Trilaciclib prior to FOLFOXIRI/bevacizumab for patients with untreated metastatic colorectal cancer: phase 3 PRESERVE 1 trial

Heinz-Josef Lenz; Tianshu Liu; Emerson Y Chen; Zsolt Horváth; Igor Bondarenko; Iwona Danielewicz; Michele Ghidini; Pilar García-Alfonso; Robert Jones; Matti Aapro; Yanqiao Zhang; Jufeng Wang; Wayne Wang; Jennifer Adeleye; Andrew Beelen; Joleen Hubbard

doi:10.1093/jncics/pkae116

Trilaciclib prior to FOLFOXIRI/bevacizumab for patients with untreated metastatic colorectal cancer: phase 3 PRESERVE 1 trial

JNCI Cancer Spectr. 2024 Nov 23:pkae116. doi: 10.1093/jncics/pkae116. Online ahead of print.

Authors

Heinz-Josef Lenz¹, Tianshu Liu², Emerson Y Chen³, Zsolt Horváth⁴, Igor Bondarenko⁵, Iwona Danielewicz⁶, Michele Ghidini⁷, Pilar García-Alfonso⁸, Robert Jones⁹, Matti Aapro¹⁰, Yanqiao Zhang¹¹, Jufeng Wang¹², Wayne Wang¹³, Jennifer Adeleye¹³, Andrew Beelen¹³, Joleen Hubbard¹⁴

Affiliations

¹ Department of Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
² Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
³ Oregon Health & Science University, Department of Medicine, Division of Hematology and Medical Oncology, Knight Cancer Institute, Portland, OR, USA.
⁴ Center of Oncoradiology, Bács-Kiskun County Teaching Hospital, Kecskemét, Hungary.
⁵ Dnipropetrovsk State Medical Academy, City Multifield Clinical Hospital, Dnipropetrovsk, Ukraine.
⁶ Szpitale Pomorskie Sp. z o.o. Gdynia, Poland.
⁷ Operative Unit of Medical Oncology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
⁸ Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria (IiSGM), Universidad Complutense de Madrid, Madrid, Spain.
⁹ Cardiff University and Velindre NHS Trust, Cardiff, UK.
¹⁰ Genolier Cancer Centre, Clinique de Genolier, Genolier, Switzerland.
¹¹ Harbin Medical University Cancer Hospital, Nangang, Harbin, Heilongjiang, China.
¹² Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
¹³ G1 Therapeutics, Inc., Research Triangle Park, NC, USA.
¹⁴ Allina Health Cancer Institute, Abbott Northwestern Hospital, Minneapolis, MN, USA.

PMID: 39579142
DOI: 10.1093/jncics/pkae116

Abstract

Background: In metastatic colorectal cancer (mCRC), improvements in survival from combining leucovorin/fluorouracil/oxaliplatin/irinotecan (FOLFOXIRI) with bevacizumab have come at the risk of increased rates of high-grade toxicities. Trilaciclib is indicated to decrease the incidence of chemotherapy-induced myelosuppression in patients receiving standard-of-care chemotherapy for extensive-stage small cell lung cancer.

Methods: Patients with untreated mCRC were randomized 1:1 to trilaciclib (n = 164) or placebo (n = 162) prior to FOLFOXIRI/bevacizumab for up to 12 cycles (induction), followed by trilaciclib or placebo prior to fluorouracil/leucovorin/bevacizumab (maintenance). Co-primary endpoints were duration of severe (grade 4) neutropenia (DSN) in cycles 1-4 and occurrence of severe neutropenia (SN) during induction. Secondary endpoints included antitumor efficacy, survival, and safety.

Results: : The study met its co-primary endpoints. Administering trilaciclib prior to FOLFOXIRI/bevacizumab resulted in significant reductions in DSN in cycles 1-4 versus placebo (mean, 0.1 vs. 1.3 days; P < .001) and occurrence of SN during induction (1.3% vs. 19.7%; adjusted relative risk [96% CI], 0.07 [0.0, 0.3]; P < .001). Grade 3/4 adverse events, including neutropenia, diarrhea, and leukopenia, were less frequent with trilaciclib versus placebo (64.8% vs. 73.1%). Trilaciclib was associated with fewer chemotherapy dose reductions and delays, and reduced administration of supportive therapies, compared with placebo. Objective response rate (41.6% vs. 57.1%; P = .009) and median progression-free survival (10.3 vs. 13.1 months; P < .001) were significantly lower with trilaciclib versus placebo.

Conclusions: : Administering trilaciclib prior to FOLFOXIRI/bevacizumab protected the neutrophil lineage from the effects of chemotherapy-induced myelosuppression. However, antitumor efficacy endpoints favored placebo.

Keywords: FOLFOXIRI; bevacizumab; colorectal cancer; metastatic; myeloprotection; myelosuppression; trilaciclib.