Favorable Management of Repeated Serous Retinal Detachment with Continued Tumor Response in a Patient with Intrahepatic Cholangiocarcinoma during Treatment with Pemigatinib

Abstract

Pemigatinib is a fibroblast growth factor receptor inhibitor (FGFRi) approved for the treatment of patients with previously treated biliary tract cancer with FGFR2 fusion. Although infrequent, ocular toxicity manifested as serous retinal detachment (SRD) has been observed and is regarded as a serious side effect. We herein report the case of a 54-year-old woman with unresectable cholangiocarcinoma-initiated pemigatinib after failure of gemcitabine plus S-1 (GS). Although the patient experienced repeated SRD after pemigatinib, dose interruption and dose reduction of pemigatinib from 13.5 mg to 9 mg, and from 9 mg to 4.5 mg led to complete recovery of SRD, and continued tumor shrinkage.

Introduction

Cholangiocarcinoma (CCA) is a malignant neoplasm with a poor prognosis. The 5-year survival rate is ＜30%, which is second lowest survival rate after pancreatic cancer (1). Current treatment guidelines recommend surgical resection for resectable cases, and chemotherapy with or without radiotherapy for unresectable cases (2). Chemotherapy accounts for 56.4% of stage IV CCA treatments. Historically, 37.5% of patients were managed with observation alone. The remaining patients had surgery, radiotherapy, surgery plus radiotherapy, or other combination therapies, excluding chemotherapy (1). Gemcitabine, the combination of gemcitabine and cisplatin, and the triple combination of gemcitabine, cisplatin, and S-1 are well-established first-line treatment options for unresectable CCA. However, no effective treatment option after first-line chemotherapy has been established due to insufficient clinical benefits, as indicated by short median overall survival (OS), ranging from 4.8 to 13.5 months (3-7). Recent sequencing technologies suggest a link between gene alterations and oncogenicity. Fibroblast growth factor receptor 2 (FGFR2) gene translocation is observed in biliary tract cancer, especially in intrahepatic CCA (iCCA) (8-11). FGFR2 fused with partner gene at C-terminal causes a conformational change and activates downstream signal transduction without ligand binding (12). In Japan, pemigatinib, a novel FGFR inhibitor (FGFRi), was approved for biliary tract cancer patients with prior chemotherapy because it was associated with a high response rate [overall response rate (ORR): 35.5%] and better prognosis (median OS: 21.1 months), as suggested by the results of a phase 2 clinical trial (FIGHT-202), in CCA patients with FGFR2 fusion (13), and was promptly incorporated into the Japanese treatment guidelines published by the Japan Liver Cancer Association (only available in Japanese).

The treatment-emergent side effects of pemigatinib can generally be well managed. One of the typical FGFRi-class specific side effects is serous retinal detachment (SRD). The FIGHT-202 study investigated the efficacy and safety of pemigatinib for patients with unresectable CCA who experienced prior systemic therapy and reported SRD in 6 of the 146 patients who participated in the study. Of note, 1 patient reported grade 3 retinal detachment, which was not considered to be related to FGFRi therapy as it lacked the typical features of serous retinal detachment and was consistent with the typical pathology for retinal detachment, including rhegmatogenous retinal detachment (13). We herein report the case of a patient with CCA who received second-line treatment with the only FGFRi authorized for this indication in Japan, pemigatinib, who experienced the onset of SRD 6 days after the initiation of pemigatinib treatment. In this case, SRD was well-managed by dose interruption and the reduction of pemigatinib, and a continued tumor response was observed even at the lowest dose of 4.5 mg of pemigatinib [quaque die (q.d.)].

Case Report

A 54-year-old female was referred to our hospital with hypercalcemia (11.3 mg/dL). Computed tomography (CT) identified a 75.7-mm primary lesion with intrahepatic multiple metastasis, lung metastasis, and mediastinal lymph node metastasis, establishing a diagnosis of unresectable iCCA (T4N1M1). The patient had a medical history of appendicitis, cesarean section, and endometrial cancer (grade 1, pT1AN0M0, 8 years previously), and was positive for HBs antibodies. Thirteen days after the diagnosis of CCA, systemic therapy with gemcitabine plus S-1 (GS) (gemcitabine 1,000 mg/m²/day and S-1 80 mg/m²/day on days 1 and 8 in a 21-day cycle) was initiated. Simultaneously, genome testing using the FoundationOne^Ⓡ next generation sequencing panel was ordered to determine FGFR2 alterations. Restaging at day 15 of cycle 2 revealed a lack of response to chemotherapy with a slight increase in the tumor burden (Fig. 1a). Meanwhile, genome testing of the patient's tumor biopsy specimen revealed an FGFR2::BICC1 fusion with CDKN2A/B loss. Consequently, pemigatinib was prescribed with 13.5 mg per os (p.o.) q.d. for 14 days followed by 7 days off in a 21-day cycle.

Figure 1.

Computed tomography (CT) scan showing the primary tumor in intrahepatic region and lung metastases before pemigatinib treatment (a, d). The primary tumor lesion decreased 24.9 mm (31.2%) from baseline after 1 cycle of 9.0 mg pemigatinib (b), and lung metastases substantially decreased (e). After 3 cycles of treatment with 4.5 mg pemigatinib, a further reduction of 44.7 mm (56.0%) was obtained in the primary lesion (c) with disappearance of lung metastases (f). The arrowhead indicated the tumor lesion.

At day 7 of cycle 1 on 13.5 mg pemigatinib q.d., the patient complained of blurred vision in both visual fields and was evaluated by a nearby ophthalmologist, including a fundus examination. Although the visual acuity was (1.2) in the both eyes. Optical coherence tomography (OCT) showed bilateral unifocal SRD (Fig. 2c-f) with grade 2 [assessed based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03)] (14). As this is a well-known side-effect of some classes of targeted drugs, including mitogen-activated protein kinase (MEK) inhibitors and FGFRi, pemigatinib treatment was immediately interrupted for 8 days followed by complete resolution of the bilateral SRD upon ophthalmological re-examination (Fig. 2d). Consequently, pemigatinib was restarted at 9.0 mg q.d. On day 13 of cycle 1 on 9.0 mg pemigatinib q.d., the patient experienced bilateral blurred vision again, and grade 2 (CTCAE v4.03) bilateral SRD was confirmed (Fig. 2e), which led to another interruption of pemigatinib treatment. Nine days after the last 9.0 mg pemigatinib dose, OCT showed re-adhesion of the retinal pigment epithelial (RPE) (Fig. 2f) with no residual SRD. Simultaneously, tumor restaging was conducted with a CT scan of the primary lesion, which showed tumor shrinkage of 31.2%. The primary lesion decreased by 24.9 mm (from 79.9 to 55 mm) (Fig. 1b), and lung metastases substantially decreased (Fig. 1e). Upon thoroughly informing the patient about the risks of repeated recurrence of SRD and confirming her intention to continue treatment, pemigatinib was reinitiated at 4.5 mg q.d. after a 14-day dose rest from the last treatment with 9.0 mg pemigatinib. A proactive ophthalmologic exam on day 16 of cycle 1 of pemigatinib 4.5 mg q.d. showed no abnormality of the retina, and pemigatinib 4.5 mg q.d. for 14 days followed by 7 days off in a 21-day cycle has been continued for five cycles up to the time of writing this report.

Figure 2.

Echography showed bilateral serous retinal detachment (SRD) after 7 days of 13.5 mg pemigatinib treatment (a-c). SRD recovered after interruption of pemigatinib for 8 days (d); however, SRD detachment recurred at 13 days after the resumption of treatment with 9.0 mg pemigatinib (e). Pemigatinib was immediately interrupted again for 9 days, and SRD was fully resolved (f). R: right eye, L: left eye

To date (190 days after the initiation of pemigatinib), the repeated episodes of SRD during treatment individualization have had a long-term adverse effect on visual acuity. Thus far, the best response after three cycles of pemigatinib 4.5 mg q.d. showed further tumor shrinkage to 44.7 mm (56.0%) from 79.9 mm at the initiation of pemigatinib (Fig. 1c). The levels of carcinoembryonic antigen and carbohydrate antigen19-9 (tumor markers) were uninformative as the patient has presented sustained normal values throughout treatment history up to this point (1.8-3.2 ng/mL, ＜2.0 U/mL, respectively). Zoledronate was initially prescribed for tumor-associated hypercalcemia during the first 3 months, but was discontinued upon serum calcium normalization (Fig. 3). The patient is currently continuing treatment with pemigatinib 4.5 mg q.d. for 14 days followed by 7 days off in a 21-day cycle with no new treatment-emergent adverse events to date.

Figure 3.

Changes in calcium values over time and systemic therapy. The arrow shows the timing of CT scanning, squares show retinal pigment epithelial (RPE) detachment, circles show the ophthalmologic examination, and arrowheads show zoledronate infusion. GS: gemcitabine plus S-1

Discussion

Pemigatinib is a selective FGFRi that binds to the C-terminal ATP binding-pocket of the intracellular tyrosine kinase and inhibits its activity in an ATP-competitive manner. In the FIGHT-202 study, pemigatinib exhibited a clinical benefit in the treatment of CCA with FGFR2 gene fusion or FGFR rearrangement (13).

As FGFRs are involved in various biological functions, including cell survival, may cause several on-target side effects. Among them, ocular toxicity, manifesting as SRD, is a treatment-emergent side effect of the FGFRi drug class that has been observed in 6 of 146 patients (4%) treated with pemigatinib, all cases were classified as grade 1 or 2 (CTCAE v4.03) (14). Of note, in 1 case, grade 3 retinal detachment was reported; however, it was not considered to be related to FGFRi therapy as it lacked the typical features of serous sub-retinal deposits and was consistent with the typical pathology for retinal detachment including rhegmatogenous retinal detachment (13). FGFR1 and 2 are expressed in the retina contributing to neovascularization in RPE cells, and play a key role in normal RPE cell maintenance, injury protection, and damage repair (15). In vitro experiments using the human RPE cell culture system identified that RPE cells expressed a hexahelical integrated membrane protein called aquaporin-1 (AQP-1). The expression level of AQP-1 was closely related to the water permeability of RPE cells (16), and MAPK signaling was associated with fluid transport (17). Although the precise mechanism underlying FGFRi-induced SRD is poorly understood, it is plausible that FGFRi might disturb AQP-1 by attenuating the biological function of RPE cells, causing a loss of fluid control at the sub-retinal membrane. Several phase 1 and 2 studies have reported ocular toxicities, including SRD, in 3-21.6% of patients treated with FGFRis, including pemigatinib, futibatinib, infigratinib, and ASP5878 (14,18,19). However, most cases were grade 1 (17,18) or 2 (14), and severe cases were rare. SRD is also reported in patients treated with targeted therapies, such as MEK inhibitors, which modulate the MAPK pathway, causing eye disorders such as retinal detachment (at frequencies ranging from 5% to 38%) (15). Similar to MEK inhibitor-associated retinopathy, pemigatinib-induced retinopathy showed no substratum changes, including a distinguishable RPE, interdigitation zone (IZ), and ellipsoid zone (EZ) after fluid disappearance, unlike central serous chorioretinopathy, which is usually accompanied by hyperreflective foci, loss of hyperreflective IZ and EZ, and disturbed RPE after resolution (20). These tyrosine kinase inhibitor-related ocular toxicities are easily manageable in the clinical setting as they are immediately identified by patients and straightforward to confirm by prompt ophthalmic examination at the time of the first visual disturbance.

In the FIGHT-202 study, where 146 patients with CCA were treated with pemigatinib 13.5 mg q.d. for 14 days followed by 7 days off in a 21-day cycle, two steps of dose reduction at 9.0 mg q.d. and 6.0 mg q.d. were allowed according to the protocol (13). Based on the tablet strength, the lowest dose of pemigatinib is 4.5 mg, which has not yet been used in clinical studies, limiting the current knowledge about the management of adverse events and the clinical benefits. In this case, SRD occurred during the first cycle of pemigatinib treatment, as previously reported for FGFRi-associated retinopathy (21), and was well managed by dose interruption followed by dose reduction, eventually reducing pemigatinib to 4.5 mg q.d.; at this dose SRD did not occur during at least 4 months of continued treatment. Considering that no predictive factors for SRD have been established, regular ophthalmic examination should be conducted, and immediate dose interruption should be implemented when patients experience SRD.

Author's disclosure of potential Conflicts of Interest (COI).

Koki Kabu: Employment, Incyte Biosciences Japan.