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 http://clinicaltrials.gov/study/NCT04083976.
  • Preliminary results of molecular eligibility screening for the RAGNAR study included 2% (2/110) of patients with esophageal cancer (predominant eligible alterations: FGFR3 fusion [50%] and FGFR3 mutation [50%]).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 esophageal cancer, the objective response rate (ORR) assessed by independent review committee (IRC) was 13%. 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 syndrome (6%), and hyperphosphatemia (5%). Safety was not separately evaluated for patients with esophageal 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, 2 (4%) had esophageal cancer. Efficacy and safety were not separately evaluated for patients with esophageal cancer.
• LUC2001 (NCT02699606) was a phase 2a, open-label, multicenter, single-arm study that evaluated the efficacy and safety of BALVERSA in a molecularly defined subset of Asian patients with with FGFR-altered advanced solid tumors with disease progression after ≥1 prior systemic treatment.^5,6 For complete study details, refer to https://clinicaltrials.gov/study/NCT02699606.
  • Park et al (2024)⁶ reported the results of the 35 efficacy-evaluable patients. One patient had metastatic esophageal cancer with FGFR3-TACC3 rearrangement and a history of radiotherapy, systemic therapy, and cancer-related surgery. The patient received BALVERSA 8 mg orally once daily and achieved a partial response. The duration of treatment, progression-free survival (PFS), and duration of response (DOR) were 10.4, 10.2, and 8.5 months, respectively. The survival time was >10.4 months. The patient discontinued treatment due to disease progression. Safety was not evaluated separately for the patient with esophageal cancer.

CLinical DATA

Phase 2 Study

Pant et al (2023)³ reported primary analysis results of the broad panel cohort of the RAGNAR study (NCT04083976; N=217), including patients with esophageal 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 uptitration 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 uptitration 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) v1.1.
  • Primary endpoint: IRC-assessed ORR.
  • Secondary endpoints: Investigator-assessed ORR, DOR, disease control rate (DCR), clinical benefit rate, PFS, overall survival (OS), safety, 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 esophageal cancer. The ORR for patients with esophageal cancer (n=8) was 13% and DCR was 38%.

Safety

• Safety was not separately evaluated for patients with esophageal 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 syndrome (6%), and hyperphosphatemia (5%).
• Serious TEAEs occurred in 39% (85/217) of patients. The most common grade ≥3 serious treatment-related adverse events (TRAEs) were stomatitis (4/217; 2%) and diarrhea (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 14% (31/217) of 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 30 August 2024.