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 7% (8/110) patients with non-small cell lung cancer (NSCLC). The predominant NSCLC FGFR alteration was FGFR3 fusion (63%), with FGFR3-TACC3 fusion as 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 9 patients with non-squamous NSCLC, the objective response rate (ORR) was 33%. For 14 patients with squamous NSCLC, the ORR was 21%. 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 NSCLC.
  • Schuler et al (2024)⁴ reported results from a subgroup of patients with NSCLC (n=23). The ORR assessed by independent review committee (IRC) was 26.1%. Responses were reported in patients with squamous and non-squamous NSCLC, FGFR2/3 alterations, and FGFR mutations or fusions. 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 not predefined as potentially susceptible (n=53), which included 1 patient with squamous NSCLC and 1 patient with non-squamous NSCLC. Efficacy and safety were not separately evaluated for patients with NSCLC.
• LUC2001 (NCT02699606) was a phase 2a, open-label, multicenter, single-arm study that evaluated the efficacy and safety of BALVERSA in molecularly defined subset of Asian patients with advanced NSCLC with disease progression after ≥1 prior systemic treatment.^6,7 For complete study details, refer to https://clinicaltrials.gov/study/NCT02699606.
  • Park et al (2024)⁷ reported the efficacy results of the LUC2001 study in patients with NSCLC. Patients with NSCLC did not achieve a complete response (CR) or partial response (PR). The median progression-free survival (PFS) was 1.8 months (95% confidence interval [CI], 0.8-1.9). Three patients with NSCLC achieved stable disease (SD), and 2 patients reported a reduction in tumor size. Safety was not separately evaluated for patients with NSCLC. At least 1 TEAE was reported in all treated patients (n=35), and grade 3 TEAEs were reported in 62.9% (22/35) of patients. The most frequently reported TEAE was hyperphosphatemia (85.7%; 30/35). All patients with NSCLC discontinued treatment due to progressive disease (n=9), adverse events (AEs; n=2), and study withdrawal (n=1).
• Results of a phase 1 study⁸ (N=187) and case reports^9-11 in patients with FGFR-mutated advanced or metastatic NSCLC receiving BALVERSA have been published.

CLINICAL DATA

Phase 2 Study - RAGNAR NSCLC Subgroup Analysis

Schuler et al (2024)⁴ reported the efficacy and safety of BALVERSA in a subgroup of patients with NSCLC in the RAGNAR study (NCT04083976; n=23).

Study Design/Methods

• Ongoing, phase 2, open-label, single-arm, global, multicenter study evaluating the efficacy and safety of BALVERSA in adult and pediatric patients (children aged ≥6 years) with unresectable, locally advanced, or metastatic solid tumor malignancies (tumor agnostic), FGFR mutations or fusions, and documented disease progression.³
• The eligible subgroup consisted of patients aged ≥12 years with advanced or metastatic squamous or non-squamous NSCLC, predefined FGFR1-4 alterations (mutations/fusions), documented disease progression after exhausting standard therapies, and have received ≥1 prior line of systemic therapy.^3,4
• Patients received BALVERSA orally once daily on a 21-day cycle until disease progression or intolerable toxicity.^3,4
  • Patients aged ≥15 years were initiated with BALVERSA 8 mg with possible pharmacodynamically-guided uptitration to 9 mg.
  • Patients aged 12 to 14 years were initiated with BALVERSA 5 mg with possible pharmacodynamically-guided uptitration to 8 mg.
• Efficacy was assessed every 6 weeks.
  • Primary endpoint: IRC-assessed ORR using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
  • Secondary endpoints: IRC-assessed 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 NSCLC are presented in Table: RAGNAR Subgroup Analysis: Demographics and Baseline Characteristics.

Efficacy

• At a data cutoff of December 04, 2023, the time to response was 1.5 months (95% CI, 1.1-2.9). Key outcomes are summarized in Table: RAGNAR Subgroup Analysis: Key Efficacy Outcomes per IRC.
  • ORR was 28.6% and 25.0% in patients with FGFR2 and FGFR3 gene alterations, respectively.
  • ORR was 30.8% and 20.0% in patients with FGFR fusions and mutations, respectively.
• FGFR co-alterations were reported in 78% of patients with squamous NSCLC and non-squamous NSCLC.
  • TP53 was the most commonly co-altered gene among patients with squamous NSCLC (71%).
  • PIK3CA was the most commonly co-altered gene among patients with non-squamous NSCLC (27%).

Safety

• At least 1 BALVERSA-related TEAE was reported in 91.3% of patients (Table: RAGNAR Subgroup Analysis: Safety).
• Grade ≥3 BALVERSA-related TEAEs were reported in 39.1% of patients. TEAEs were managed with supportive care and treatment interruptions or reductions.
• BALVERSA-related serious TEAEs were reported in 8.7% of patients.
• BALVERSA-related TEAEs led to treatment discontinuation in 8.7% of patients.
• BALVERSA-related TEAEs leading to dose reduction and interruption were reported in 56.5% and 78.3% of patients, respectively.
• No treatment-related deaths were reported.

Phase 2 Study - LUC2001

Park et al (2024)⁷ reported the results of the LUC2001 study (NCT02699606; N=35).

Study Design/Methods

• LUC2001 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 advanced NSCLC with disease progression after ≥1 prior systemic treatment.^6,7
• Patients received BALVERSA 8 mg orally once daily on a 28-day cycle, with uptitration to 9 mg permitted after a protocol amendment was implemented.
  • Uptitration to 9 mg once daily was performed if the serum phosphate level on cycle 1 day 14 was less than the upper limit of normal (ULN) in the absence of drug-related toxicity.
• Prior to the protocol amendment, patients received BALVERSA 10 mg for 7 days on/7 days off on a 28-day cycle, with an option of uptitration based on serum phosphate levels measured on cycle 1 day 21 or observed toxicity.
• Select inclusion criteria: age ≥18 years, presence of pathologically or cytologically confirmed advanced or refractory NSCLC (predefined as squamous or non-squamous), Eastern Cooperative Oncology Group performance status 0-1, and progression after ≥1 line of treatment. Additionally, patients with NSCLC with RET proto-oncogene-activating mutations or RET translocations were also eligible.
• Select exclusion criteria: receipt of chemotherapy, targeted therapies, immunotherapy, or treatment with an investigational anti-cancer agent within 2 weeks or ≥5 half-lives of the drug; receipt of prior selective FGFR inhibitor treatment or RET inhibitor treatment; uncontrolled intercurrent illness; serum phosphate level persistently being >ULN during screening; and nonrecovery from reversible toxicity of prior anti-cancer therapy.
• Primary endpoint: Investigator-assessed ORR (CR+PR) per RECIST v1.1.
• Secondary endpoints: PFS, DOR, DCR (CR+PR+SD), OS, safety, and pharmacokinetics.

Results

Patient Characteristics

• Between August 22, 2016, and November 19, 2021, patients were centrally screened for FGFR-activating or RET-activating mutations/rearrangements.
• Of the 35 enrolled patients, 12 were diagnosed with NSCLC.
• Eight patients received BALVERSA 8 mg orally once daily, while 4 patients received BALVERSA 10 mg (7 days on/7 days off).
• Demographics and baseline characteristics of the enrolled patients with NSCLC are summarized in Table: LUC2001: Demographics and Baseline Characteristics of Patients With NSCLC.

Efficacy

• The median treatment duration for patients with NSCLC (n=12) was 1.7 months (range, 0.5-9.4).
• None of the patients with NSCLC achieved CR or PR.
• SD was achieved by 3 patients with NSCLC, whereas 2 patients reported a reduction in tumor size.
• No death was reported, and median OS was not evaluable.
• Efficacy outcomes from the LUC2001 study are summarized in Table: LUC2001: Investigator-Assessed Efficacy Data in Patients With NSCLC.

Safety

• At the data cutoff of November 19, 2021, all patients with NSCLC discontinued treatment due to progressive disease (n=9), AEs (n=2), and study withdrawal (n=1).
• Safety was not separately evaluated for patients with NSCLC.
• At least 1 TEAE was reported in all patients (n=35), and grade ≥3 TEAEs were reported in 62.9% (22/35) of patients.
• Serious AEs occurred in 45.7% (16/35) of patients, with 8.6% (3/35) of these being drug-related.
• The most frequently reported TEAE was hyperphosphatemia (85.7%; 30/35).
• Other common TEAEs included dry mouth, stomatitis, increased alanine aminotransferase, increased aspartate aminotransferase, diarrhea, decreased appetite, dry skin, and constipation.
• TEAEs leading to dose reduction occurred in 54.3% (19/35) of patients due to nail disorder, hyperphosphatemia, and stomatitis.
• TEAEs leading to discontinuation occurred in 5.7% (2/35) of patients due to arthralgia and rash erythematous and were considered related to the treatment.
• One patient died due to sepsis, which was not considered related to the treatment.

Phase 1 Study

Bahleda et al (2019)⁸ reported efficacy and safety results from a phase 1, multicenter study of BALVERSA in patients aged ≥18 years with advanced or refractory solid tumors and FGFR mutations or fusions (NCT01703481; N=187), including patients with NSCLC (n=24).

Results

Efficacy

• A total of 187 patients were included in the study with a median age of 60 years (range, 21-84 years), 57% female, and 91% Caucasian.
• Of the 24 patients with NSCLC as the primary cancer, patients presented with the following FGFR alterations: amplification (21%; 5/24), mutation (42%; 10/24), fusion (33%; 8/24) and an undetermined or negative FGFR alteration status (17%; 4/24).
• The ORR for evaluable patients with NSCLC was 5% (1/21).

Safety

• Safety was not separately evaluated for patients with NSCLC.
• The most common treatment-related TEAEs (incidence ≥10%) for the evaluable safety population were hyperphosphatemia (64%), dry mouth (42%), and stomatitis (37%), which were grade 1/2 in severity except for 1 patient with grade 3 hyperphosphatemia.
• Skin, nail and eye changes were reported in 43%, 33%, and 28% of patients, respectively, and were mostly grade 1/2 in severity.
• The most frequently reported grade 3 TEAEs were anemia (n=17; 9%) and stomatitis (n=12; 6%).
• Serious TEAEs were experienced in 47% of patients (n=88).

Case Reports

Urrutia and Hanna (2020)⁹ presented a case of a 51-year-old male with moderately differentiated lung adenocarcinoma who was treated with BALVERSA.

• The patient presented with bilateral lung masses and liver and bone metastases, confirmed by a biopsy.
• Immunohistochemistry (IHC) staining was positive for CK-7 and CK-20.
• The tumor exhibited an FGFR2-BICC1 fusion in 10.5% of cell-free DNA.
• The patient was initially treated with carboplatin, pemetrexed, and pembrolizumab resulting in SD for 8 months, followed by gemcitabine with SD for 5 months.
• A repeat biopsy of a liver metastasis confirmed the same histology, IHC staining, and FGFR2-BICC1 fusion.
• The patient received BALVERSA for 12 weeks, requiring a dose reduction due to hyperphosphatemia. No other patient-reported clinical or laboratory AEs were noted.
• Repeat CT scans demonstrated a reduction compatible with a PR in the lung masses, some reduction in the liver metastases, and resolution of pleural effusion.

Haura et al (2020)¹⁰ presented a case of a 39-year-old male with lung adenocarcinoma who was treated with combination therapy of osimertinib and BALVERSA.

• The patient was diagnosed with lung adenocarcinoma with metastases to the spine, rib, pelvis, and brain.
• Molecular testing of blood-circulating DNA (Biodesix GeneStrat) revealed an activating epidermal growth factor receptor (EGFR) exon19 p.E746-A750del mutation.
• The patient received osimertinib 90 mg PO daily and reported a PR.
• After 10 months, repeat imaging showed no evidence of metastasis in the brain, stable bone metastasis, but progressive lung metastasis.
• A lung mass biopsy analyzed with the Moffitt STAR panel-Illumina TST170 platform identified FGFR3-TACC3 fusion in addition to confirming the presence of the EGFR exon19del mutation.
• BALVERSA 8 mg PO daily was added while continuing osimertinib.
• Within days, the patient reported less left-sided pleuritic chest pain. Other AEs observed were grade 2 hyperphosphatemia, mild skin dryness, and dry eyes.
• With the addition of BALVERSA, a repeat CT scan on day 36 revealed an obvious PR.

Pham et al (2023)¹¹ reported on a female patient with FGFR3-TACC3 fusion squamous NSCLC who achieved a radiographic response and disease control for 11 months with BALVERSA daily treatment and subsequently obtained an additional 8 months of disease control after BALVERSA retreatment (after 5 months of intervening chemotherapy).

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 29 August 2024.