Although trilaciclib appears to reduce neutropenia following treatment with FOLFOXIRI and bevacizumab in patients with metastatic colorectal cancer, the phase 3 PRESERVE 1 trial will be stopped due to a lack of responses.
Treatment with trilaciclib (G1T28) in patients with metastatic colorectal cancer (CRC) receiving folinic acid, fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab (Avastin) significantly reduced the incidence of neutropenia compared with placebo but did not yield improvements in anti-tumor efficacy, according to a press release on the shutdown of the phase 3 PRESERVE 1 trial (NCT04607668).
During induction, the trilaciclib arm experienced a severe neutropenia rate of 1% vs 20% in the placebo arm (P <.001). Additionally, the mean duration of severe neutropenia in cycles 1 to 4 were 0.1 days vs 1.3 days in each respective cohort (P <.001). Other safety benefits with the trilaciclib combination included reductions in chemotherapy-induced diarrhea, febrile neutropenia, and erythropoiesis-stimulating agent administration compared with placebo.
Despite the observed benefits related to safety and tolerability, the overall response rate (ORR) was 50% in the trilaciclib cohort vs 61% in the placebo cohort. Based on the early efficacy data and low probability of reaching the progression-free survival (PFS) and overall survival (OS) end points, the investigators of the PRESERVE 1 study have decided to discontinue their research.
“Unfortunately, despite the robust myeloprotection and improved tolerability, early survival indicators, including the observed [ORR] in this trial, favor patients receiving placebo,” Raj Malik MD, chief medical officer at G1 Therapeutics, said in the press release. “These results in PRESERVE 1 are inconsistent with what we’ve observed in other tumors with different chemotherapy backbones. As a result of these topline results, we have made the decision to terminate this study.”
Investigators of the randomized, double-blind phase 3 PRESERVE 1 trial compared the efficacy and safety of trilaciclib plus FOLFOXIRI and bevacizumab with placebo plus the same chemotherapy backbone among patients with metastatic CRC. Patients received trilaciclib or matched placebo followed by FOLFOXIRI plus bevacizumab intravenously for a maximum of 12 cycles before maintenance therapy.
The primary end points of the trial were the occurrence and mean duration of neutropenia following treatment. Secondary end points included quality of life, PFS, ORR, and OS.
Patients 18 years or older with mismatch repair proficient or microsatellite stable, histologically or cytologically confirmed adenocarcinoma of the colon or rectum were eligible for enrollment. Additional inclusion criteria included having unresectable and measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, a formalin-fixed paraffin-embedded tumor specimen, and adequate organ function.
Patients who received prior systemic therapy for metastatic CRC or any radiotherapy, chemotherapy, immunotherapy, biologic, investigational, or hormonal therapy within 3 weeks before beginning study treatment were not eligible for enrollment. Patients were also unsuitable for enrollment if they had central nervous system metastases, a history of long QT syndrome, symptomatic peripheral neuropathy, a history of interstitial lung disease, or prior allogeneic or autologous hematopoietic stem cell or bone marrow transplantation.
G1 Therapeutics announces top line results from pivotal phase 3 trial of trilaciclib in patients receiving triplet therapy with folfoxiri + bevacizumab for metastatic colorectal cancer (CRC) (PRESERVE 1). News release. G1 Therapeutics, Inc. February 13, 2023. Accessed February 13, 2023. bit.ly/3YtyTPT