SUMMARY

• RAGNAR (NCT04083976) is a phase 2, open-label, single-arm, global, multicenter study evaluating the efficacy and safety of BALVERSA in adult and pediatric patients (children ≥6 years) with locally advanced, or metastatic solid tumor malignancies (tumor agnostic), fibroblast growth factor receptor (FGFR) mutations or fusions, and documented disease progression. Patients must have received ≥1 prior line of systemic therapy in the advanced, unresectable, or metastatic setting; or be a child or adolescent with a newly diagnosed solid tumor and no acceptable standard therapies.¹ The primary endpoint is the objective response rate (ORR) assessed by independent review committee. Secondary endpoints were investigator assessed ORR, duration of response (DOR), disease control rate (DCR), clinical benefit rate, progression free survival (PFS), overall survival (OS), safety, and health-related quality of life and pharmacokinetics.². For complete study details, go to https://www.clinicaltrials.gov/ct2/show/NCT04083976.
  • Preliminary results of molecular eligibility screening for the RAGNAR study included  5 patients (5%) with breast cancer (FGFR1 and FGFR2 fusions and mutations).³
  • Pant et al (2023) presented 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. The ORR for 16 patients with breast cancer was
  • 31% and the DCR was 69%. The most common grade 3 or higher treatment emergent adverse events (TEAEs) related to BALVERSA were stomatitis (12%), palmar-plantar erythrodysesthesia syndrome (6%), and hyperphosphatemia (5%). The most commonly occurring serious treatment-related adverse events (grade 3 or higher) were stomatitis (2%) and diarrhea (1%). There were no treatment-related deaths.² Safety was not separately evaluated for patients with breast cancer.
• An ongoing, phase 1b study (NCT03238196) is evaluating the safety, tolerability, and anti-tumor 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).⁴
  • Mayer et al (2021)⁵ presented preliminary results from the phase 1b study of      26 patients with ER+/HER2-/FGFR-amplified MBC. Of the 18 patients evaluable for antitumor effect, 8 had stable disease (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 progression-free survival (PFS) was 3 months, but in 6/8 patients with high levels of FGFR1 amplification and both patients with FGFR3 amplification, PFS was 6 months. Clinical benefit rate was
  • 28% at 6 months. Grade 1 and 2 AEs included mucositis (67%), hyperphosphatemia (61%), dysgeusia (52%), diarrhea (48%), fatigue (48%), neutropenia (47%), hand-foot syndrome (38%), anemia (29%), and onycholysis (14%).
• A phase 1, multicenter study (NCT01703481) evaluated the pharmacokinetic (PK)/pharmacodynamic (PD), safety, and efficacy of BALVERSA at various doses/dosing regimens in patients with advanced/refractory solid tumors, including 36 (19%) patients with breast cancer.⁶
  • Bahleda et al (2019)⁷ reported that the ORR in breast cancer was 9% (3/34). Thirteen patients with breast cancer had FGFR1 amplification, and 2 had FGFR2 amplification; both patients with FGFR2 amplification had a response. The most common TEAEs for the entire study population were hyperphosphatemia (64%), dry mouth (42%), and stomatitis (37%), generally grade 1/2 in severity. Safety was not separately evaluated for patients with breast cancer.

CLINICAL DATA

Phase 2 Study

Pant et al (2023)² reported primary analysis results of the broad panel cohort of the RAGNAR study (N=217).

Study Design/Methods

• Phase 2, open-label, single-arm, global, multicenter study evaluating the efficacy and safety of once daily oral BALVERSA in adult and pediatric patients (children ≥6 years) with unresectable, locally advanced, or metastatic solid tumor malignancies (tumor agnostic), FGFR mutations or gene fusions, and documented disease progression.⁸
• The primary cohort consisted of patients ≥12 years of age with unresectable, locally advanced or metastatic solid tumors (except urothelial carcinoma), predefined
• FGFR1-4 alterations (mutations/fusions), documented disease progression, who received ≥1 prior line of systemic therapy and no alternative standard therapy and received BALVERSA orally once daily on a 21-day cycle until disease progression or intolerable toxicity.²
  • Adults and adolescent patients (≥15 to <18 years of age) were initiated with BALVERSA 8 mg with possible up-titration to 9 mg based on cycle 1 day 14 serum phosphate levels.²
  • Adolescent patients (≥12 to <15 years of age) were initiated with BALVERSA 5 mg with possible up-titration to 6 mg or further to 8 mg based on cycle 1 day 14 and cycle 2 day 7 serum phosphate levels.²
  • Efficacy for patients with non-central nervous system (CNS) tumors was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis every 6 weeks for 12 months, and then every 12 weeks thereafter.²
  • Efficacy for patients with primary brain tumors was assessed using Response Assessment in Neuro-Oncology (RANO) by a brain MRI performed at baseline every  6 weeks for disease assessment for the first 12 months and then every 12 weeks thereafter.²
  • Primary endpoint: ORR per independent review committee.²
  • Secondary endpoints: Investigator-assessed ORR, DOR, DCR, clinical benefit rate, PFS, OS, safety, and health-related quality of life and pharmacokinetics.²

Results

Efficacy²

• At a median follow-up for efficacy was 17.9 months (inter quartile range [IQR], 13.6-23.9), median treatment duration was 4.3 months (IQR, 2.1-9.2), and ORR per independent review committee assessment was 64 (30%; 95% CI, 24-36) of            217 patients. Investigator-assessed ORR was 25% (95% CI, 20-32), median DOR was 6.9 months (95% CI, 4.4-7.1) (investigator-assessed median DOR was 7 months [5.5-8.5]), DCR was 74% (95% CI, 67-80), clinical benefit rate was 46% (95% CI, 39-53), median PFS was 4.2 months (95% CI, 4.1-5.5; there were 160 PFS events), and median OS was 10.7 months (95% CI, 8.7-12.1).
  • Responses were observed in 16 solid tumor types including breast cancer. The ORR for patients with breast cancer (n=16) was 31% and the DCR was 69%.

Safety²

• At a median treatment exposure of 4.3 (IQR, 2.1-9.2) months, 216 (99.5%) patients experienced at least one TEAEs.
• Grade 3 or higher TEAEs related to BALVERSA occurred in 100 (46%) patients.
  • The most frequent were stomatitis (12%), palmar-plantar erythrodysesthesia (6%), and hyperphosphatemia (5%).
• Serious TEAEs occurred in 85 (39%) patients. The most common serious treatment-related adverse events (trAEs) of grade 3 or higher were stomatitis in 4 (2%) patients and diarrhea in 2 (1%) of 217 patients. The most common trAEs that led to discontinuation were palmar-plantar erythrodysesthesia syndrome in 3 (2%) patients and stomatitis in 3 (2%) patients.
• Central serous retinopathy events occurred in 31 (14%) patients.
  • Grade 1-2
    • Chorioretinopathy occurred in 8 (4%) patients, detachment of retinal pigment epithelium occurred in 7 (3%) patients, and retinal detachment occurred in        6 (3%) patients.
  • Grade 3
    • Retinal edema (<1%).  
• TEAEs led to death in 8 (4%) patients (multiple organ dysfunction syndrome, pyrexia, COVID-19, sepsis, pulmonary embolism, respiratory failure, cardiac arrest, and subdural hematoma), all were considered unrelated to BALVERSA by investigator assessment.
• Safety was not separately evaluated for patients with breast cancer.

Phase 1b Study

Mayer et al (2021)⁵ reported results of a phase 1b study to evaluate the safety, tolerability, and anti-tumor activity of BALVERSA plus fulvestrant/palbociclib in patients with ER+/HER2-/FGFR-amplified MBC (NCT03238196).

Study Design/Methods

• Patients had evaluable ER+/HER2- MBC with FGFR1-4 amplification and at least one endocrine therapy regimen in the metastatic setting but ≤2 lines of chemotherapy.
• Patients received fulvestrant, palbociclib (standard of care dosing/schedule), and oral BALVERSA (4-8 mg 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, but in 6/8 patients with high levels of FGFR1 amplification (fluorescence in situ hybridization [FISH] FGFR1:CEP8 ratio >5; gene copy >10) and both patients with FGFR3 amplification, PFS was 6 months.
• Clinical benefit rate was 28% at 6 months.

Safety

• MTD was 6 mg of BALVERSA.
• Grade 1 and 2 AEs included mucositis (67%), hyperphosphatemia (61%), dysgeusia (52%), diarrhea (48%), fatigue (48%), neutropenia (47%), hand-foot syndrome (38%), anemia (29%), and onycholysis (14%).
• Five percent 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 26 May 2023.