Advancing Ocular Safety Profile Assessment: A Novel Grading Scale for Ocular Adverse Reactions Associated with Bemarituzumab

Targeted cancer therapies, in contrast to systemic cytotoxic chemotherapy, aim to inhibit specific molecular pathways critical for cancer cell growth, survival, and progression. Targeted therapy involves the use of small molecules, such as kinase and angiogenesis inhibitors, and macromolecules, such as monoclonal antibodies, polypeptides, and nucleic acids. The mechanism of action of these targeted therapies may affect other tissues of the body that express the same targets [1, 2]. The eye is one such unintended target, with several overlapping molecular pathways. Important proteins in these signaling pathways include vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), programmed cell death protein 1 (PD-1) and its ligand (PD-L1), and fibroblast growth factor receptor (FGFR), among many others. These are vital for ocular function but often become unintended targets of anticancer drugs [3]. FGFR isoforms 1–4 are receptor tyrosine kinases (TKs) expressed throughout various parts of the eye and play an important role in normal homeostasis. FGFR1, FGFR3, and FGFR4 are primarily expressed in the corneal epithelium and endothelium. Two major isoforms of FGFR2 exhibit tissue-specific expression, with FGFR2b expressed in normal epithelial tissues and FGFR2c expressed in the mesenchymal tissues [4]. FGFR2-dependent signaling is imperative for epithelial cell proliferation and differentiation in the embryonic developmental stage [5, 6]. Additionally, all FGFR isoforms are expressed in all the retinal layers [7]. This distinct pattern of FGFR expression in the eye could explain the ocular adverse reactions reported with the use of FGFR inhibitors such as erdafitinib, infigratinib, and pemigatinib used in the treatment of various malignancies. Some of the frequently reported ocular adverse reactions associated with the use of these therapies include dry eye, blurred vision, corneal disorders such as keratitis, and retinopathy [8‐12].

FGFR2 signaling is one of the promising therapeutic targets for gastric cancer and gastroesophageal junction adenocarcinoma (G/GEJC) as up to approximately 38% of patients with G/GEJC may overexpress the FGFR2b protein biomarker [13]. Bemarituzumab is a first-in-class humanized monoclonal antibody targeting FGFR2b with a dual mechanism of action: inhibition of FGFR2b signaling and enhanced antibody-dependent cell-mediated cytotoxicity [14]. In the randomized, double-blind, placebo-controlled, phase 2 FIGHT study in patients with HER2 nonpositive, FGFR2b-expressing advanced G/GEJC, patients receiving bemarituzumab and mFOLFOX6 (modified 5-fluorouracil, leucovorin, and oxaliplatin) showed a 5.7-month longer overall survival compared with patients receiving mFOLFOX6 alone (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.52–1.14) [15]. Consequently, bemarituzumab is currently being evaluated as a therapeutic option in the first-line setting in combination with chemotherapy, with or without nivolumab, in the ongoing phase 3 studies—FORTITUDE-101(NCT05052801) and FORTITUDE-102 (NCT05111626)—in patients with previously untreated advanced G/GEJC with FGFR2b overexpression.

In preclinical studies, bemarituzumab was associated with adverse ocular reactions such as thinning of the corneal epithelium and meibomian gland atrophy, which were reversible once the drug was discontinued [14]. In the phase 2 FIGHT study, corneal treatment-emergent adverse events (TEAEs) were the most common cause of treatment discontinuation in the bemarituzumab–mFOLFOX6 arm among all TEAEs. Corneal adverse events (AEs) of any grade such as dry eye, keratitis, punctate keratitis, and corneal epithelial defect were reported in up to two-thirds of patients in the bemarituzumab–mFOLFOX6 arm. Additionally, there were some reports of cases of limbal stem cell deficiency (LSCD) in the bemarituzumab–mFOLFOX6 arm [16]. While FGFR expression is expected in the retina and retinal pigment epithelial detachment is typically reported in patients treated with oral FGFR-TK inhibitors, it was not observed with bemarituzumab in the FIGHT study [12, 17]. The key ocular safety findings from the FIGHT study suggest that the cornea is the primary anatomical region of the eye impacted due to an off-tumor effect of bemarituzumab.

The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) is a standardized system used to classify and grade the severity of AEs by system organ class (SOC) and is widely used in clinical trials. The grades range from 1 to 5, with 1 being the lowest severity and 5 the highest, indicating an event associated with a fatal outcome [18]. Within the SOC eye disorders, the most recent CTCAE (version 5.0) provides 26 terms with grades such as blurred vision, dry eye, retinal disorders, scleral disorders, conjunctival disorders, and corneal disorders. The general CTCAE grading methodology applicable to these 26 terms is presented below in Table 1. As grade 5 indicates an event with a fatal outcome, this grading is generally not applicable for eye disorders [18].

Even though the CTCAE provides a framework for classifying and grading ocular disorders, it may not adequately capture the variety and possible ocular sequelae that may arise across the ever-broadening landscape of anticancer agents emerging beyond traditional chemotherapy. Several specific ocular conditions such as corneal epitheliopathy are either insufficiently detailed or entirely absent from the CTCAE scale [18]. Furthermore, grading in CTCAE relies primarily on the description of symptoms and/or impact on visual acuity rather than objective findings during ophthalmologic evaluations. In the early stages of these ocular conditions, objective examination findings may precede the onset of symptoms or any noticeable decline in visual acuity. Therefore, incorporating ophthalmic exam findings into the grading scale is likely to increase the sensitivity of such a tool. Lastly, in the CTCAE grading scale, the observed decrease in visual acuity is a key component of grading corneal adverse reactions. Changes in the cornea are reflective of the structural integrity of the eye, while the corresponding decrease in visual acuity is indicative of a functional change. The severity of the corneal condition and its impact on the visual acuity may vary between patients, and in our opinion, these should therefore be assessed as separate findings with their own dedicated severity grading.

Owing to these limitations of the CTCAE grading scale, Amgen collaborated with ophthalmologists to create a novel ocular adverse reaction severity grading scale. It is being used across the bemarituzumab clinical development program, including the phase 3 trials FORTITUDE-101 (NCT05052801) and FORTITUDE-102 (NCT05111626), to aid characterization of ocular safety profile, appropriate dose modification, and management of ocular adverse reactions. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

The novel ocular adverse reaction severity grading scale developed by Amgen organizes the reporting of ocular adverse reactions by anatomical regions, prioritizing key corneal and retinal conditions. This grading scale includes corneal conditions such as corneal epithelial defect, LSCD, and ulcerative keratitis, all of which are missing from the CTCAE grading scale. Each severity grade is anchored to observable criteria on ophthalmic examination. Table 2 lists the parameters and grading definitions included in this novel ocular adverse reaction severity grading scale.

In the scale (Table 2), decrease in visual acuity is an independent measure separate from the severity grading of any corneal or retinal condition. Worsening of visual acuity is calculated based on number of lines of decreased vision from baseline [19]. Various modalities are used worldwide to measure visual acuity. Some of the common modalities include Snellen, decimal notation, Landolt C, Han Chun Suk, and visual angle notation [20]. In the clinical studies with bemarituzumab, logarithm of the minimum angle of resolution (LogMAR) equivalent methodology is used, which requires conversion of visual acuity measurements from aforementioned modalities into its corresponding value on the LogMAR scale. This equivalence provides a standardized way to represent visual acuity regardless of the method used for measurement [21]. This method was adopted due to its effectiveness and applicability in different clinical scenarios [22]. In the novel grading scale developed for use with bemarituzumab, change in visual acuity is quantified by the change in the number of lines from baseline, based on the standard Snellen chart. Therefore, while any locally available modality can be used for baseline and subsequent visual acuity assessments, the results need to be converted to their corresponding values on the standard Snellen notation to ensure accurate severity grading per the scale. Eye care provider documentation may be unfamiliar to oncologists, with a potential for communication challenges when cross-specialty collaboration is needed. To make accurate recommendations for dose modifications due to ocular adverse reactions, this interdisciplinary communication needs to be standardized and clear. Using this tool, the eye care provider can assess the severity grade of all ophthalmic conditions diagnosed and the oncologist can use the highest severity grade to adjust the medication dose as clinically appropriate.

Ocular adverse reactions have been associated with modern targeted anticancer therapies. A detailed standard severity grading tool is needed for the interdisciplinary communication between an eye care provider and oncologist to manage patient safety. While the CTCAE provides a general framework for grading adverse events, it is often not sufficient to capture the broad spectrum of potential ocular adverse reactions. For the Amgen-sponsored clinical trials with bemarituzumab, a novel severity grading scale was developed with the intent to capture the specific mechanisms and clinical manifestations of ocular effects associated with targeted therapies. This scale is intended for use with bemarituzumab and may not serve the needs of another product with ocular side effects. In the absence of a standard scale endorsed by regulatory agencies across the world, such customized scales are inherently restricted in their utility. This highlights a significant opportunity for regulatory agencies, pharmaceutical sponsors, and academic eye care providers to collaborate and help improve ocular safety, facilitate early detection and intervention, and develop robust overall management strategies for patients undergoing these treatments.