Successful Treatment and Retreatment With Erdafitinib for a Patient With FGFR3-TACC3 Fusion Squamous NSCLC: A Case Report

FGFR3-TACC3 fusions have been identified in patients with multiple cancer types, and tumors with these alterations are potentially sensitive to selective FGFR inhibitors. However, there are no FGFR inhibitors approved by the U.S. Food and Drug Administration for the treatment of patients with NSCLC with FGFR alterations. Here, we report a case of a patient with FGFR3-TACC3 fusion squamous NSCLC who achieved a radiographic response and disease control for 11 months on initial treatment with erdafitinib and subsequently obtained an additional 8 months of disease control after erdafitinib retreatment after 5 months of intervening chemotherapy. Further investigation into FGFR inhibitor treatment specifically and targeted therapy retreatment for patients with NSCLC may increase our therapeutic options for these patients.


Introduction
Among the recently identified potentially therapeutically actionable pathogenic variants, FGFR alterations have been implicated in various cancer types (roughly 5%-10% of all cancers). 1 Though not as common as FGFR amplification (66%) or single nucleotide variants (26%), FGFR fusions account for roughly 8% of all FGFR alterations, and FGFR3-TACC3 fusions have been observed to be potentially associated with squamous NSCLC tumorigenesis. 1,2 FGFR fusions are potentially therapeutically actionable, though there are no agents approved by the U.S. Food and Drug Administration (FDA) to target FGFR in patients with NSCLC. However, multiple selective FGFR-tyrosine kinase inhibitors (TKIs) are FDA-approved for other oncologic indications (erdafitinib, pemigatinib, infigratinib, and futibatinib). 1 Previous studies have reported several cases of patients with NSCLC having FGFR alterations who achieved disease response on FGFR inhibitor treatment (pemigatinib and erdafitinib specifically) ( Table 1). [3][4][5][6] Furthermore, there is a growing body of literature suggesting the potential therapeutic efficacy of targeted agent rechallenge (predominantly with the EGFR TKI osimertinib) after intervening therapy in patients with NSCLC. 7,8 Here, we present a case of a patient with FGFR3-TACC3 fusion squamous NSCLC who experienced radiographic response and disease control with erdafitinib treatment on two separate occasions. To our knowledge, this is the first report of successful erdafitinib treatment and retreatment for NSCLC with an FGFR3-TACC3 fusion.

Case Presentation
A 51-year-old woman with a 28 pack-years history of smoking presented to the emergency department for evaluation of upper back pain. Computed tomography imaging revealed a large left lower lobe lung mass and multiple bilateral pulmonary nodules. Biopsy of the left lung mass revealed squamous cell carcinoma that was p40-positive, consistent with NSCLC. Her initial TNM stage was IV (cT2bN0M1a). Broad-based next-generation sequencing (NGS) was not performed at this time.
The patient received first-line chemoimmunotherapy with a partial response and subsequent disease control for 12 months. At first progression, she was treated with docetaxel plus ramucirumab with a radiographic response but developed substantial toxicities, which prompted a transition to a clinical trial with a novel agent plus avelumab and radiation. Her clinical trial treatment provided an additional 5 months of disease control. Figure 1 illustrates the full treatment timeline.
At the time of progression on the third line clinical trial, biopsy was performed on the patient's left upper lobe tumor and sent for NGS testing with a 648 gene Tempus xT panel. Pathological findings revealed squamous NSCLC with an FGFR3-TACC3 fusion and an NFE2L2 R34Q mutation at 70.7% variant allele frequency with a tumor mutational burden of 4.7 mutations per megabase. Her case was reviewed by the institutional molecular tumor board, and FGFR inhibitor treatment was recommended. She began treatment with erdafitinib (8 mg daily) with a radiographic response on the first imaging and 11 months of disease control before further progression of her pulmonary masses ( Fig. 1A and B). While on erdafitinib, the patient experienced fatigue, intermittent diarrhea, weight loss, hyperphosphatemia, corneal ulceration, onycholysis, and hand-foot syndrome during the first 3 months, which prompted a dose reduction to 6 mg for 1 month, followed by further dose reduction to 4 mg for 7 months. All the adverse events were grade 1 or 2, except her corneal ulceration (grade 3).
Subsequently, the patient received gemcitabine with 4 months of disease control, followed by 1 month of vinorelbine. At this time, a right upper lobe lung mass biopsy was pursued with broad-based NGS testing with the Tempus xT panel. Results revealed squamous NSCLC with an FGFR3-TACC3 fusion and an NFE2L2 R34Q mutation at 85.1% variant allele frequency with a tumor mutational burden of 6.3 mutations per megabase. Because of the previous prolonged disease control with erdafitinib and the patient's preference to retry oral targeted therapy, her case was again reviewed in the molecular tumor board. FGFR inhibitor rechallenge was noted to be a reasonable next line of therapy.
With an off-erdafitinib interval of 5 months, the patient restarted erdafitinib (8 mg daily, reduced to 6 mg daily 1 month after because of hand-foot syndrome) and experienced disease control (stable disease on radiographic imaging) for a total of 8 months (Fig. 1C and D).

Discussion
Since their identification in 2012 in a patient with glioblastoma, FGFR3-TACC3 fusions have garnered attention because of their sensitivity to selective FGFR inhibitors despite their low frequency recorded across human cancer types. 1 In the NSCLC cohort, FGFR3-TACC3 fusions have been recorded in 0.2% to 1.1% of screened populations, with the most common pathological subtype being squamous cell carcinoma. 2,4 In addition, the emergence of FGFR3-TACC3 fusions has been documented as an acquired resistance mutation during EGFR TKI therapy. In this context, successful combination treatment with an FGFR inhibitor and EGFR TKI has been observed. 9 Here, we report the case of a patient with FGFR3-TACC3 fusion squamous NSCLC who was treated with erdafitinib on two separate occasions, with an intervening period of chemotherapy, and achieved disease control for 11 months and 8 months, respectively, highlighting the potential clinical use of FGFR inhibitors in patients with NSCLC. Erdafitinib is currently FDA-approved for patients with FGFR2/3 alterations and locally advanced or metastatic urothelial carcinoma. 1 In the era of widespread, broad molecular testing, we encounter rare mutations that are potentially actionable but not thoroughly evaluated in the specific histologic context in which they are identified. Furthermore, patients with certain targetable oncogenic mutations may have inferior results when treated with immunotherapy, limiting therapeutic options to targeted agents and chemotherapy. 10 The emerging body of literature supporting both off-label targeted therapy use and targeted therapy rechallenge is of utmost importance to improve outcomes in these patients.
This case presents evidence for consideration of both treatment and retreatment with FGFR inhibitors in patients with FGFR fusion-driven NSCLC, specifically FGFR3-TACC3.
In conclusion, we present a case of a patient with squamous NSCLC with an FGFR3-TACC3 fusion who achieved an initial response on erdafitinib treatment and further disease control on erdafitinib rechallenge. This provides evidence for off-label FGFR inhibitor use in settings in which a potentially actionable FGFR mutation is identified, and it supports a growing body of literature suggesting the potential utility of rechallenge with oral targeted therapies.