (18.9)
10 (8.5)
Any AE leading to discontinuation of any study drug
Grade 3 or 4 hematologic AEs by collapsed preferred term; patients with multiple AE entries in the same collapsed preferred term were only counted once within a particular collapsed preferred term at the highest CTCAE grade.
Abbreviations: AE = adverse event; AESI = adverse event of special interest (condensed terms: injection site reactions, phlebitis/thrombophlebitis, and acute drug hypersensitivity reactions); CTCAE = Common Terminology Criteria for Adverse Events.
a Occurring in ≥10% of patients in either treatment group, ordered from highest to lowest frequency in the trilaciclib group.
b Grade 3 or 4 hematologic AEs by collapsed preferred term; patients with multiple AE entries in the same collapsed preferred term were only counted once within a particular collapsed preferred term at the highest CTCAE grade.
c Neutrophil count decreased.
d Platelet count decreased.
e Macrocytic anemia, red blood cell count decreased, hemoglobin decreased.
The most frequently reported AEs (reported in ≥20% of patients) of any grade in both groups were neutropenia, anemia, thrombocytopenia, nausea, and fatigue. Fewer patients in the trilaciclib group had grade 3/4 AEs, which was driven by substantially fewer patients in the trilaciclib group having grade 3/4 hematologic AEs than in the placebo group (Table 3). The number of patients hospitalized due to CIM or sepsis was 5 (4.1%) with trilaciclib versus 16 (13.6%) with placebo (P = .0088), and the incidence of hospitalizations was 0.94/100 cycles versus 5.7/100 cycles, respectively.
Trilaciclib AEs of special interest included injection site reactions (13.9% with trilaciclib vs. 2.5% with placebo), phlebitis/thrombophlebitis (9.0% vs. 0.8%), and acute drug hypersensitivity reactions (4.1% vs. 3.4%). Most AEs of special interest were low grade and did not result in dose modification.
AEs leading to permanent discontinuation of any study treatment for patients receiving trilaciclib included pneumonia, grades 3 and 4 (n = 2); asthenia, grades 2 and 3 (n = 2); grade 2 injection site reaction; grade 3 thrombocytopenia; grade 5 cerebrovascular accident; grade 3 ischemic stroke; grade 2 infusion-related reaction; grade 4 respiratory failure; and grade 3 myositis (n = 1 for each). All AEs were considered related to both trilaciclib and chemotherapy, with the exception of the grade 2 infusion-related and injection site reactions, which were considered to be related solely to trilaciclib.
Patient Experience
For each study, PRO completion rates were >80% in both the trilaciclib and placebo groups. At baseline, across all of the studies, mean scores for PWB, FWB, fatigue, anemia-TOI, and FACT-An were similar between the trilaciclib groups, with the placebo groups having slightly higher values (indicating better HRQoL).
Adjusted mean changes from baseline in each of these PRO measures during the first four cycles are presented in Figure 2. Over the first four cycles, maximum likelihood-based, repeated measures analyses of adjusted mean change from baseline for the selected FACT-An subscales and domains showed that patients receiving trilaciclib generally improved or remained stable, whereas patients receiving placebo remained stable or worsened from baseline. A larger proportion of patients experienced improvement from baseline, and a smaller proportion experienced deterioration at all visits in all scores in the trilaciclib versus the placebo group.
Figure 2Adjusted Mean Change from Baseline in (A) Physical Wellbeing, (B) Functional Wellbeing, (C) Fatigue, (D) Anemia Trial Outcome Index, and (E) Functional Assessment of Cancer Therapy-Anemia Scores.
Trilaciclib also delayed deterioration of patient functioning and symptom measures over time compared with placebo. For each of the PRO endpoints, median TTCD for patients receiving trilaciclib was significantly longer than for patients receiving placebo (HR range, 0.45-0.62) (Figure 3). The median TTCD in fatigue among patients receiving trilaciclib was 4.7 months longer than for patients receiving placebo. Similarly, median TTCDs in FWB and anemia-TOI were 3.8 months and 3.4 months longer, respectively, in patients receiving trilaciclib.
Figure 3Time to Confirmed Deterioration in Selected PRO Measures of FACT-An. Worsening Was Defined As a Decrease From Baseline by a Clinically Meaningful Threshold for Two Consecutive Visits: ≤3 Points for Physical Wellbeing, Functional Wellbeing, and Fatigue; ≤6 Points for Anemia Trial Outcome Index Points; ≤7 Points for FACT-An Total Scores.
Abbreviations: CI = confidence interval; FACT-An = Functional Assessment of Cancer Therapy-Anemia; NYR = not yet reached; PRO = patient-reported outcome; TTCD = time to confirmed deterioration.
Tumor response rates were similar between treatment groups, with an objective response achieved by 56/114 (49.1%) and 59/114 (51.8%) response-evaluable patients receiving trilaciclib or placebo (P = .7879), and median DORs of 5.7 months (95% CI, 4.7–7.0) and 4.6 months (95% CI, 4.1-5.0), respectively. For the trilaciclib and placebo groups, median PFS times were 5.3 months (95% CI, 4.6–6.1) and 5.0 months (95% CI, 4.4–5.5), respectively (HR, 0.80; 95% CI, 0.61-1.06; P = .1404), and median OS times were 10.6 months (95% CI, 9.1–11.7) and 10.6 months (95% CI, 7.9–12.8), respectively. The HR (trilaciclib vs. placebo) was 1.00, with a 95% CI of 0.75 to 1.35 (P = .8136) (Figure 4).
Figure 4Kaplan–Meier Estimates of (A) Probability of Progression-Free Survival and (B) Probability of Overall Survival.
ES-SCLC results in significant patient suffering. Although chemotherapy is the mainstay of treatment, it is associated with significant treatment-related toxicity, commonly in the form of CIM and its sequalae, which represent a substantial economic and social burden. In general, patients with lung cancer have worse HRQoL than patients with many other types of malignancies.
Specifically, in SCLC, both disease progression and treatment have a substantial impact on overall HRQoL, most notably on physical functioning and activities of daily living.
Three global, randomized, double-blind, placebo-controlled, phase II studies were conducted to evaluate the effects of administering trilaciclib prior to SoC chemotherapy regimens. The first study (G1T28-02)
Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.
was a proof-of-concept study to investigate the administration of trilaciclib prior to E/P, which was the first-line SoC for ES-SCLC at the time. The G1T28-05 study was performed to confirm the myeloprotective benefits of trilaciclib in patients receiving E/P/A for the treatment of ES-SCLC.
Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: a multicentre, randomised, double-blind, placebo-controlled phase II trial [e-pub ahead of print].
Finally, the supportive G1T28-03 study was performed to investigate the administration of trilaciclib prior to topotecan, a chemotherapy regimen that is more myelosuppressive than E/P, in the second-/third-line setting.
Myelopreservation with trilaciclib in patients receiving topotecan for small cell lung cancer: results from a randomized, double-blind, placebo-controlled phase II study.
All three studies demonstrated a clear multilineage myeloprotection benefit through clinically meaningful reductions in multiple measures of CIM and the need for supportive care interventions. To allow the myeloprotective effects of trilaciclib to be evaluated with greater statistical precision, data from all three studies were pooled for the analysis detailed herein.
Overall, the results of the pooled analysis support those of the individual studies. Compared with placebo, trilaciclib significantly reduced DSN in cycle 1 and the occurrence of SN. DSN is commonly used as a surrogate endpoint to assess the clinical efficacy of G-CSFs and is strongly predictive of the occurrence of chemotherapy-induced FN and the risk of infection.
Dose response of pegfilgrastim in Japanese breast cancer patients receiving six cycles of docetaxel, doxorubicin, and cyclophosphamide therapy: a randomized controlled trial.
Consistent with this, there was an approximate threefold decrease in the occurrence of FN among patients receiving trilaciclib compared with placebo, although the total number of events in each study was small. Furthermore, there was an approximate 6-fold decrease in the incidence of hospitalizations due to CIM or sepsis. Additionally, in the pooled analyses, the percentage of patients with infection SAEs or IV antibiotic use was similar or slightly lower for the trilaciclib group compared with the placebo group, despite the fact that, starting from cycle 2, patients in both treatment groups could receive prophylactic G-CSF. Notably, the use of G-CSF among patients receiving trilaciclib was approximately half that of patients receiving placebo.
Trilaciclib also demonstrated improvements in myelosuppression endpoints associated with other hematopoietic lineages, including reduction in the use of ESAs, lower rates of grade 3/4 anemia, and the need for fewer RBC transfusions. Indeed, patients receiving trilaciclib required approximately half as many RBC transfusions as those receiving placebo, which may translate to additional benefits with regard to the time and costs associated with outpatient transfusion visits,
as well as helping to preserve this limited resource for use in patients where there are no alternative options available. The heterogeneity of treatment effect on thrombocytopenia indicated by the Breslow–Day test suggests that caution should be taken when interpreting data from the pooled analysis of platelet endpoints.
The myeloprotection benefit of trilaciclib translated into a HRQoL benefit, providing an improved patient experience as assessed by improvements in PRO measures of symptoms and functional limitations associated with cancer and CIM. Importantly, PRO completion rates were high across all studies included in this analysis, which, together with the double-blind study design, indicates that the potential for bias was minimal.
In this analysis, patients receiving trilaciclib reported significant improvements in several areas of HRQoL, including physical and functional wellbeing, symptoms and impact of fatigue, and the symptoms and effects on physical and functional wellbeing due to anemia. In a large survey of patients with lung cancer, fatigue and shortness of breath were considered very important QoL issues by more than half of the patients.
Furthermore, relief from tiredness, one of the main elements of fatigue, has been identified as one of the biggest unmet needs among patients with lung cancer.
Because fatigue, which can be associated with both chemotherapy-induced anemia and neutropenia, is present during the entire course of the disease, its proactive management is essential to improve patients’ day-to-day living and overall HRQoL.
Although PROs showed a decrease in fatigue with trilaciclib, AEs of fatigue were more frequent in patients receiving trilaciclib. At baseline, all patients reported some level of fatigue as assessed by validated PRO instruments; however, patients in the trilaciclib group reported more fatigue than patients in the placebo group. Particularly, patients in the trilaciclib group who experienced an AE of fatigue reported more fatigue at baseline than patients who did not experience an AE of fatigue. Consistent with previous observations,
How accurate is clinician reporting of chemotherapy adverse effects? A comparison with patient-reported symptoms from the Quality-of-Life Questionnaire C30.
patients’ perceptions of symptoms often differ from CTCAE data; therefore, it is possible that the higher rate of fatigue AEs may reflect a discrepancy between how fatigue was reported by patients when asked directly via a PRO instrument versus what was reported by patients to their physicians.
Compared with placebo, the administration of trilaciclib prior to chemotherapy resulted in an improved overall safety profile for the treatment regimen, with markedly fewer patients experiencing high-grade hematologic AEs that are frequently associated with CIM. Rates of grade 4 neutropenia, for example, were six times lower in the trilaciclib group than in the placebo group. Theoretically, trilaciclib could also induce transient G1 arrest of CDK4/6-dependent cells outside of the hematopoietic system.
Interestingly, among patients receiving trilaciclib, the rate of alopecia was almost halved compared with placebo (13.1% vs. 25.4%), with favorable numerical trends also seen with some gastrointestinal AEs. The findings with respect to alopecia are of interest, as they suggest further humanistic benefit with trilaciclib and are consistent with its mechanism of action. We note, however, that these studies were not specifically designed to evaluate alopecia, and the number of patients was small. Therefore, we regard these findings as hypothesis generating, and further investigation is warranted.
Fewer high-grade hematologic AEs may allow patients to minimize dose reductions or delays to chemotherapy, affording their particular treatment regimen the best chance of efficacy. In this analysis, patients who received trilaciclib prior to chemotherapy appeared three times less likely to require chemotherapy dose reductions than patients who received placebo, and they had numerically higher RDIs of etoposide and carboplatin. Consistent with findings from the individual studies,
Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.
Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: a multicentre, randomised, double-blind, placebo-controlled phase II trial [e-pub ahead of print].
Myelopreservation with trilaciclib in patients receiving topotecan for small cell lung cancer: results from a randomized, double-blind, placebo-controlled phase II study.
maintaining the dose intensity of chemotherapy did not translate to an improvement in PFS or OS. This is perhaps not surprising, as studies in patients with SCLC have shown that increasing the RDI of chemotherapy beyond the SoC rarely translates into significant improvements in response rates or survival.
Although a weak trend toward improved PFS was observed in this pooled analysis, it was not significant, and none of the individual studies was powered to detect differences in antitumor efficacy. Therefore, larger studies are needed to investigate the relationship between delivered chemotherapy dose intensity and outcomes in settings where improvements in RDI have been shown to result in improved survival.
Conclusion
In this analysis, data from three randomized, double-blind, placebo-controlled studies of trilaciclib in patients with SCLC were pooled to evaluate the overall effects of trilaciclib with regard to myeloprotection, safety, HRQoL, and antitumor efficacy. The administration of trilaciclib prior to chemotherapy reduced the incidence of CIM and improved the benefit/risk profile for chemotherapy in patients receiving chemotherapy for ES-SCLC, including both treatment-naïve individuals and patients who had been previously treated with myelosuppressive chemotherapy. The myeloprotection of multiple blood cell lineages resulted in less hematologic toxicity, the reduced use of supportive care interventions and CIM-related hospitalizations, and ultimately, improved HRQoL. As a result of the consistency and reproducibility of results across the three studies, with different treatment lines and regimens, trilaciclib is a new SoC for reducing the incidence of CIM in adult patients receiving E/P- or topotecan-containing regimens for the treatment of ES-SCLC.
Clinical Practice Points
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SoC treatments for patients with ES-SCLC, including E/P, E/P/A, and second-/third-line topotecan often cause clinically significant CIM.
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Trilaciclib is an intravenous CDK4/6 inhibitor administered prior to chemotherapy to protect hematopoietic stem and progenitor cells from chemotherapy-induced damage (myelopreservation or myeloprotection).
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Data from three randomized, double-blind, placebo-controlled phase II studies have shown that administering trilaciclib prior to chemotherapy results in a reduction in the incidence of CIM and an improved benefit/risk profile for the chemotherapy regimens used to treat patients with ES-SCLC.
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In this analysis, data from these three trials were pooled to evaluate the effects of trilaciclib administered prior to SoC chemotherapy (first-line E/P, first-line E/P/A, and second-/third-line topotecan) in patients with ES-SCLC with greater statistical precision.
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Compared with placebo, administering trilaciclib prior to chemotherapy resulted in significant decreases in most measures of multilineage CIM, with a reduction in the incidence of chemotherapy-related hematologic adverse events.
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The myeloprotective benefits of trilaciclib translated into a reduced need for supportive care interventions and hospitalizations due to CIM or sepsis, as well as improvements in health-related quality of life domains, including fatigue, physical wellbeing, and functional wellbeing, with no impact on the antitumor efficacy of the individual chemotherapy regimens.
•
Despite differences in patient populations and chemotherapy regimens, the consistency and reproducibility of the results across these three studies, as well as across the different myelosuppression endpoints, indicate that trilaciclib represents an important step forward in the care of patients with SCLC.
We thank the patients and investigators involved in each of the studies. We also thank Jie Xiao (G1 Therapeutics, Inc.) for her statistical support. This study was funded by G1 Therapeutics, Inc. The study sponsor was involved in the study design; collection, analysis, and interpretation of data; writing the report; and in the decision to submit the article for publication. Medical writing support, provided by Fiona Bolland, PhD, from Alligent Europe (Envision Pharma Group), was funded by G1 Therapeutics, Inc.
Disclosure
J. Weiss has received research funding and honoraria from G1 Therapeutics, Inc. J. Goldschmidt has received research funding from G1 Therapeutics, Inc., and speakers bureau fees and honoraria from Amgen and Bristol Myers Squibb. Z. Andric has received research funding from G1 Therapeutics, Inc. K.H. Dragnev has received research funding from G1 Therapeutics, Inc. C. Gwaltney has received consultancy fees from IQVIA Consulting Services and G1 Therapeutics, Inc. K. Skaltsa is a paid employee of IQVIA Consulting Services and has received consultancy fees from G1 Therapeutics, Inc. Y. Pritchett is a paid employee and shareowner of G1 Therapeutics, Inc. J.M. Antal was a paid employee and shareowner of G1 Therapeutics, Inc., at the time of study completion and manuscript preparation. S.R. Morris was a paid employee and shareowner of G1 Therapeutics, Inc., at the time of study completion and manuscript preparation. D. Daniel has received research funding from G1 Therapeutics, Inc., and Genentech.
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Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.
Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: a multicentre, randomised, double-blind, placebo-controlled phase II trial [e-pub ahead of print].
Myelopreservation with trilaciclib in patients receiving topotecan for small cell lung cancer: results from a randomized, double-blind, placebo-controlled phase II study.
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Dose response of pegfilgrastim in Japanese breast cancer patients receiving six cycles of docetaxel, doxorubicin, and cyclophosphamide therapy: a randomized controlled trial.
How accurate is clinician reporting of chemotherapy adverse effects? A comparison with patient-reported symptoms from the Quality-of-Life Questionnaire C30.
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