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://www.clinicaltrials.gov/study/NCT04083976.
  • Preliminary results of molecular eligibility screening for the RAGNAR study included 4% (4/110) of patients with endometrial cancer (FGFR2 mutation [100%] with FGFR2-C382R mutation as being the most frequent variant).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 8 patients with endometrial cancer, the objective response rate (ORR) assessed by independent review committee (IRC) was 50%. 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 separately evaluated for patients with endometrial cancer.
  • Lugowska et al (2024)⁴ 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, 6 (11%) had endometrial cancer. Efficacy and safety were not separately evaluated for patients with endometrial cancer.

CLinical DATA

Phase 2 Study - RAGNAR

Pant et al (2023)³ reported primary analysis results of the broad panel cohort of the RAGNAR study (NCT04083976; N=217), including patients with endometrial cancer (n=8).

Study Design/Methods

• 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.
• The primary cohort consisted of patients aged ≥12 years 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.
• Patients received BALVERSA PO once daily on a 21-day cycle until disease progression or intolerable toxicity.
  • Adults and adolescent patients (aged ≥15 to <18 years) were initiated with BALVERSA 8 mg with possible up-titration to 9 mg based on cycle 1 day 14 serum phosphate levels.
  • Adolescent patients (aged ≥12 to <15 years) 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.
• Efficacy for patients with non-central nervous system tumors was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
  • Primary endpoint: IRC-assessed ORR.
  • Secondary endpoints: 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.

Results

Efficacy

• The primary cohort included 217 patients with 16 solid tumor types.
  • Median follow-up for efficacy was 17.9 months (interquartile range [IQR], 13.6-23.9), and median treatment duration was 4.3 months (IQR, 2.1-9.2)
  • IRC-assessed ORR was 30% (64/217; 95% confidence interval [CI], 24-36).
  • 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, 7 months [95% CI, 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; PFS events, n=160), and median OS was 10.7 months (95% CI, 8.7-12.1).  
• Responses were observed in 16 solid tumor types, including endometrial cancer. The ORR for patients with endometrial cancer (n=8) was 50% and DCR was 75%.

Safety

• Safety was not separately evaluated for patients with endometrial cancer.
• At a median treatment exposure of 4.3 (IQR, 2.1-9.2) months, 99.5% (216/217) of patients experienced ≥1 TEAE.
• BALVERSA-related grade ≥3 TEAEs occurred in 46% (100/217) of patients. The most common grade ≥3 TEAEs were stomatitis (12%), palmar-plantar erythrodysesthesia (6%), and hyperphosphatemia (5%).
• Serious TEAEs occurred in 39% (85/217) of patients. The most common grade 
  ≥3 serious treatment-related adverse event (TRAEs) were stomatitis in (4/217; 2%) and diarrhea in (2/217; 1%).
• The most common TRAEs that led to discontinuation were palmar-plantar erythrodysesthesia syndrome and stomatitis (3/217; 2% each).
• Central serous retinopathy events occurred in 31 (14%) patients.
  • Grade 1-2: Chorioretinopathy (8/217; 4%), detachment of retinal pigment epithelium occurred (7/217; 3%), and retinal detachment (6/217; 3%).
  • Grade 3: Retinal edema (<1%).
• TEAEs leading to death were reported in 4% (8/217) of patients (multiple organ dysfunction syndrome, pyrexia, coronavirus disease 2019 [COVID-19], sepsis, pulmonary embolism, respiratory failure, cardiac arrest, and subdural hematoma); all were considered unrelated to BALVERSA by investigator assessment.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and DerwentDrug File (and/or other resources, including internal/external databases) was conducted on 10 July 2024.