FDA Grants Fast Track Designation to CFI-402257 for ER+/HER2– Breast Cancer

The FDA has granted a fast track designation to best-in-class threonine tyrosine kinase (TTK) inhibitor CFI-402257, both as monotherapy and in combination with fulvestrant (Faslodex), for the treatment of adult patients with estrogen receptor (ER)–positive/HER2-negative advanced breast cancer after disease progression on prior CDK4/6 inhibitors and endocrine therapy.¹

TTK, which is correlated with high grade in tumors and poor patient outcomes, is upregulated in several cancers. Preclinical models showed that treatment with CFI-402257 suppressed tumor growth in ER-positive/HER2-negative cell lines and patient-derived xenograft models.²

“There is an urgent need for new, safe, and efficacious therapies to treat ER-positive/HER2-negative breast cancer, particularly when standard-of-care regimens fail," Mark Bray, PhD, chief science officer and co-founder of Treadwell Therapeutics, stated in a news release. “CFI-402257 has shown early signs of durable activity with a manageable safety profile, as a monotherapy and in combination with fulvestrant in [patients with] ER-positive/HER2-negative breast cancer that have failed CDK4/6 inhibitors.”

Investigators evaluated CFI-402257 as monotherapy and in combination with fulvestrant in a phase 1 trial (NCT02792465) in patients with advanced solid tumors with HER2-negative breast cancer expansion cohorts.

Findings presented at the 2022 San Antonio Breast Cancer Symposium showed that among 66 patients with advanced solid tumors treated with CFI-402257 alone, the confirmed overall response rate (ORR) was 5% for t. In 20 patients with ER-positive and/or progesterone receptor (PR)–positive, HER2-negative breast cancer treated with CFI-402257 plus fulvestrant, the confirmed ORR was 10%. Additionally, 1 patient with ER-positive/HER2-negative breast cancer experienced an unconfirmed partial response to CFI-402257 monotherapy and remains on study.

Of the patients to experience responses to CFI-402257 monotherapy or the combination, 5 had ER-positive/HER2-negative breast cancer, and 1 had hepatocellular carcinoma.

Patients were required to be at least 18 years of age with measurable disease. In the dose-escalation phase and in cohort A of the dose-expansion phase, the trial enrolled patients with measurable advanced cancer that had no further standard anticancer therapy available.

The expansion phase also included patients with triple-negative breast cancer or ER-positive breast cancer following treatment with a CDK4/6 inhibitor and up to 4 lines of chemotherapy who had prior treatment with anthracycline and a taxane and were not candidates for endocrine therapy (cohort B), and patients with ER- and/or PR-positive, HER2-negative breast cancer who had prior treatment with an aromatase inhibitor in combination with a CDK4/6 inhibitor for at least 3 months prior to disease progression (cohort C).

Key exclusion criteria for all patients included treatment with radiotherapy, chemotherapy, biological therapy, or an investigational agent less than 4 weeks prior to first study treatment; growth factors within 14 days of starting study drug or requiring ongoing growth factor treatment during the study; or prior treatment with TTK or MPS1 inhibitor. Patients in cohort C could not have received prior treatment with, or have a contraindication to, fulvestrant.

During dose escalation, patients with advanced solid tumors were treated with daily CFI-402257 at 84 mg (n = 4), 126 mg (n = 3), 168 mg (n = 6), 210 mg (n = 5), and 294 mg (n = 3). After dose escalation established 168 mg per day as the recommended phase 2 dose (RP2D) of CFI-402257, patients in cohorts received the RP2D. Those in cohort C were administered the RP2D of CFI-402257 in combination with fulvestrant.

The primary objectives of the study included safety, tolerability, identifying the maximum tolerated dose and RP2D, pharmacokinetics, and antitumor activity. The study also evaluated the safety and tolerability of CFI-402257 monotherapy in the dose-escalation phase, then as a single agent and in combination with fulvestrant during the dose-expansion phase.

Among all enrolled patients across the dose-escalation and -expansion phases (n = 86), the median age was 60 years (range, 31-81). Fifty-two percent of patients had breast cancer, and other tumor types included gynecological (13%), gastrointestinal (9%), genitourinary (5%), and other (12%). The median prior lines of therapy was 5 (range, 0-17), and 41% of patients had an ECOG performance status of 0.

Within cohort C (n = 20), the median age was 54 (range 31-70), and the median prior lines of therapy was 4 (range, 1-9). Half of patients had an ECOG performance status of 0.

Additional data showed that the clinical benefit rate of stable disease for at least 6 months, partial response, or complete response was 12% and 25% for patients given CFI-402257 monotherapy and in combination with fulvestrant, respectively.

Ninety-two percent of all patients have discontinued from the study, and the most common reason was due to progression disease (74%). Three patients, who were all treated with CFI-402257 monotherapy, discontinued due treatment-emergent adverse effects (TEAEs) of biliary obstruction febrile neutropenia, and pancytopenia.

Forty percent of patients died on study, with the most common cause of death being progressive disease (33%). Notably, 5 patients died due to TEAEs, including 2 from malignant neoplasm progression, and 1 each due to pancytopenia, hepatic failure, and unknown cause.

Among all patients, any-grade TEAEs occurred in 99% of patients, and grade 3 or higher TEAEs were reported in 37% of patients. TEAEs related to CFI-402257 were observed in 70% of patients. The most common grade 3 or higher TEAEs included anemia (8% and 5% in the monotherapy and combination groups, respectively), neutropenia (6% and 5%), and febrile neutropenia (5% and 5%).

Twenty-four percent of patients experienced serious AEs. Seven percent of patients had serious AEs related to CFI-402257.

Investigators are also evaluating the safety and tolerability of CFI-402257 monotherapy and in combination with fulvestrant in patients with advanced solid tumors and in advanced breast cancer to obtain further safety, efficacy, pharmacokinetics, and pharmacodynamics data for the TTK inhibitor in the ongoing phase 1/2 trial (NCT05251714).³

References

1. Treadwell Therapeutics announces fast track designation granted by the FDA to CFI-402257 for the treatment of ER+/HER2- breast cancer. News release. January 10, 2023. Accessed January 11, 2023. https://bit.ly/3Gy0BTV
2. Hilton JF, Renouf DJ, Cescon DW, et al. An update to a phase I trial of CFI-402257, an oral TTK inhibitor, in patients with advanced solid tumors with HER2-negative breast cancer expansion cohorts. Presented at: 2022 San Antonio Breast Cancer Symposium. December 6-10, 2022; San Antonio, TX. Poster P6-10-13. https://bit.ly/3k7wtam
3. CFI-402257, a potent and selective TTK inhibitor, in solid tumors and with fulvestrant in breast cancer. ClinicalTrials.gov. Updated July 29, 2022. Accessed January 11, 2023. https://clinicaltrials.gov/ct2/show/NCT05251714