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 9 patients (8%) with pancreatic carcinoma (FGFR1 and 2 fusions).²
  • Pant et al (2023)³ 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. For 18 patients with pancreatic carcinoma, the objective response rate (ORR) was 56%. In the overall population, BALVERSA-related grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 100/217 (46%) patients. The most common grade ≥3 TEAEs were stomatitis (12%), palmar-plantar erythrodysesthesia syndrome (6%), and hyperphosphatemia (5%). Safety was not evaluated separately for patients with pancreatic carcinoma.
  • Pant et al (2023)⁴ presented results after a median follow-up of 13.83 months from a primary cohort of patients with pancreatic cancer (n=18) in the RAGNAR study. The ORR by independent review committee (IRC) for 18 patients with pancreatic cancer was 55.6% (95% confidence interval [CI], 30.8-78.5), disease control rate (DCR) was 94% (95% CI, 73-100), median duration of response (DOR) and median progression-free survival (PFS) were both 7 months, and median overall survival (OS) was 20 months. The most common adverse events (AEs) related to patients with pancreatic cancer receiving BALVERSA were dry mouth, diarrhea, stomatitis, dry skin, hyperphosphatemia, and fatigue.
• Gong et al (2024)⁵ reported the primary efficacy analysis results of the NCI-MATCH (EAY131; NCT02465060) Subprotocol K2 study (EAY131-K2), a phase 2, open-label, single-arm study that evaluated the efficacy and safety of BALVERSA in patients with treatment-refractory solid tumors harboring FGFR1-4 mutations or FGFR1-3 fusions (N=35), including patients with pancreatic carcinoma (n=2). Efficacy and safety were not evaluated separately for patients with pancreatic carcinoma.
• A phase 1, first-in-human study (NCT01703481) of the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of BALVERSA in adults with advanced or refractory solid tumors and FGFR mutations or fusions included 4 patients with pancreatic carcinoma (N=65).⁶
• A case report presented BALVERSA use in a 28-year-old male patient with stage IV pancreatic ductal adenocarcinoma (PDAC) harboring a FGFR2 fusion, resulting in durable treatment response. AEs resulting from BALVERSA use were not reported.⁷
• A case reported presented a 68-year-old female patient with metastatic pancreatic carcinoma and an FGFR2-TACC2 fusion who achieved a durable complete response (CR) for 10 months with BALVERSA use. AEs included hyperphosphatemia, diarrhea, and transient central serous retinopathy (CSR), which were resolved with dose reduction.⁸

CLINICAL DATA

Phase 2 Study

Pant et al (2023)^3,4,9 reported primary analysis results of the broad panel cohort of the RAGNAR study (NCT04083976; N=217), including patients with pancreatic cancer (n=18).

Study Design/Methods

• Ongoing, 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.¹⁰
• 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
• Patients received BALVERSA orally once daily on a 21-day cycle until disease progression or intolerable toxicity.³
  • 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.³
  • 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.³
• Efficacy for patients with non-central nervous system (CNS) tumors was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.³
  • Primary endpoint: ORR per IRC.³
  • Secondary endpoints: Investigator-assessed ORR, DOR, DCR, clinical benefit rate, PFS, OS, safety, and health-related quality of life and pharmacokinetics.³

Results

Patient Characteristics⁴

• At data cutoff (median survival follow-up was 15.24 months), 18 patients with pancreatic cancer received BALVERSA.
• Seventeen (94.4%) patients had visceral metastases, and there was a median of 3 prior lines of systemic therapy (range, 1-9); 1 (5.6%) patient responded to last line of therapy.
• All patients had FGFR fusions (14 FGFR2, 4 FGFR1); none had FGFR mutations.
• No patients had KRAS co-alterations (none had known KRAS gatekeeper mutations).
• The baseline demographics and disease characteristics of patients in the RAGNAR pancreatic cancer group are summarized in Table: RAGNAR Pancreatic Carcinoma Group: Baseline Demographics and Disease Characteristics.

Efficacy

• Responses were observed in 16 solid tumor types including pancreatic cancer. At a median follow-up of 13.83 months, the ORR by IRC for patients with pancreatic cancer (n=18) was 55.6% (95% CI, 30.8-78.5) (tumor lesions shrunk adequately), this was the second highest ORR across responses observed over 16 tumor types.⁴
• Median time to onset of response in patients with pancreatic cancer was 1.45 months, and responses were observed in patients with FGFR1 and FGFR2 fusions.⁴
• Investigator-assessed efficacy data were comparable to IRC.⁴
• The efficacy measures by IRC in the RAGNAR pancreatic group are summarized in Table: RAGNAR Pancreatic Carcinoma Group: Efficacy Measures by IRC.

Safety

• In patients with pancreatic cancer, the most common AEs were dry mouth, diarrhea, stomatitis, dry skin, hyperphosphatemia, and fatigue. Five patients (28%) with pancreatic cancer had serious AEs and 2 patients (11%) discontinued BALVERSA due to AEs. No treatment-related deaths were observed.⁴
• The most frequent adverse events reported in the RAGNAR pancreatic carcinoma group are summarized in Table: RAGNAR Pancreatic Carcinoma Group: Most Frequent AEs (≥50).

Case Reports

Ng et al (2022)⁷ described a case report of BALVERSA use in a 28-year old Hispanic male patient with stage IV PDAC harboring a FGFR2 fusion, resulting in a durable treatment response.

• The patient presented with epigastric pain.
• Cross-sectional imaging and upper endoscopic ultrasound detected presence of a pancreatic neck mass. Imaging also showed liver and lung lesions.
• Biopsies of the pancreatic mass and liver confirmed the presence of poorly differentiated adenocarcinoma, consistent with metastasis from pancreaticobiliary tract origin.
• The patient had a history of FOLFOXIRI (folinic acid/ fluorouracil/ oxaliplatin/ irinotecan) use and enrollment of the Dual-Affinity Targeting Trial, with disease progression occurring.
• Two individual genetic reports using the pancreas tumor specimen were generated, and both tests conferred the presence of FGFR2 rearrangement.
• Subsequently the patient received BALVERSA and responded well to the therapy.
  • CT scans performed after initiation of therapy showed significant reduction in pulmonary lesions when compared to CT scans prior to therapy.
  • Initial physical examination showed PDAC-related weight loss, ascites, and hypercalcemia, which were resolved with BALVERSA use.
  • The patient's CA 19-9 level, a tumor marker for pancreatic cancer, decreased from 12.3 to 10.9 after 1 month of BALVERSA use.
• The patient continued BALVERSA treatment for >12 months with an excellent response at the time of publication.

Poon et al (2021)⁸ described a case report of BALVERSA use for the treatment of metastatic pancreatic carcinoma resulting in CR at 10 months after initiation in a 68-year-old ethnic Chinese female patient.

• The patient had a prior history of intraductal papillary mucinous neoplasm (IPMN) with an 8 mm cystic side branch communicating with the main duct in the body and 4 mm cystic lesion in the uncinate process of the pancreas in 2013 and remained stable from 2013-2018.
• In 2020, an MRI scan revealed a mass in the head of pancreas, encasing both the superior mesenteric artery and vein, compressing the common bile duct, and invading the duodenum.
  • The diagnosis of adenocarcinoma of the pancreas was confirmed by ultrasound guided biopsy of the segment 6 liver metastasis.
• The patient initially received treatment with CAPOX, and her performance status (PS) was Eastern Cooperative Oncology Group (ECOG) 2 at presentation.
  • After two cycles, the patient’s condition worsened with severe loss of appetite, abdominal pain, and rapid weight loss (10 kg).
  • Progressive disease was then documented with CT imaging.
  • CA 19-9 levels increased from 2139 U/mL to 5516.3 U/mL (normal range, 0-37 U/mL).
  • The patient was admitted into the hospital for hydration and sodium repletion, with a ECOG PS 4.
• Tumor profiling detected an FGFR2-TACC2 fusion and treatment with BALVERSA 5 mg daily was initiated.
• Within 2 weeks of initiating BALVERSA 5 mg daily, the patient had increased serum phosphate levels (8.5 mg/dL, grade 2), experienced diarrhea (grade 2), and transient CSR.
• The patient had a 1-week treatment cessation and dose reduced to BALVERSA 4 mg daily. Serum phosphate levels decreased (<3 mg/dL) and remained stable with a dietary phosphate restriction to <800 mg/day; diarrhea was managed with loperamide and did not recur; and transient CSR was resolved.
• Repeat CT imaging 2 months after BALVERSA initiation showed complete resolution of the primary pancreatic tumor and the liver metastases.
• The patient maintained a complete response, ECOG PS 0, normal CA 19-9 levels, and remained symptom-free 10 months after BALVERSA initiation.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 25 September 2024.