Editor's Note: On November 23rd, Dr. Tianshu Liu's team from Zhongshan Hospital published a study titled "Trilaciclib prior to FOLFOXIRI/bevacizumab for patients with untreated metastatic colorectal cancer: phase 3 PRESERVE 1 trial" in JNCI Cancer Spectrum(IF=3.4). The PRESERVE 1 trial sheds light on trilaciclib's potential to reduce chemotherapy-related toxicity in mCRC. While its efficacy in mitigating myelosuppression is evident, the antitumor results are concerning. Further studies are needed to explore the balance between toxicity reduction and efficacy, and to determine trilaciclib's optimal use in cancer treatment.In metastatic colorectal cancer (mCRC), the combination of leucovorin/fluorouracil/oxaliplatin/irinotecan (FOLFOXIRI) with bevacizumab has significantly improved survival outcomes. However, this regimen is associated with increased rates of high-grade toxicities, particularly myelosuppression. To address this issue, the PRESERVE 1 trial investigated the efficacy and safety of trilaciclib, a small-molecule inhibitor of cyclin-dependent kinase 4/6, in reducing chemotherapy-induced myelosuppression in patients with untreated mCRC.
The PRESERVE 1 trial was a multicenter, randomized, double-blind, placebo-controlled phase 3 study conducted at 88 sites in eight countries. Eligible patients had histologically or cytologically confirmed pMMR/MSS mCRC, were aged ≥18 years, and had measurable disease with an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomized 1:1 to receive trilaciclib or placebo prior to FOLFOXIRI/bevacizumab induction therapy, followed by maintenance therapy with trilaciclib or placebo combined with fluorouracil/leucovorin/bevacizumab.
The co-primary endpoints of the study were the duration of severe (grade 4) neutropenia (DSN) in cycles 1-4 and the occurrence of severe neutropenia (SN) during induction. Secondary endpoints included antitumor efficacy, survival, and safety.
A total of 326 patients were randomized to the trilaciclib (n=164) or placebo (n=162) groups. Baseline demographic and clinical characteristics were similar between the two groups. Trilaciclib significantly reduced the mean DSN in cycles 1-4 compared to placebo (0.1 vs. 1.3 days; P<0.001) and the occurrence of SN during induction (1.3% vs. 19.7%; adjusted relative risk [95% CI], 0.07 [0.0, 0.3]; P <0.001). Additionally, trilaciclib decreased the incidence of febrile neutropenia (0% vs. 5.0%), grade 3/4 anemia (3.1% vs. 4.4%), and grade 3/4 thrombocytopenia (1.9% vs. 2.5%) compared to placebo (Figure 1).
Despite these myeloprotection benefits, trilaciclib was associated with lower antitumor efficacy compared to placebo. The objective response rate (ORR) was significantly lower in the trilaciclib group (41.6% vs. 57.1%; P = 0.009), and median progression-free survival (PFS) was shorter (10.3 vs. 13.1 months; hazard ratio, 1.94 [95% CI: 1.34, 2.79]; P < 0.001). No significant difference was observed in the disease control rate between the two groups.
In terms of safety, the incidence of grade 3/4 adverse events (AEs) was lower in the trilaciclib group (64.8% vs. 73.1%), primarily due to the reduced rates of neutropenia, diarrhea, and leukopenia. Fewer patients in the trilaciclib group experienced chemotherapy dose reductions or delays compared to the placebo group. Serious AEs were reported in a similar proportion of patients in both groups, with the primary reason for death being progressive disease.
The mechanism by which trilaciclib may attenuate the antitumor activity of FOLFOXIRI is not fully understood. One potential explanation involves a drug-drug interaction that inhibits the transport proteins responsible for intracellular 5-fluorouracil accumulation. Additional mechanistic studies are needed to clarify this observation.
In conclusion, the PRESERVE 1 trial demonstrated that trilaciclib significantly reduces chemotherapy-induced myelosuppression in patients with untreated mCRC receiving FOLFOXIRI/bevacizumab. However, the antitumor efficacy of trilaciclib in this setting was inferior to placebo. Further research is warranted to explore the potential use of trilaciclib in combination with other chemotherapy regimens and in different patient populations.
