Trilaciclib Plus Bevacizumab/FOLFOXIRI Reduces Severe Neutropenia, Fails to Improve Efficacy in mCRC

Adding trilaciclib (Cosela) to FOLFOXIRI and bevacizumab (Avastin) led to statistically significant reductions in instances of severe neutropenia during induction and duration of severe neutropenia in cycles 1 to 4. However, the combination failed to improve antitumor activity vs placebo plus FOLFOXIRI/bevacizumab in patients with metastatic colorectal cancer (mCRC), according to topline data from the phase 3 PRESERVE 1 trial (NCT04607668).¹

The trial met its co-primary end points for rates of severe neutropenia during induction and in cycle 1, antitumor efficacy data for overall response rate (ORR) and preliminary measures of survival favored the placebo arm. G1 Therapeutics plans to discontinue PRESERVE 1 based on these findings.

In the trilaciclib arm, 1% of patients experienced severe neutropenia during induction compared with 20% of patients in the placebo arm (P < .001). The mean duration of severe neutropenia was 0.1 days and 1.3 days in the trilaciclib and placebo arms, respectively (P < .001).

However, ORR was just 50% in the trilaciclib arm compared with 61% for patients in the placebo arm. Full data will be presented at an upcoming scientific congress and submitted for publication.

“PRESERVE 1 is the first clinical evaluation of trilaciclib in a 5-fluorouracil–based chemotherapeutic backbone,” Raj Malik, MD, chief medical officer of G1 Therapeutics, stated in a news 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.

Malik noted that the ORR favored placebo even though the experimental treatment was associated robust myeloprotection and improved tolerability, both of which are early indicators of survival.

“These results in PRESERVE 1 are inconsistent with what we’ve observed in other tumors with different chemotherapy backbones,” he added. “As a result of these topline results, we have made the decision to terminate this study. While we are disappointed, we are grateful for the patients, clinical investigators and their office staff, our partner Simcere, and the G1 team—all of whom contributed to the conduct of this trial.”

The global, multicenter, randomized, placebo-controlled, line extension PRESERVE 1 trial evaluated FOLFOXIRI and bevacizumab in combination trilaciclib or placebo as first-line treatment for 326 patients with metastatic CRC. Patients were required to be at least 18 years of age with unresectable and measurable or evaluable disease per RECIST v1.1, an ECOG performance status of 0 or 1, and adequate organ function.²

Key exclusion criteria included prior systemic therapy for mCRC; any radiotherapy, chemotherapy, immunotherapy, biologic, investigational, or hormonal therapy for cancer treatment within 3 weeks of first study treatment; central nervous system metastases or leptomeningeal disease requiring immediate treatment with radiation therapy or steroids; or symptomatic peripheral neuropathy.

Patients received treatment for two consecutive days of every 14-day cycle. Trilaciclib or placebo was administered prior to chemotherapy for a maximum of 12 cycles of induction therapy, followed by maintenance therapy.1

The trial’s secondary end points included progression-free survival, overall survival, and quality of life.

Additional data showed that patients in the trilaciclib arm experienced a clinically meaningful reduction in the rate of chemotherapy-induced diarrhea, including a 50% reduction in the rate of grade 3/4 diarrhea and a 30% reduction in the rate of any-grade diarrhea vs placebo. Those given trilaciclib also had fewer chemotherapy dose reductions and delays.

Additionally, no patients in the trilaciclib arm experienced febrile neutropenia, compared with 5% of patients in the placebo arm. Three percent of patients in the trilaciclib group received erythropoiesis-stimulating agents compared with 7% in the placebo group.

“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,” Jack Bailey, chief executive officer of G1 Therapeutics, stated in a news 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.”

References

1. 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. February 13, 2023. Accessed February 13, 2023. http://investor.g1therapeutics.com/news-releases/
2. Trilaciclib, a CDK 4/6 Inhibitor, in patients receiving FOLFOXIRI/bevacizumab for metastatic colorectal cancer (mCRC): (PRESERVE1). ClinicalTrials.gov. Updated January 4, 2023. Accessed February 13, 2023. https://clinicaltrials.gov/ct2/show/NCT04607668