BLU-222 Shows Safety, Tolerability in Combination Therapy for Patients With Breast Cancer

Patients with breast cancer showed promising responses when treated with BLU-222 combined with ribociclib and fulvestrant. | Image Credit: Pixel-Shot - stock.adobe.com

BLU-222 as a monotherapy and in combination with ribociclib and fulvestrant showed safety and tolerability in patients with hormone receptor (HR)–positive and HER2-negative breast cancer.¹

At the 2024 American Society of Clinical Oncology annual meeting, a poster presentation displayed data focused on the successful combination of the selective CDK2 inhibitor with ribociclib, an FDA-approved CDK4/6 inhibitor, and fulvestrant, an estrogen receptor antagonist.

The aim of the study was to find an approach to treat or prevent CDK4/6 inhibitor resistance in patients with advanced breast cancer. The investigational, oral, potent, and highly selective CDK2 inhibitor known as BLU-222 had already demonstrated activity as a monotherapy and in combination treatment in preclinical models of HR-positive and HER2-negative breast cancers, along with CCNE1-amplified solid cancers.

Methods

The research was conducted in VELA (NCT05252416), an international, open-label, first-in-human, phases 1 and 2 trial. The safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of BLU-222 as a monotherapy was measured among all adult patients with advanced solid tumors and combined with ribociclib and fulvestrant for patients with HR-positive and HER2-negative breast cancer.

The primary outcomes of the trial included the maximum tolerated dose, the recommended phase 2 dose, the overall safety of BLU-222, and the disease response per RECIST for phase 2 only. Additional assessments included plasma BLU-222 concentrations and biomarker assessments.

The study utilized the Eastern Cooperative Oncology Group (ECOG) Performance Status (PS), which is a scaling model that measures the disease impact on patient’s daily lives by describing the level of function of their ability to care for themselves, complete daily activities, and physical abilities. Measurement grades begin at 0, being the most active, to 5, death.²

Patients were considered eligible if they were 18 years or older, had an ECOG PS score between 0 to 2, had confirmed nonresectable advanced solid tumors, experienced progression after standard of care treatment, and were enrolled regardless of CCNE1 status.¹

Results

By April 10, 2024, the study had 75 patients in the safety population; 84% of the monotherapy cohort and 100% of the combination treatment cohort identified as female. The population included 56 patients in the monotherapy cohort who received 50 mg to 800 mg of BLU-222 twice daily (BID). The other cohort consisted of 19 patients who received combination therapy of 100 mg to 400 mg BLU-222 BID with 400 mg ribociclib and 500 mg fulvestrant, a triple combination.

Ribociclib is an FDA-approved oral drug used to target advanced or metastatic breast cancer, including cancer that has spread to nearby lymph nodes, muscle, and skin.³ Typically, ribociclib is not prescribed as a monotherapy and almost always is accompanied by a hormone therapy drug.

On the other hand, fulvestrant is an FDA-approved injection that can be administered as a monotherapy or in combination with another chemotherapy medication.⁴ Unlike ribociclib, fulvestrant belongs to the estrogen receptor antagonist class rather than a CDK4/6 inhibitor.

The monotherapy cohort had an average age of 65 years, and the combination treatment cohort had an average age of 58 years.¹

None of the participants in the combination cohort had an ECOG PS grade of 2 (grade 0, 52.6%; grade 1, 47.4%). However, the monotherapy group patients at baseline ECOG PS scores ranging from 0 to 2 (grade 0, 42.9%; grade 1, 50%; grade 2, 7.1%).

Monotherapy

Safety

The monotherapy cohort demonstrated safety of BLU-222 and did not identify a maximum tolerated dose. Common treatment-emergent adverse events (TEAEs) included diarrhea (55%), nausea (54%), fatigue (39%), vomiting (38%), anemia (29%), photophobia (18%), and hypokalemia (18%). None of the participants in the cohort experienced cardiac-related AEs.

Only 2 patients experienced dose-limiting toxicities (DLTs), but they improved shortly after dose reduction. Additionally, treatment-related hematologic and gastrointestinal AEs were reported to be mild. Around 28.6% of patients reported treatment-related visual AEs. Only 3 patients discontinued treatment based on the impact of AEs.

Pharmacokinetics

Study results were comparable to previous BLU-222 reports where the plasma concentrations increased in a dose-proportional trend up to 600 mg BID. On average, the effective half-life for the treatment was 16 hours.

Pharmacodynamics

Participants treated with BLU-222 monotherapy observed dose-proportional reductions in TK1 activity, with the highest reductions noticed at dose levels 400 mg or greater. Patients also identified reductions in retinoblastoma protein (pRb) when treated with at least 400 mg BLU-222.

Efficacy

A total of 16 patients with HR-positive and HER2-negative breast cancer were treated with BLU-222 monotherapy. Almost half of the treated patients (n = 7) were dosed in the active range (≥400 mg BID), and 3 patients out of the 7 showed evidence of clinical benefit.

Timothy Yap, MBBS, PhD, FRCP, medical oncologist and physician-scientist based at the University for Texas MD Anderson Cancer Center professor in the Department for Investigational Cancer Therapeutics, Division of Cancer Medicine, commented on the BLU-222 study, which he contributed to, in an interview with The American Journal of Managed Care^®. Yap stated, “One patient had a significant reduction in disease-related bone pain and another patient with measurable disease had a confirmed partial response by RECIST criteria.”

Combination Therapy

Safety

The combinations of BLU-222 (100 mg, 200 mg, 400 mg), ribociclib (400 mg), and fulvestrant (500 mg) were well-tolerated among patients. None of the patients in the cohort experienced DLTs, treatment-related severe adverse events (SAEs), or grade 4/5 AEs.

There were mostly mild treatment-related hematologic AEs, with 2 patients who experienced grade 3 white blood cell decrease and neutropenia. Patients had low rates of diarrhea and gastrointestinal AEs were mainly grade 1. Only 1 patient discontinued treatment based on a ribociclib AE.

Pharmacokinetics

The combination therapy increased in a dose-proportional manner across the 100 mg, 200 mg, and 400 mg BLU-222 BID cohorts. Based on previous reports, ribociclib exposure was comparable to prior publications.

Pharmacodynamics

The deepest TK1 reduction was expressed among patients treated with 400 mg BLU-222 combined with 400 mg ribociclib and 500 mg fulvestrant. Significant decrease in TK1 was directly associated with the heightened exposure to BLU-222 rather than ribociclib in patients treated with BLU-222, ribociclib, and fulvestrant combined.

Reductions in ctDNA were identified in 6 out of 6 patients who had ctDNA available and were treated with 400 mg BLU-222 combined with 400 mg ribociclib and 500 mg fulvestrant.

Yap concluded, “We've shown through preclinical studies that CDK2 inhibition, when combined with CDK4/6 inhibitors and endocrine therapy, there [is] antitumor activity there. That's really why it's such an attractive therapeutic option for these patients with HR-positive breast cancer, particularly to either treat the CDK4/6 inhibitor resistance or to prevent the CDK4/6 inhibitor resistance from coming in.”

Ongoing clinical trials are investigating the optimal dose of BLU-222 in combination with different treatment regimens, including ribociclib at 400 mg or 600 mg and fulvestrant. Additionally, future cohorts will confirm effective doses for the combination of BLU-222 with ribociclib and letrozole.

References:

1. Juric D, Patel MR, Duska LR, et al. BLU-222, an investigational, oral, potent, and highly selective CDK2 inhibitor, as monotherapy in patients with advanced solid tumors and in combination with ribociclib and fulvestrant in HR+/HER2– breast cancer. Presented at: ASCO 2024; May 31-June 4, 2024; Chicago, IL. Abstract 1056. https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.1056

2. ECOG performance status scale. ECOG-ACRIN Cancer Research Group. 2022. Accessed July 3, 2024. https://ecog-acrin.org/resources/ecog-performance-status/

3. Ribociclib (Kisqali). Cancer Research UK. April 15, 2024. Accessed July 9, 2024. https://www.cancerresearchuk.org/about-cancer/treatment/drugs/ribociclib

4. Fulvestrant injection. MedlinePlus Drug Information. February 15, 2024. Accessed July 9, 2024. https://medlineplus.gov/druginfo/meds/a607031.html#:~:text=Fulvestrant%20injection%20is%20used%20alone