Use of BALVERSA in Breast Cancer

SUMMARY

• RAGNAR (NCT04083976) is an ongoing, phase 2, open-label, single-arm, global, multicenter study evaluating the efficacy and safety of BALVERSA in adult and pediatric patients with unresectable, locally advanced, or metastatic solid tumor malignancies (tumor agnostic), fibroblast growth factor receptor (FGFR) mutations or fusions, and documented disease progression.¹ For complete study details, refer to https://clinicaltrials.gov/study/NCT04083976.
  • Preliminary results of molecular eligibility screening for the RAGNAR study included 5% (5/110) of patients with breast cancer (FGFR1 and FGFR2 fusions and mutations).²
  • Pant et al (2023)³ reported primary analysis results after a median follow-up of 17.9 months from a primary cohort of patients (n=217) with 16 different solid tumor types in the RAGNAR study. For 16 patients with breast cancer, the objective response rate (ORR) assessed by independent review committee (IRC) was 31%. In the overall population, BALVERSA-related grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 46% (100/217) of patients. The most common grade ≥3 TEAEs were stomatitis (12%), palmar-plantar erythrodysesthesia (6%), and hyperphosphatemia (5%). Safety was not evaluated separately for patients with breast cancer.
  • Carranza et al (2024)⁴ reported results from a subgroup of patients with breast cancer (n=16). The ORR assessed by IRC was 31% at a median follow-up period of 14.1 months. Responses were reported in patients with FGFR1-3 alterations. The safety data was consistent with the known safety profile of BALVERSA.
  • Lugowska et al (2024)⁵ reported results from an exploratory cohort of patients with FGFR mutations that were not predefined as potentially susceptible alterations (n=53). Of the 53 patients, 7 (13%) had breast cancer. One patient with breast cancer and a FGFR3 mutation had a partial response for 2.79 months. Efficacy and safety were not evaluated separately for patients with breast cancer.
• Gong et al (2024)⁶ reported the primary efficacy analysis results of the NCI-MATCH (EAY131; NCT02465060) Subprotocol K1 study (EAY131-K1), a phase 2, open-label, single-arm study that evaluated the efficacy and safety of BALVERSA in patients with chemotherapy-refractory solid tumors harboring FGFR1-4 amplifications (N=35). Among the 18 efficacy-evaluable patients, 9 (50%) patients had breast cancer. Of these 9 patients, 2 had stable disease (SD), 4 had disease progression, and 3 were unevaluable for response. A prolonged progression-free survival (PFS) of 8.9 months was observed in 1 patient with FGFR1-amplified breast cancer. Safety was not evaluated separately for patients with breast cancer.
• Gonzalez-Ericsson et al (2025)⁷ presented results from a phase 1b study evaluating the safety, tolerability, and efficacy of BALVERSA plus fulvestrant and palbociclib in patients with hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC; NCT03238196; N=35). The maximum tolerated dose (MTD) for BALVERSA was established as 6 mg. Data on safety are presented in Table: Summary of AEs. Among the 31 efficacy-evaluable patients, the overall response rate was 10%, the clinical benefit rate (CBR) at 6 months was 23%, and the median PFS was 12 weeks.
• Bahleda et al (2019)⁸ reported results from a phase 1, multicenter study evaluating the pharmacokinetics (PK)/pharmacodynamics, safety, and efficacy of BALVERSA at various doses/dosing regimens in patients with advanced/refractory solid tumors (NCT01703481; N=187), including 36 (19%) patients with breast cancer. The ORR in breast cancer was 9% (3/34). Overall, 13 patients with breast cancer had FGFR1 amplification; 2 had FGFR2 amplification and both had a response to BALVERSA. Safety was not evaluated separately for patients with breast cancer.

CLINICAL DATA

Phase 2 Study – RAGNAR Breast Cancer Subgroup Analysis

Carranza et al (2024)⁴ reported the efficacy and safety of BALVERSA in a subgroup of patients with breast cancer in the RAGNAR study (NCT04083976; n=16).

Study Design/Methods

• RAGNAR is an ongoing, phase 2, open-label, single-arm, global, multicenter study evaluating the efficacy and safety of BALVERSA orally (PO) once daily in adult and pediatric patients (children aged ≥6 years) with unresectable, locally advanced, or metastatic solid tumor malignancies (tumor agnostic), FGFR mutations or gene fusions, and documented disease progression.^1,3 
• The eligible subgroup consisted of patients aged ≥12 years with unresectable, locally breast cancer, predefined FGFR1-4 alterations (mutations/fusions), documented disease progression, who received ≥1 prior line of systemic therapy and no alternative standard therapy.^3,4 
• Patients received BALVERSA 8 mg PO once daily on a 21-day cycle until disease progression or intolerable toxicity.^3,4 
  • Possible uptitration of BALVERSA to 9 mg was based on cycle 1 day 14 serum phosphate levels.
• Efficacy was assessed every 6 weeks.^3,4 
  • Primary endpoint: IRC-assessed ORR using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
  • Secondary endpoints: Investigator-assessed ORR, duration of response (DOR), disease control rate (DCR), PFS, overall survival (OS), and safety.

Results

Patient Characteristics

• Demographics and baseline characteristics of BALVERSA-treated patients with breast cancer are presented in Table: RAGNAR Subgroup Analysis: Demographics and Baseline Characteristics.
• All 16 patients had visceral metastasis.
• Co-alterations of TP53 and PIK3CA were found in 6 patients.
• Patients received a median of 5 lines of prior anti-cancer therapy; 1 patient responded to their last line of therapy.

Efficacy

• At a data cutoff of December 4, 2023, the median treatment duration was 3.4 months and the median follow-up period was 14.1 months.
• Treatment discontinuation occurred due to progressive disease (n=13, 81.3%); study terminated by the sponsor, patient withdrawal, and other (n=1 each, 6% each).
• Key outcomes are summarized in Table: RAGNAR Subgroup Analysis: Key Efficacy Outcomes.

• The median efficacy follow-ups were 14.1 months and 30.29 months, per IRC and investigator assessment, respectively.
• All 6 patients with SD as the best overall response per IRC had SD of ≥4 months.
• Of the 5 responders, the median time to response was 1.4 months.
• The responders had FGFR2 fusions (n=3), FGFR2 mutation (n=1), and FGFR3 mutation (n=1).

Safety

• All 16 treated patients experienced drug-related treatment-emergent adverse events (TEAEs; see Table: RAGNAR Subgroup Analysis: Safety).
• No TEAEs led to treatment discontinuation or death.

Phase 2 Study - NCI-MATCH Subprotocol K1 Study

Gong et al (2024)⁶ reported the primary efficacy analysis results of the NCI-MATCH (EAY131; NCT02465060) Subprotocol K1 study (EAY131-K1; N=35).

Study Design/Methods

• This phase 2, open-label, single-arm study evaluated the efficacy and safety of BALVERSA in patients with chemotherapy-refractory solid tumors (except transitional cell carcinoma of the bladder or urothelial carcinoma) harboring FGFR1-4 amplifications.
• Patients received BALVERSA 8 mg PO once daily in a 28-day cycle with possible uptitration to 9 mg on cycle 1 day 15 based on serum phosphate levels and in the absence of significant toxicity.
• The primary efficacy analysis cohort included patients with FGFR amplifications confirmed by the National Cancer Institute (NCI) central laboratory using the NCI-MATCH sequencing assay.

Results

Patient Characteristics

• Of the 35 enrolled patients, 18 were considered evaluable for the primary efficacy analysis, including 9 (50%) with breast cancer.
• Patients with breast cancer harbored FGFR1 (n=7), FGFR2 (n=1), and FGFR4 (n=1) amplifications.

Efficacy

• At the data cutoff on July 27, 2022, all 18 patients in the primary efficacy analysis cohort discontinued BALVERSA.
• Of the 9 patients with breast cancer, 2 had SD as the best overall response, 4 had disease progression, and 3 were unevaluable for response.
• A prolonged PFS of 8.9 months was observed in 1 patient with FGFR1-amplified breast cancer receiving BALVERSA (Table: BOR and PFS Duration in Patients With FGFR-Amplified Breast Cancer).

Safety

• Safety was not evaluated separately in patients with breast cancer.
• Of the 35 patients who received BALVERSA, 33 were assessed for safety.
• AEs leading to BALVERSA discontinuation were reported in 9.1% (3/33) of patients.
• The most common grade 1-2 TRAEs were dry mouth (15/33; 45.5%), hyperphosphatemia (10/33; 30.3%), fatigue (10/33; 30.3%), and diarrhea (8/33; 24.2%).
• The most common grade 3 TRAEs were mucositis (3/33; 9.1%), vomiting (3/33; 9.1%), and hyponatremia (2/33; 6.1%).
• One patient reported a treatment-related grade 5 hepatic failure, which investigators deemed related to BALVERSA.

Phase 1b Study

Gonzalez-Ericsson et al (2025)⁷ presented results from a phase 1b study evaluating the safety, tolerability, and efficacy of BALVERSA plus fulvestrant and palbociclib in patients with HR+/HER2- MBC (NCT03238196; N=35).

Study Design/Methods

• This was an open-label, multi-institution, dose-escalation and expansion phase 1b study in postmenopausal women with clinical stage IV or inoperable locoregional recurrent histologically confirmed HR+/HER2- invasive mammary carcinoma.
  • Eligible patients had not received prior FGFR inhibitors and had received ≥1 line of systemic therapy in the metastatic setting (≤2 lines of chemotherapy; no limit on endocrine therapy; and prior CDK4/6 inhibitor and fulvestrant exposure permitted); they had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1 and no intercurrent uncontrolled illness or symptomatic brain metastases.
• In the expansion cohort, ≥50% of patients were required to have tumors with FGFR1–FGFR4 amplification, as determined by targeted capture next-generation sequencing (NGS), ctDNA analysis, or FISH.
• The primary endpoint of the study was determination of the MTD, defined as the highest dose at which 20% of patients experienced a dose-limiting toxicity (DLT).⁷
• Secondary endpoints included PFS, ORR, clinical benefit rate (defined as complete response [CR] + partial response [PR] + SD without disease progression at 6 months), and safety.^7,9
• In the dose-escalation phase, patients received fulvestrant and palbociclib in combination with BALVERSA using a standard 3+3 design.
  • BALVERSA was administered orally once daily and was available as 3, 4, and 5 mg tablets; treatment was initiated in 3 patients at 5 mg and evaluated for DLTs over a 4-week period before initiating the next cohort at escalating doses of 6 mg and then 8 mg.
  • Fulvestrant was administered intramuscularly at 500 mg on Days 1 and 15 of Cycle 1 (loading dose), followed by every 28 days. Palbociclib was administered at 125 mg orally once daily on a 3-weeks-on/1-week-off schedule.
  • Patients were required to receive ≥75% of the study drug during Cycle 1 to be evaluable for DLT assessment.
• In the expansion phase, patients received BALVERSA at the MTD.
• Dose reductions were permitted after the 4‑week DLT observation period during both the escalation and expansion phases.
• Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal/noncompliance with the protocol.

Results

Patient Characteristics

• Demographics and baseline characteristics are presented in Table: Demographics and Baseline Characteristics.

MTD

• The MTD for BALVERSA was established as 6 mg.
  • No DLTs occurred in 3 patients treated with BALVERSA 5 mg; DLTs occurred in 1/6 (16.6%) and 3/4 (75%) patients treated with BALVERSA 6 mg and 8 mg, respectively.
  • DLTs were grade 3 palmar-plantar erythrodysesthesia syndrome (6 mg), oral mucositis (8 mg, n=2), and elevated aspartate aminotransferase/alanine aminotransferase levels (8 mg).
  • All DLTs resolved within 2 weeks after treatment interruption.

Safety

• Data on treatment duration and compliance are presented in Table: Treatment Duration and Compliance with BALVERSA plus Fulvestrant and Palbociclib Combination Treatment.

• AEs most likely related to BALVERSA, palbociclib, and the combination treatment are presented in Table: Summary of AEs.
  • Grade 1, 2, 3, and 4 toxicities were recorded by the treating investigators, and no grade 5 toxicities were experienced in this study.

Efficacy

• Efficacy data for the combination treatment are summarized in Table: Response to BALVERSA plus Fulvestrant and Palbociclib Combination Treatment Based on FGFR1-4 Amplification Status.

• Overall response rate was 10%; disease progression was recorded in 28 patients during the follow-up period, with 3 patients lost to follow-up after treatment discontinuation.
• Among responders, the duration of response (PR to progressive disease) was
  18-136 weeks.
• Among patients with evaluable disease, treatment time was 5-168 weeks, with a median of 8.7 weeks.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and DerwentDrug File (and/or other resources, including internal/external databases) was conducted on 2 June 2026.