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.
• Mayer et al (2021)⁷ presented preliminary results from an ongoing, phase 1b study evaluating the safety, tolerability, and antitumor activity of BALVERSA plus fulvestrant/palbociclib in patients with estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-)/FGFR-amplified metastatic breast cancer (MBC; NCT03238196; N=26). Of the 18 efficacy-evaluable patients, 8 had SD (4 discontinued treatment due to an adverse event [AE]), 7 had disease progression, 3 did not complete their first tumor assessment, and 4 were still on treatment. Median PFS was 3 months, and clinical benefit rate was 28% at 6 months. Grade 1 and 2 AEs were consistent with the safety profiles of BALVERSA and/or palbociclib.
• 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

Mayer et al (2021)⁷ presented preliminary results from a phase 1b study evaluating the safety, tolerability, and efficacy of BALVERSA plus fulvestrant/palbociclib in patients with ER+/HER2-/FGFR-amplified MBC (NCT03238196; N=26).

Study Design/Methods

• Patients had evaluable ER+/HER2- MBC with FGFR1-4 amplification and ≥1 endocrine therapy regimen in the metastatic setting but ≤2 lines of chemotherapy.
• Patients received fulvestrant, palbociclib (standard of care dosing/schedule), and BALVERSA PO (4-8 mg once daily).
• Upon reaching maximum tolerated dose (MTD), an expansion portion of the study is planned to enroll 20 patients.

Results

Patient Characteristics

• As of August 2017, 26 patients were enrolled across 4 institutions (13 patients in escalation and 13 in ongoing expansion).
• Median age was 53 years (range, 35-75) and 22 were Caucasian. Patients had FGFR1 (n=23), FGFR3 (n=2), and FGFR4 (n=1) amplifications.
• Patients received a median number of 4 (range, 1-5) lines of treatment in the metastatic setting, of which prior lines included endocrine therapy (100%), cycline dependent kinase 4/6 inhibitor (CDK4/6i; 100%), phosphoinositide 3 kinase (PI3K) pathway inhibitor (80%), 1 line of chemotherapy (65%), 2 lines of chemotherapy (45%), and fulvestrant (28%).

Efficacy

• Of the 26 patients, 18 were evaluable for antitumor effect; 8 had SD (4 discontinued treatment due to an AE), 7 had disease progression, 3 did not complete their first tumor assessment, and 4 were still on treatment.
• Median PFS was 3 months.
  • Median PFS was 6 months in 6/8 patients with high levels of FGFR1 amplification and 2/8 patients with FGFR3 amplification.
• Clinical benefit rate was 28% at 6 months.

Safety

• MTD was 6 mg of BALVERSA.
• Grade 1 and 2 AEs were consistent with the safety profiles of BALVERSA and/or palbociclib and included mucositis (67%), hyperphosphatemia (61%), dysgeusia (52%), diarrhea (48%), fatigue (48%), neutropenia (47%), hand-foot syndrome (38%), anemia (29%), and onycholysis (14%).
• Overall, 5% of patients experienced febrile neutropenia.
• No central serous retinopathy or drug-drug interaction was observed.
• Serious AEs included grade 4 elevation of transaminases (n=1; dose-limiting toxicity attributed to fulvestrant), grade 3 colitis (n=1; attributed to BALVERSA), and thromboembolic event (n=1; attributed to palbociclib).

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and DerwentDrug File (and/or other resources, including internal/external databases) was conducted on 13 June 2025.