Trial Readouts Will Enforce the Role of Trilaciclib Across Multiple Cancers in 2023

Starting with the PRESERVE 1 trial of patients with metastatic colorectal cancer, 5 pivotal trials evaluating trilaciclib will announce results in 2023.

Five clinical trials evaluating trilaciclib (Cosela), its on-target effects of myeloprotection, and enhanced immune function with potential for improved efficacy outcomes are expected to have data readouts in 2023. These trial are evaluating patients with metastatic colorectal (mCRC), bladder or urothelial cancer (mUC), and triple negative breast cancer (TNBC).1

Trilaciclib is a first-in-class CDK4/6 inhibitor which is intravenously administered. The agent is designed to preserve bone marrow and immune system function during cytotoxic therapy to improve patient outcomes.

“Cytotoxic therapy remains the backbone of treatment for many metastatic tumors, either alone or in combination with targeted therapies,” said Raj Malik, MD, chief medical officer of G1 Therapeutics, Inc, in the press release. “But the high toxicity of these cytotoxic agents poses a risk of serious adverse events that can compromise patient well-being and patient outcomes. Trilaciclib represents a novel approach to protect against the side effects of cytotoxic therapy, but it also holds the potential to extend survival in certain cancer types, especially in combination with other novel anti-cancer interventions such as [antibody-drug conjugates] and checkpoint inhibitors—a benefit we are currently exploring in a variety of clinical trials with important readouts throughout 2023.”

Clinical Trial Readouts Expected in 2023

In February 2023, findings from the ongoing phase 3 PRESERVE 1 trial of 326 patients with mCRC will be released. Patients in the trial received trilaciclib administered prior to treatment with FOLFOXIRI and bevacizumab (Avastin).

Investigators are assessing primary end point of trial myeloprotection, which will be reported in the data. If these findings are positive, the trial will serve as the basis for extending the label to trilaciclib as a myeloprotective agent in patients with mCRC.

“Triplet therapy with FOLFOXIRI and bevacizumab is highly efficacious compared to doublet therapy, but it is also the most myelotoxic regimen with higher rates of neutropenia, febrile neutropenia, and diarrhea - which limits its use to a small population of first-line CRC patients,” said Malik, in the press release. “Trilaciclib may be an important addition to this regimen to enable a broader population of patients to benefit from this therapy and potentially further improve anti-tumor efficacy by allowing increased duration and exposure to chemotherapy.”

Then in the second quarter of 2023, findings from a phase 2 trial of trilaciclib (NCT05112536) in patients with refractory TNBC will be reported. The ongoing trial is evaluating trilaciclib administered prior to sacituzumab govitecan-hziy, an antibody-drug conjugate, in patients with unresectable locally advanced or metastatic TNBC. The data will include the anti-tumor efficacy end points of the trial, including the primary end point of progression-free survival.

According to initial results released from the study,trilaciclib reduced adverse events when administered prior to sacituzumab govitecan-hziy (Trodelvy). Initial data were on the first 18 patients enrolled and showed a clinically meaningful on-target effect of trilaciclib to reduce the rates of multiple AEs vs sacituzumab govitecan-hziy.

Phase 2 data from a trial evaluating the mechanism of action of trilaciclib in patients with neoadjuvant TNBC will also be released in the first half of 2023. Comprehensive data from the trial will be announced based on 24 patients and will analyze the secondary end point of pathologic complete response rate at the time of definitive surgery and the safety of trilaciclib combined with neoadjuvant chemotherapy.

Previously, initial results regarding the primary end point of trial were presented at the 2022 San Antonio Breast Cancer Symposium and showed there to be favorable alterations in the tumor microenvironment from trilaciclib monotherapy at a single dose. Future analyses of the trial will continue to analyze the immune-based mechanism of action of a single dose of trilaciclib.

For the phase 2 PRESERVE 3 trial (NCT04887831) evaluating trilaciclib in the first-line for patients with mUC, additional safety and efficacy data are to be presented midway through 2023. These findings will evaluate the primary end point of the anti-tumor efficacy of trilaciclib when combined with platinum-based chemotherapy and avelumab (Bavencio) maintenance therapy.

Findings announced in January 2023 showed that the confirmed objective response rate (ORR) was comparable between arms at the time of the data cutoff date. Still, longer-term follow-up is needed to evaluate the additional anti-tumor end points, including duration of confirmed ORR and PFS.

In this trial, though early, the safety and tolerability profile of trilaciclib when given before chemotherapy is overall consistent with that expected in patients treated with gemcitabine plus cisplatin/carboplatin and avelumab maintenance for patients with previously untreated advanced or mUC.

The phase 3 PRESERVE 2 (NCT04799249) trial evaluating patients with metastatic TNBC will also have a readout in mid 2023. This trial builds on phase 2 data which revealed a statistically significant survival improvement in 2 arms of the trial administered trilaciclib prior to gemcitabine plus cisplatin vs the arm given gemcitabine plus cisplatin alone (HR, 0.31 and 0.40, respectively).

An interim analysis of overall survival (OS) at 70% of events is expected this year which will in examine the effect of trilaciclib on OS in this patient population. If the interim OS analysis reaches the threshold of statistical significance and shows trilaciclib to have superior OS efficacy, the trial will end, and data will be reported with the potential of filing for approval of the agent in this space.

Lastly, the phase 3 PRESERVE 1 trial in mCRC is also expected to release initial PFS data regarding the combination of trilaciclib administered prior to FOLFOXIRI and bevacizumab.

Each of these 5 trials will pave the way in informing experts of the potential synergistic potential of trilaciclib. If data are positive, they may serve as the basis for seeking additional indications beyond extensive-stage small cell lung cancer.

G1 Therapeutics announces upcoming 2023 readouts from its phase 2 and pivotal phase 3 clinical trials of trilaciclib. News release. G1 Therapeutics, Inc. January 9, 2023. Accessed January 10, 2023.