We found out that three patients among 19 patients (15.79%) on Vandetanib, one among 202 patients (0.50%) on Osimertinib and five among five (100%) on ABT-414 showed vortex keratopathy. All patients except those deceased shortly after initiation of chemotherapy complained of decreased visual acuity due to corneal epithelial changes. While old drugs showed low incidence of corneal change causing vision deterioration, recently used novel drugs in clinical trials revealed obviously high incidence of ocular side effect. Fortunately, full recovery of vision and the cornea were confirmed in seven patients (Table 3).
Vortex keratopathy is a condition characterized by a whorl-like pattern of corneal deposits in the corneal epithelium. Well-known causes of the disease are Amiodarone use or Fabry disease, also known as lysosomal storage disorder.[5] Beyond Amiodarone, other drugs that are known to cause vortex keratopathy include Vandetanib and Osimertinib.[5] There have been few case reports of vortex keratopathy after EGFR inhibitor chemotherapy. Ahn and associates reported a case of vortex keratopathy after six one-month cycles of Vandetanib of 300mg/day.[10] Chia et al. reported vortex keratopathy presumed to develop eight months after use of AZD9291, a third generation tyrosine kinase inhibitor (TKI), currently known as Osimertinib. Both case reports did not address the prognosis of the corneal lesions.[12] We reviewed a tertiary hospital database for patients who used any kind of EGFR or FGFR inhibitors. Although there could be some variation depending on region, country and institution, we calculated the incidence of vortex keratopathy for each of the drugs. Furthermore, we confirmed that the keratopathy had cleared or at least improved after discontinuation of the agents.
Drug-induced vortex keratopathy is typically associated with cationic and amphiphilic medications that penetrate lysosomes and bind to cellular lipids. It is believed that drug-lipid complexes are the intra-lysosomal inclusion bodies observed in the basal layers of the corneal epithelium.[10, 13] The mechanism of vortex keratopathy with EGFR receptor inhibitors was thought to be either deposits of chemotherapy agent-derived metabolites in the cornea or abnormal turnover or migration of corneal epithelial cells due to inhibition of corneal EGFR.[5] Recently, interactions between Vandetanib and lysozymes and their characteristics were described, providing support for the previously suggested role of drug metabolites.[14]
Strikingly, every patient who used ABT-414 in the Abbie-study showed vortex keratopathy. It is quite alarming, given that there were 3 cases out of 19 patients on Vandetanib and 1 out of 192 patients on Osimertinib. Moreover, in one case, vortex keratopathy developed within only 22 days after the first infusion of the drug. In the Abbie-study, patients received prophylactic steroid eye drops three times a day for a week starting two days prior to each infusion and continuing for four days after. According to Phase I study of ABT-414, patients showed dose-related ophthalmologic toxicities such as dry eyes, blurry vision, eye pain, photophobia, watery eyes, and finding of microcyst development within the cornea. Although it is unclear whether this microcystic development refers to vortex keratopathy, the article suggested that steroid eye drops to be used to help reduce the incidence and severity of those side effects.[6] Despite the previous reports on the usefulness of prophylactic steroid eye drops in reducing the incidence of ocular side effects from ABT-414[6,15], the treatment did not seem effective to prevent the development of vortex keratopathy in our study since all five patients with ABT-414 had developed such corneal lesions.
ABT-414 is an antibody-drug conjugate (ADC) consisting of three components: an EGFR-targeting humanized monoclonal antibody, a potent microtubule agent (monomethyl auristatin F (MMAF)) and a non-cleavable maleimidocaproly (mc) linker that connects MMAF to the antibody.[7] In clinical development, ABT-414 was designed to limit binding to wild-type EGFR.[15] Therefore, MMAF is supposed to have lower cytotoxicity, attenuated potency and improved aqueous solubility compared to its uncharged counterpart, monomethyl auristatin E (MMAE).[16]
However, the reduced toxicity does not appear to extend to ocular toxicity. According to a review article on ADCs with MMAF and MMAE published in 2015, there were five cases of corneal microcystic epithelial changes and four cases of corneal deposits or inclusions.[17] Interestingly, among the list of ADCs associated with ocular side effects, four out of thirteen used MMAF as a cytotoxin. However, all ADCs using MMAE as a cytotoxin were not associated with ocular side effects.[17]
The cytotoxin MMAF, an antimitotic auristatin derivative with a charged C-terminal phenylalanine residue,[16] is a microtubule inhibitor that induces apoptosis in cells undergoing mitosis. However, a recent study showed that it may also disrupt non-dividing cells in interphase.[15] Although it is not clear why MMAF preferentially disrupts corneal cells, the ocular toxicity of the substance seems to have affected instant formation of vortex keratopathy following dosing with ABT-414.
Despite the extensive number of medical records, conventional EGFR inhibitors such as Erlotinib, Geftinib, Afatinib and Cetuximab were not linked with corneal epithelial changes in any cases. There was few patients who had chart record of simple punctate epithelial erosions but there was no evidence of vortex keratopathy. Although the mechanisms are not clear, the latest EGFR inhibitors seem to affect the corneal epithelium more directly than conventional drugs.
Although we could not calculate the accurate incidence of vortex keratopathy after use of EGFR inhibitors as chemotherapy due to the nature of this study, it does not seem uncommon when dealing with recently developed agents. Vandetanib is a second-generation EGFR inhibitor and Osimertinib is a third-generation EGFR inhibitor that can target T790M and EGFR TKI-sensitizing mutations while sparing wild-type EGFR.[18] ABT-414 is an investigational compound. Quite a few patients developed vortex keratopathy after using these three chemotherapy agents. There were some new or investigational drugs without vortex keratopathy patients such as Olmutinib, Naquotinib, Rociletinib, AZD3759, JNJ-61186372 and Regorafenib. Howeverthere is a possibility that lesions could be found in much larger cohort.
On the other hand, we suspected corneal dysmaturation in patients who used FGFR inhibitors. Corneal dysmaturation is a benign and indolent condition that leads to a frosted corneal epithelium or individual islands of opalescent epithelium. Fibrovascular corneal pannus is not present.[19] Unlike vortex keratopathy, corneal dysmaturation is scarcely reported in the literature, which complicated our ability to obtain evidence. Although histological findings are important for accurate diagnosis, we did not have access to samples of corneal lesions since this was a retrospective study. Nevertheless, the opacification pattern was different from that of vortex keratopathy and was clearly distinguishable when we compared it to that of EGFR inhibitors. As there is no supporting evidence of histopathologic specimen on our patients, we cannot conclude those keratopathy after FGFR inhibitor chemotherapy as corneal dysmaturation. However, there haven’t been any reports regarding corneal changes associated with the use of FGFR inhibitors as far as we know. Therefore, our findings are meaningful that we found out the clinical features were different from vortex keratopathy. It would be unwise to draw conclusion that actual incidence of this corneal epithelial change after FGFR inhibitors treatment are as high as we suggested since the total number of patients is too small.
We also reviewed records of NSCLC patients on Regorafenib, a multikinase inhibitor that also blocks FGFR1 and 2 and various other receptors, and Pazopanib, a multikinase inhibitor that blocks FGFR, VEGR, Platelet-derived growth factor receptor (PDGFR), but did not find any cases similar to those of the three patients on an FGFR inhibitor. We hypothesize that a selective strong affinity of ASP5878 and FPA144 toward FGFR affected corneal changes in three patients. Since we could not find any report describing ophthalmological findings following FGFR inhibitor chemotherapy, further research on the influences of FGFR inhibitors on the corneal epithelium is needed.
It is difficult to define the exact time lapse between the start of chemotherapy and the appearance of corneal epithelial changes because not all patients had regular follow-up exams during and after chemotherapy. However, it is clear that these corneal lesions could develop quite fast, suggesting the possibility that previously reported cases might have been diagnosed far later than the onset of keratopathy. One of our cases on Vandetanib developed vortex keratopathy 91 days after the first chemotherapy, which is much quicker than previously reported. One case on ASP5878 only took 55 days to develop a corneal lesion and two patients on FPA144, an enhanced monoclonal antibody against FGFR2b, took two months. Furthermore, nearly everyone in the ABT-414 group took less than one month to develop vortex keratopathy.
All of the patients who developed corneal epithelial changes were treated under recommended regimen as follows. According to FDA, recommended dose of Osimertinib is 80 mg tablet once a day until disease progression or unacceptable toxicity. In ABT-414, recommended regimen is 1.25 mg/kg via intravenous (IV) infusion every 2 weeks over 30–40 min.[6, 20] In clinical studies of Vandetanib, patients received vandetanib 300 mg once daily.[21, 22] In clinical trials of ASP5878, varying oral dose of 2mg bid to 20mg bid were given to patients.[8] In our Center, 12mg bid was given orally. The recommended dose of FPA144 is 15mg/kg via by IV infusion every 2 weeks.[23] Although it is not clear, it seems that there are certain accumulated doses of drugs that evoke corneal epithelial changes as patients complained of decreased visual acuity after the lapse of certain time. As nearly all patients were recovered from corneal epithelial changes after discontinuation of the drugs, decrease of accumulated dose of chemotherapy agents might be important for prognosis of corneal lesions.
It is important to check which other chemotherapy agents the affected patients in the study took before receiving EGFR or FGFR inhibitors discussed above to state those agent indeed caused the corneal epithelial lesions. Table 4 shows prior chemotherapy agents before EGFR and FGFR inhibitor therapy in affected patients. First, in the matter of Geftinib and Afatinib, authors could not found evidence of vortex keratopathy in this study as we discussed and there was no report on the literatures. Secondly, authors reviewed through literatures dealing with ocular side effects of listed chemotherapy agents in Table 4. Although quite a few agents listed above had variety of ocular side effects, none of them had any evidence specifically dealing with corneal epithelial changes (Table 5). Moreover, Vandetanib and Osimertinib already have few reports on corneal epithelial changes. Therefore, authors concluded it is reasonable to believe that those corneal epithelial changes occurred in the twelve patients were induced by EGFR or FGFR inhibitors that we pointed out.
Two cases on Vandetanib and one case on Osimertinib took much longer for diagnosis of ocular complications. However, the delay may have been due to late consultation with the ophthalmology department, as these patients did not have regular ophthalmologic examinations before they complained of decreased visual acuity. In our study, among 6,871 patients, only 16.89% had any record of ophthalmologic examination. Furthermore, only one-third of those had consultation or follow-up associated with their chemotherapy treatment. The rest of the medical records did not relate to the patient’s chemotherapy.
A lack of knowledge of corneal epithelial changes after use of EGFR or FGFR inhibitors among clinicians may cause them to disregard the importance of consultation with the ophthalmology department before, during and after chemotherapy. Moreover, visual impairment may not be considered important compared with other systemic side effects of chemotherapy. Therefore we are unable to estimate how many patients may have experienced symptoms without referral or diagnosis.
Furthermore, due to the nature of the study, patients were detected by retrospective chart review, which leaves the matter of selection bias. Subtle symptoms and clinical findings may have caused by these agents and may be described as “puntate epithelial erosions or dry eyes,” which were not included as cases. Therefore, the percentages of patients affected by a given agent do not accurately summarize the prevalence of ocular toxicity associated with that agent. In other words, the actual incidence of corneal epithelial changes after EGFR or FGFR chemotherapy could have been underestimated.
Another limitation of our study is a possibility that actual cause of corneal epithelial changes could be more complicated. Drugs discussed here are varied with different mechanism of action. Some results could be off-target effect or could be affected by many other drugs that patient took during chemotherapy. However, vortex keratopathy associated with Osimertinib, Vandetanib, ABT-414 was already reported in previous articles. Also, ASP5878 and FPA144 are not multi-TKI. Therefore, the result of our study, although somewhat inaccurate, has significance that it had long-term follow-up records and confirmed full recovery of keratopathy in nearly all cases.
In our study, steroid eye drops were not effective in preventing corneal epithelial changes after treatment with ABT-414. Nevertheless, all patients showed improved visual acuity and corneal surfaces after discontinuing the drug. Reardon et al. also pointed out that once ABT-414 dosing was held or discontinued, ocular symptoms gradually resolved spontaneously in the majority of patients. They speculated that cornea would regenerate after discontinuation of the ABT-414, eliminating microcysts caused by the drug.[6] Therefore, considering the possible side effects of steroid eye drops, it is wise not to use them for prophylaxis. Furthermore, patients undergoing chemotherapy with EGFR or FGFR inhibitors should be educated about the possibility of corneal epithelial changes that reduce visual acuity and reassured that the condition is generally reversible after end of treatment.