On February 13, 2023 G1 Therapeutics, Inc. (Nasdaq: GTHX), a commercial-stage oncology company, reported topline results from its pivotal Phase 3 PRESERVE 1 trial showing that the trial achieved its co-primary endpoints related to severe neutropenia with statistical significance; however, early anti-tumor efficacy data, including overall response rate (ORR) and preliminary measures of survival, favored the placebo arm (Press release, G1 Therapeutics, FEB 13, 2023, View Source [SID1234627102]). Other clinical trials of trilaciclib in combination with different chemotherapies in patients with extensive-stage small cell lung cancer and triple negative breast cancer did not demonstrate this adverse survival signal. Given that placebo outperformed trilaciclib in these analyses of PRESERVE 1, the Company has made the decision to discontinue the colorectal (CRC) trial. The Data Monitoring Committee (DMC) has independently reached the same conclusion.
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PRESERVE 1 was designed to evaluate the efficacy and safety of trilaciclib administered in addition to triplet therapy with FOLFOXIRI + bevacizumab in patients with metastatic CRC. Detailed Phase 3 results will be presented at an upcoming scientific congress and submitted for publication.
PRESERVE 1 achieved its co-primary endpoints showing clinically meaningful and statistically significant reductions in both occurrence of severe neutropenia during induction (placebo=20% vs. trilaciclib=1%; p<0.001) and mean duration of severe neutropenia in Cycles 1 through 4 (placebo=1.3 days vs. trilaciclib=0.1 days; p<0.001). In addition, patients receiving trilaciclib had 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, compared to placebo. Further, patients receiving trilaciclib experienced fewer chemotherapy dose reductions and delays. Other secondary measures of myeloprotection also favored trilaciclib, including reductions in Febrile Neutropenia (placebo=5% vs. trilaciclib=0%) and ESA administration (placebo=7% vs. trilaciclib=3%).
However, despite the achievement of the co-primary endpoints and other secondary measures of myeloprotection and tolerability, early anti-tumor efficacy data, including overall response rate (ORR), favor patients receiving placebo compared to trilaciclib (61% and 50% ORRs, respectively). Given the differential in these anti-tumor efficacy metrics and the low likelihood of achieving the progression-free survival (PFS) and overall survival (OS) endpoints, G1 has made the decision to discontinue PRESERVE 1.
"PRESERVE 1 is the first clinical evaluation of trilaciclib in a 5-FU-based chemotherapeutic backbone," said Raj Malik, M.D., G1 Therapeutics’ Chief Medical Officer. "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. 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."
"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. "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."
About PRESERVE 1
PRESERVE 1 is a global multi-center, randomized placebo-controlled, line extension pivotal Phase 3 trial of trilaciclib in 326 patients with metastatic CRC receiving first line trilaciclib administered to triplet therapy with FOLFOXIRI (fluorouracil (5-FU), folinic acid, oxaliplatin and irinotecan) and bevacizumab. The regimen was given for two consecutive days of every 14-day cycle. Patients received trilaciclib or placebo administered prior to their chemotherapy for a maximum of 12 cycles of induction followed by maintenance therapy.
Webcast and Conference Call
G1 will host a webcast and conference call at 8:30 a.m. ET today to discuss PRESERVE 1 and the Company’s ongoing commercial and clinical programs.
Please note that there is a new process to access the call via telephone. To register and receive a dial in number and unique PIN to access the live conference call, please follow this link to register online. While not required, it is recommended that you join 10 minutes prior to the start of the event. A live and archived webcast will be available on the Events & Presentations page of the company’s website: www.g1therapeutics.com. The webcast will be archived on the same page for 90 days following the event.