Trilaciclib improves overall survival when given with gemcitabine/carboplatin (GC) in patients with metastatic triple negative breast cancer (mTNBC) in a randomized phase II trial

Background Trilaciclib (T) is an IV cyclin dependent kinase (CDK) 4/6 inhibitor and first-in-class myelopreservation agent. Previous results from this phase II trial demonstrated that adding T to GC in mTNBC resulted in: 1) a longer duration and higher administered total dose of chemotherapy, 2) higher response rates and longer PFS, and 3) reduction in the frequency of some myelosuppression events. We now report preliminary OS and updated PFS.TableLBA22TableGroup 1 GC D1, 8 n=34Group 2 Trilaciclib + GC D1, 8 n=33Group 3 Trilaciclib D1, 2, 8, 9 + GC D2, 9 n=35Group 2 + Group 3 n=68Progression-free survival (PFS)Patients with events [n (%)]18 (52.9%)19 (57.6%)18 (51.4%)37 (54.4%)Median PFS (95% CI) [months]5.7 (3.4, 9.2)9.4 (6.1, 13.0)7.3 (6.2, 12.9)8.8 (6.4, 10.9)HR0.600.590.59p-value0.12560.11670.0628Overall survival (OS)Patients with death [n (%)]19 (55.9%)11 (33.3%)14 (40.0%)25 (36.8%)Median OS (95% CI) [months]12.6 (6.3, 15.6)20.1 (10.2, NE)17.8 (12.9, NE)20.1 (15.3, NE)HR0.370.390.40p-value0.04110.00440.0032 Methods This randomized, phase II, open-label study enrolled mTNBC patients with 0-2 prior chemotherapy regimens for recurrent/metastatic disease. Patients were randomized to GC alone on day 1, 8 (Group 1) or T + GC (Group 2) or T + GC (Group 3) using an alternative schedule (T D1, 2, 8, 9 + GC D2, 9) every 21 days until disease progression or unacceptable toxicity. The primary endpoint was reduction in GC-related neutropenia. PFS and OS were secondary endpoints. Results Among 102 enrolled patients, 98 were treated. 52% had ECOG PS 0 and 37.3% received prior chemotherapy for mTNBC. Median follow-up is 10.5 months; 3 patients remain on treatment. There have been no SAEs related to T. Drug exposure in Group 2/3 patients receiving T (median 168 days, 8 cycles) is longer than with GC alone (median 101 days, 4 cycles). PFS and OS in the intent to treat (ITT) population are summarized in the table below. Groups 2+3 (receiving T) had longer PFS compared with GC alone, HR of 0.59, p=0.0628, and OS was statistically improved with HR of 0.37 and 0.39 in Groups 2 and 3, p=0.0411 and p=0.0044, respectively. ORR were 36.7%, 50.0%, and 33.3% in Groups 3, 2, and 1, respectively. Conclusions The addition of T to GC resulted in a significant increase in OS in both T groups. Previously observed PFS benefit with T was also confirmed. Clinical trial identification NCT02978716. Legal entity responsible for the study G1 Therapeutics, Inc. Funding G1 Therapeutics, Inc. Disclosure J. O'Shaughnessy: Honoraria (self): AbbVie Inc; Honoraria (self): Agendia; Honoraria (self): Amgen Biotechnology; Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Celgene Croporation; Honoraria (self): Eisai; Honoraria (self): Genentech; Honoraria (self): Genomic Health; Honoraria (self): GRAIL; Honoraria (self): Immunomedics; Honoraria (self): Heron Therapeutics; Honoraria (self): Ipsen Biopharmaceuticals; Honoraria (self): Jounce Therapeutics; Honoraria (self): Lilly; Honoraria (self): Merck; Honoraria (self): Myriad; Honoraria (self): Novartis; Honoraria (self): Ondonate Therapeutics; Honoraria (self): Pfizer. G.S. Wright: Honoraria (self): Total Health Conferencing; Shareholder / Stockholder / Stock options: Roche Holdings Ltd; Shareholder / Stockholder / Stock options: Odonate Therapeutics; Shareholder / Stockholder / Stock options: Puma Biotech; Research grant / Funding (institution), Shareholder / Stockholder / Stock options, PI does not receive direct research funding; institution received payment for conduct of trials: Macrogenics ; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: AbbVie; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Incyte; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Genentech; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Novartis; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Lilly; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Janssen; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Astellas; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Celgene; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: AstraZeneca; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Bristol-Myers Squibb; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Boehringer Ingelheim; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Medivation; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Merrimack; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Tesaro; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Pfizer. A. Thummala: Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Comprehensive Cancer Centers of Nevada. H.S. Han: Advisory / Consultancy: Lilly; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Novartis; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Pfizer; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Tesaro; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: TapImmune; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Seattle Genetics; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: BMS Prescient; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Horizon; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Karyopharm. S. Wilks: Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: US Oncology. J.A. Sorrentino: Shareholder / Stockholder / Stock options, Full / Part-time employment: G1 Therapeutics. Z. Yang: Shareholder / Stockholder / Stock options, Full / Part-time employment: G1 Therapeutics. J.K. Horton: Shareholder / Stockholder / Stock options, Full / Part-time employment: G1 Therapeutics; Honoraria (self), Research grant / Funding (self): Varian Medical Systems; Honoraria (self): Qfix; Leadership role: International Journal of Radiation Oncology, Biology, Physics; Leadership role: American Board of Radiology; Leadership role: ASTRO. A.R. Tan: Advisory / Consultancy: Celgene; Advisory / Consultancy: Immunomedics; Advisory / Consultancy, Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Research grant / Funding (self): Merck; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: G1 Therapeutics; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Roche; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Tesaro; Leadership role, Breast Cancer Leader: Caris Precision Oncology Alliance. All other authors have declared no conflicts of interest.