An unanticipated result of a randomized phase II study was the improvement in overall survival achieved with the investigational CDK4/6 inhibitor trilaciclib in women with metastatic triple-negative breast cancer. The drug was not being evaluated for its anticancer effects, but rather as a means of ameliorating myelosuppression.
“The improved overall survival seen with the addition of trilaciclib to chemotherapy was unexpected,” said Joyce O’Shaughnessy, MD, Chair of Breast Cancer Research at Baylor-Sammons Cancer Center and Texas Oncology, US Oncology, Dallas, who presented the findings at the European Society for Medical Oncology (ESMO) Congress 2019.1 The study was concurrently published in The Lancet Oncology.2
The improved overall survival seen with the addition of trilaciclib to chemotherapy was unexpected.— Joyce O’Shaughnessy, MD
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Although median overall survival improved by more than 60% with the addition of the intravenously administered inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) to gemcitabine/carboplatin chemotherapy, the regimen did not reduce the frequency and duration of severe neutropenia compared with chemotherapy alone—which were the study’s co-primary endpoints.
“The primary endpoints were negative, yet it looked like trilaciclib provided some bone marrow protection. Patients got twice as many cycles of chemotherapy [median, 7–8 cycles], with no worsening of toxicity,” Dr. O’Shaughnessy said in an interview. “There’s something positive happening hematologically; otherwise, we would not be able to give that many cycles.” Dr. O’Shaughnessy added that the data showing bone marrow protection in small cell lung cancer are “impressive.” This study is building upon that experience, she said.
Trilaciclib was evaluated in this study for its ability to ameliorate the cumulative myelosuppression that can accompany treatment with gemcitabine/carboplatin and might compromise antitumor efficacy. The drug has shown myelopreservative benefits when used with atezolizumab and chemotherapy in patients with small cell lung cancer.
As Dr. O’Shaughnessy explained, chemotherapy-induced immune cell toxicity may limit host immune system responses against triple-negative breast cancer. Trilaciclib induces transient G1 arrest in immune cells and hematopoietic stem and progenitor cells, potentially helping to preserve T-cell function and bone marrow.
Trilaciclib is not being developed as an anticancer therapy because, unlike the other available CDK4/6 inhibitors that are oral, it is delivered intravenously, she noted.
G1T28-04, a global, multicenter, randomized phase II trial, was conducted to evaluate the impact of adding trilaciclib to gemcitabine/carboplatin chemotherapy in patients with metastatic triple-negative breast cancer. The study randomly assigned 102 previously treated or treatment-naive patients to three treatment arms:
The primary endpoints of the trial were the duration of grade 4 neutropenia in cycle 1 and the occurrence of grade 4 neutropenia during treatment. Key secondary endpoints were the need for red blood cell transfusions, growth factors, and platelet transfusions. The efficacy endpoints of objective response rate, progression-free survival, and overall survival were all secondary.
More Treatment Exposure With Trilaciclib
The addition of trilaciclib increased the duration of chemotherapy exposure and cumulative chemotherapy doses compared with administration of chemotherapy without the CDK4/6 inhibitor, which, according to Dr. O’Shaughnessy, may have led to the improved survival.
The median treatment duration was 5.3 months on the trilaciclib-concurrent arm and 5.5 months on the additional trilaciclib arm, vs 3.3 months with chemotherapy alone. The median number of cycles was 7 and 8 vs 4, respectively. The median cumulative doses of gemcitabine and carboplatin were also higher with trilaciclib on board, she reported.
Primary Endpoint Not Met
The addition of trilaciclib, however, did not reduce the duration of severe neutropenia during cycle 1, which averaged 1 to 2 days across the three groups. The proportion of patients with severe neutropenia during treatment ranged from 22.9% to 36.4%, with no significant differences among the study arms (P = .70). All other secondary safety and tolerability endpoints were similar as well.
“Despite more gemcitabine/carboplatin being delivered in groups 2 and 3, hematologic toxicity was similar between the groups,” Dr. O’Shaughnessy reported. “No serious treatment-emergent adverse events or those leading to treatment discontinuation were considered related to trilaciclib. Trilaciclib also did not adversely affect patients’ overall function,” as determined by numerous quality-of-life instruments.
Overall Survival Benefit
The objective response rates ranged from 33% to 50%, with no differences among the study arms. Median progression-free survival was numerically greater in the trilaciclib groups (9.4 and 7.3 months), but not significantly better than that achieved with chemotherapy alone (5.7 months).
However, in the overall survival analysis, trilaciclib stood out in both arms, compared with chemotherapy alone, with both dosing schedules:
A pooled analysis of the two trilaciclib arms showed a significant benefit in overall survival (HR = 0.36; P = .0015) and a consistent benefit among subgroups. In addition, longer median progression-free survival was reported in the two trilaciclib arms than in the chemotherapy arm alone.
Why a Survival Benefit?
“Possible explanations include the increased duration of chemotherapy exposure in the trilaciclib arm—patients received twice as many chemotherapy cycles—without increased toxicity or worsening of overall function,” Dr. O’Shaughnessy proposed. “We also observed that trilaciclib-treated patients had a higher number of activated CD8-positive T cells over the first five cycles of chemotherapy, suggesting a potentially more functional leukocyte population with trilaciclib that could enhance antitumor immunity. CDK4/6 inhibitors can also increase platinum sensitivity and decrease proliferation by inhibiting FOXM1 phosphorylation, which is commonly overexpressed in triple-negative breast cancer.”
The investigators are designing phase III trials in triple--negative breast cancer and colorectal cancer and conducting additional biomarker studies. They include an analysis of programmed cell death ligand 1 expression, to evaluate the potential immune effects of trilaciclib on outcomes, noted Dr. O’Shaughnessy. ■
DISCLOSURE: The study was sponsored by G1 Therapeutics. Dr. O’Shaughnessy has served as a consultant for G1 Therapeutics, AbbVie, Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, Genentech, Genomic Health, GRAIL, Immunomedics, Heron Therapeutics, Ipsen Biopharmaceuticals, Jounce Therapeutics, Lilly, Merck, Myriad, Novartis, Ondonate Therapeutics, Pfizer, Puma Biotechnology, Prime Oncology, Roche, Seattle Genetics, and Syndax Pharmaceutical.
1. O’Shaughnessy J, Wright G, Thummala A, et al: Trilaciclib improves overall survival when given with gemcitabine/carboplatin in patients with metastatic triple negative breast cancer in a randomized phase II trial. ESMO Congress 2019. Abstract LBA22. Presented September 28, 2019.
2. Tan AR, Wright GS, Thummala AR, et al: Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: A multicentre, randomised, open-label, phase 2 trial. Lancet Oncol. September 27, 2019 (early release online).
Mafalda Oliveira, MD, PhD
Invited study discussant, Mafalda Oliveira, MD, PhD, of Vall d’Hebron University Hospital in Barcelona, said the phase II G1T28-04 study was “a ‘negative’ trial with clinically ‘positive’ results: an improved toxicity profile and overall survival benefit…. Despite...