Trilaciclib plus FOLFOXIRI/Bevacizumab Inhibits Myelosuppression in CRC

Antitumor efficacy end points favored placebo over trilaciclib prior to FOLFOXIRI/bevacizumab in patients with untreated metastatic colorectal cancer.

Treatment with trilaciclib (Cosela) prior to folinic acid [leucovorin], 5-fluorouracil, oxaliplatin (FOLFOXIRI) and bevacizumab (Avastin) inhibited the effects chemotherapy-induced myelosuppression in patients with untreated metastatic colorectal cancer (CRC), according to findings from the phase 3 PRESERVE 1 trial (NCT04607668) published in JNCI Cancer Spectrum.¹ Furthermore, antitumor efficacy end points favored placebo vs trilaciclib to treat this patient population.

Myeloprotection efficacy data revealed that in the intention to treat (ITT) population (n = 296), trilaciclib given prior to FOLFOXIRI/bevacizumab significantly reduced chemotherapy-induced neutropenia vs placebo, with a mean duration of severe neutropenia (DSN) in treatment cycles 1 to 4 of 0.1 days (SD, 0.8) and 1.3 days (SD, 3.1) in each respective arm (mean difference; –1.2 days [96% CI, –1.7 to –0.6]; P <.001). Additionally, severe neutropenia (SN) was reported in 1.3% and 19.7% of patients treated with respective agents, with an adjusted relative risk of 0.07 (96% CI, 0.0-0.3; P <.001).

Febrile neutropenia (FN) occurrence was also reduced with trilaciclib, with 0% of patients reporting FN vs 5% of those taking placebo. Additionally, grade 3/4 anemia occurrence was 3.1% vs 4.4% with respective regimens; for grade 3 or 4 thrombocytopenia, it was 1.9% vs 2.5%. Furthermore, granulocyte colony-stimulating factor (G-CSF) agent administration was significantly lower in the trilaciclib arm vs placebo; 19.5% vs 43.5% (adjusted relative risk, 0.48; 95% CI, 0.33-0.69; P <.001).

Among patients evaluable for response, the confirmed objective response rate (ORR) in the trilaciclib arm was 41.6% (95% CI, 33.3%-50.3%) vs 57.1% (95% CI, 48.5%-65.5%) in the placebo arm. The confirmed disease control rate (DCR) was 90.5% (95% CI, 84.3%-94.9%) vs 92.9% (95% CI, 87.3%-96.5%) in each respective arm.

“Results from this study showed that administering trilaciclib prior to FOLFOXIRI/bevacizumab was associated with significant reductions in DSN in cycles 1 to 4 and occurrence of SN during induction vs administering placebo, suggesting that trilaciclib is effective in protecting the neutrophil lineage from the effects of chemotherapy-induced myelosuppression,” Heinz-Josef Lenz, MD, professor of Medicine and Preventive Medicine and J. Terrence Lanni chair in Gastrointestinal Cancer Research at the Keck School of Medicine of the University of Southern California, wrote in the publication with study coauthors.¹ “However, despite this study achieving its primary and other myeloprotection and safety end points, early survival indicators, including the confirmed ORR and PFS, did not favor trilaciclib over placebo.”

The multicenter, double-blind phase 3 trial was conducted at 88 sites across 8 countries, and enrolled patients 18 years and older with histologically or cytologically confirmed proficient mismatch repair/microsatellite stable (pMMR/MSS) unresectable metastatic CRC. Patients were randomly assigned 1:1 to receive either trilaciclib (n = 164) or placebo (n = 162) prior to FOLFOXIRI/bevacizumab. Those undergoing random assignment were stratified by country, prior adjuvant/neoadjuvant therapy, and BRAF V600E mutational status.

Patients received intravenous trilaciclib or placebo on days 1 and 2 prior to FOLFOXIRI/bevacizumab in 14-day cycle for up to 12 cycles during the induction phase. FOLFOXIRI/bevacizumab treatment consisted of 165 mg/m²of irinotecan, 85 mg/m² of oxaliplatin, 400 mg/m² of leucovorin or 200 mg/m² of levoleucovorin, and 5 mg/kg of bevacizumab administered intravenously on day 1; 2400-3200 mg/m² of intravenous fluorouracil was administered as a continuous infusion over 46-48 hours beginning on day 1. 240 mg/m² of intravenous trilaciclib or placebo was given over 30 ± 5 minutes prior to chemotherapy on days 1 and 2 of each cycle.

For the maintenance phase, trilaciclib or placebo prior to intravenous fluorouracil and leucovorin plus bevacizumab at the same dose and schedule in 14-day cycles were continued. Treatment occurred until disease progression, unacceptable toxicity, withdrawal of consent, investigator decision, or end of study.

Patients in the investigational and control arms had a median age of 58 years (range, 26-81) and 55 years (range, 30-79), and 63.1% vs 61.9% were males. In respective arms, 69.8% vs 66.0% were White and 21.5% vs 22.4% were Asian, 49.0% vs 51.0% had an ECOG performance status score of 1, and 18.8% vs 20.4% had prior adjuvant or neoadjuvant systemic therapy. The site of primary tumor was in the colon in 70.5% vs 73.5% of respective arms, 42.3% vs 46.9% had KRAS mutation, and 6.7% vs 5.4% had BRAF V600E mutations.

The coprimary end points were DSN and SN occurrence in cycles 1 to 4 of treatment.² Secondary end points included overall survival, ORR, DCR, duration of response (DOR), progression-free survival (PFS), and safety.

In the investigational and control arms, respectively, any grade adverse effects (AEs) occurred in 98.7% and 99.4% of patients. The most common AEs across treatment arms included diarrhea (63.0%), nausea (58.6%), neutropenia (48.0%), anemia (37.0%), vomiting (37.3%), and fatigue (32.9%).

Additionally, grade 3/4 AEs were reported in 64.8% vs 73.1% of respective arms. The most common grade 3/4 AEs were (17.6% vs 40.0%), hypertension (12.6% vs 9.4%), diarrhea (6.92% vs 12.5%), vomiting (4.4% vs 6.88%), leukopenia (3.1% vs 8.8%), and neutrophil count decrease (3.8% vs 6.3%).

References

1. Lenz HJ, Liu T, Chen EY, et al. Trilaciclib prior to FOLFOXIRI/bevacizumab for patients with untreated metastatic colorectal cancer: phase 3 PRESERVE 1 trial. JNCI Cancer Spectr. 2024;9(1):pkae116. doi:10.1093/jncics/pkae116
2. Trilaciclib, a CDK 4/​6 inhibitor, in patients receiving FOLFOXIRI/​bevacizumab for metastatic colorectal cancer (mCRC): (PRESERVE1). ClinicalTrials.gov. Updated November 26, 2024. Accessed February 28, 2025. https://tinyurl.com/26ebkr6j