Trilaciclib Plus Chemotherapy and Avelumab Maintenance Generates Comparable ORR in Advanced/Metastatic Urothelial Carcinoma

Raj Malik, MD

Adding the CDK4/6 inhibitor trilaciclib (Cosela) to platinum-based chemotherapy and avelumab (Bavencio) maintenance produced an overall response rate (ORR) comparable to chemotherapy and maintenance avelumab alone in patients with previously untreated locally advanced or metastatic urothelial carcinoma.¹

Initial data from the phase 2 PRESERVE3 trial (NCT04887831) showed that patients treated in the trilaciclib arm (n = 45) achieved an ORR of 40% compared with 46.7% for patients in the control arm (n = 45). G1 Therapeutics said that it expects additional safety and efficacy data, including the primary end point of progression-free survival (PFS), to be in the middle of 2023.

“The immunomodulatory mechanism of action of trilaciclib lends itself to longer-term antitumor efficacy end points like PFS, as opposed to shorter-term response rate end points, as was noted in the phase 2 trial in triple-negative breast cancer,” Raj Malik, MD, chief medical officer at G1 Therapeutics, stated in a press release. “We look forward to the results of the maintenance portion of this trial, particularly given the preclinical work that we have conducted showing the potential synergy of trilaciclib with checkpoint inhibitors—which we seek to validate clinically in this study with longer-term duration of response and PFS data.”

The randomized, open-label PRESERVE3 study enrolled patients who were at least 18 years of age with histologically documented, locally advanced (T4b, any N; or any T, N 2-3) or metastatic urothelial carcinoma (M1, stage IV).² Patients were required to have measurable disease per RECIST v1.1 criteria; no prior systemic therapy in the inoperable, locally advanced, or metastatic setting including chemotherapy, immune checkpoint inhibitor therapy, targeted therapy, or investigational agents; an ECOG performance status of 0 to 2; and adequate organ function.

Key exclusion criteria included malignancies other than urothelial carcinoma within 3 years prior to randomization, the presence of central nervous system metastases/leptomeningeal disease requiring immediate treatment with radiation therapy or steroids, prior hematopoietic stem cell or bone marrow transplantation, solid organ transplantation, or an active autoimmune disease.

Investigators randomly assigned patients in a 1:1 fashion to the experimental or control groups. Those in the experimental arm received trilaciclib at 240 mg/m2 plus gemcitabine at 1000 mg/m2 on days 1 and 8 and cisplatin at 70 mg/m2 or carboplatin at an area under the curve of 4.5 on day 1 of each 21-day cycle, followed by maintenance with trilaciclib at 240 mg/m2 plus avelumab at 800 mg on day 1 of each 14-day cycle. Trilaciclib was administered prior to chemotherapy and avelumab maintenance on each day the respective treatments were given. Patients in the control arm received the same regimen of chemotherapy and avelumab maintenance without trilaciclib.

Along with the primary end point of PFS, secondary end points included antitumor effects and myeloprotective effects.

Regarding safety, the data monitoring committee recommended that the study continue as planned. The safety and tolerability trilaciclib administered prior to chemotherapy was generally consistent with that expected in patients treated with gemcitabine plus cisplatin/carboplatin and avelumab maintenance for previously untreated advanced or metastatic urothelial carcinoma.

References

1. G1 Therapeutics provides initial update on phase 2 bladder cancer trial; progression free survival (PFS) data expected in mid-2023. News release. G1 Therapeutics. January 4, 2023. Accessed January 5, 2023. https://bit.ly/3vG0fWd
2. Trilaciclib, a CDK 4/6 inhibitor, in patients with advanced/metastatic bladder cancer receiving chemotherapy then avelumab (PRESERVE3). ClinicalTrials.gov. Updated October 26, 2022. Accessed January 5, 2023. https://clinicaltrials.gov/ct2/show/NCT04887831