PRESERVE 1 Trial of Trilaciclib in mCRC Ended Due to Efficacy Results

Despite achieving the co-primary end points, the phase 3 PRESERVE trial of trilaciclib in patients with metastatic colorectal cancer will be terminated.

The phase 3 PRESERVE 1 trial (NCT04607668) evaluating trilaciclib (Cosela) for the treatment of patients with metastatic colorectal cancer (mCRC) receiving chemotherapy will be terminated, according to G1 Therapeutics, Inc.1

In the trial, trilaciclib led to clinically meaningful and statistically significant reductions in the occurrence of severe neutropenia during induction (20% with placebo vs 1% with trilaciclib; P < .001) and mean duration of severe neutropenia in cycles 1-4 (1.3 days vs 0.1 days; P < .001. However, the early anti-tumor efficacy data, including overall response rate (ORR) and preliminary measures of survival, favored treatment with placebo compared with trilaciclib.

While the study met its primary end points, the placebo outperformed trilaciclib in this analysis of the PRESERVE 1 trial. The Company and the Data Monitoring Committee have decided to discontinue the colorectal trial.

"The results of this trial were relatively discouraging for further development of trilaciclib as a strategy to enhance the delivery of more consistent dose intensity of chemotherapy by reducing severe neutropenia. The study did achieve its primary goal, but unfortunately suggested a detrimental effect for adding trilaciclib to chemotherapy in colon cancer. In colon cancer, and perhaps most GI malignancies which share common chemotherapy backbones, further strategies to develop trilaciclib will likely prove futile," Tanios Bekaii-Saab, MD, FACP, medical oncologist, medical director, Cancer Clinical Research Office, vice chair and section chief, medical oncology, Department of Internal Medicine, Mayo Clinic, Phoenix, Arizona, told Targeted OncologyTM.

PRESERVE 1 was a randomized, double-blind, placebo-controlled, global, multicenter, phase 3 trial assessing the efficacy and safety of trilaciclib given to patients with mCRC in addition to triplet therapy with folinic acid, 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (FOLFOXIRI) and bevacizumab (Avastin).2

The trial enrolled patients aged 18 years of age or older with proficient mismatch repair/microsatellite stable, histologically or cytologically-confirmed adenocarcinoma of the colon or rectum. If patients had BRAF or KRAS mutations, they were eligible. Further, patients must have had disease that was unresectable and measurable, or evaluable per RECIST v1.1, an ECOG performance status of 0-1, and adequate organ function.

Patients were randomly assigned to treatment with placebo or intravenous trilaciclib on 2 consecutive days of every 14-day cycle for a maximum of 12 cycles of induction followed by maintenance therapy.

Findings showed that the PRESERVE 1 study achieved its co-primary end points by demonstrating clinically meaningful and statistically significant reductions in the occurrence of severe neutropenia during induction and mean duration of severe neutropenia. Treatment with trilaciclib led to a clinically meaningful reduction in the rate of chemotherapy-induced diarrhea. This included a 50% reduction in the rate of grade 3 or 4 diarrhea and a 30% reduction in the rate of any grade diarrhea vs placebo. Additionally, those given trilaciclib had fewer chemotherapy dose reductions and delays.

Trilaciclib also led to reductions in febrile neutropenia at 5% with placebo vs 0% with trilaciclib, and ESA administration with 7% for placebo vs 3% for trilaciclib.

Despite reaching its co-primary end points and other secondary measures of myeloprotection and tolerability, the early anti-tumor efficacy data favored placebo compared with trilaciclib. Patients receiving placebo had an ORR of 51% vs 50% with trilaciclib. As a result and given the low likelihood of achieving the end points of progression-free survival and overall survival, the PRESERVE 1 trial has been discontinued.

Results from this phase 3 trial are expected to be presented at an upcoming scientific congress and submitted for publication.

“PRESERVE 1 is the first clinical evaluation of trilaciclib in a 5-FU-based chemotherapeutic backbone,” said Raj Malik, MD, chief medical officer of G1 Therapeutics, in the press release. “This study reaffirms that trilaciclib is a highly effective drug for myeloprotection that all but eliminated neutropenia as a concern for patients with CRC in the trial, which helps inform our ongoing combination studies with other highly myelotoxic regimens like ADCs. Unfortunately, despite the robust myeloprotection and improved tolerability, early survival indicators, including the observed overall response rate in this trial, favor patients receiving placebo. 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...”

“All of us at G1 are disappointed in this surprising outcome for patients with CRC, but we remain committed to the potential of trilaciclib to impact the lives of many cancer patients in other indications,” said Jack Bailey, G1 Therapeutics’ chief executive officer, in the press release. “We are increasingly encouraged by the real-world performance of trilaciclib in patients with extensive stage small cell lung cancer and look forward to upcoming readouts in our other ongoing trials.”

G1 Therapeutics announces topline 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. February 13, 2023. Accessed February 13, 2023.
Trilaciclib, a CDK 4/6 inhibitor, in patients receiving FOLFOXIRI/bevacizumab for metastatic colorectal cancer (mCRC): (PRESERVE1). Accessed February 13, 2022.
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