Abstract
Background
The aim of this review is to elucidate the type and frequency of ocular adverse events associated with selinexor with a goal to quantify the occurrence of these events in our investigator‐initiated trial.
Methods
We retrospectively reviewed medical records of 174 patients treated with at least one dose of selinexor in combination with multiple standard chemotherapy or immunotherapy agents between July 2015 and July 2020 at a comprehensive cancer center in the U.S. All reported ocular adverse events were assessed.
Results
A total of 174 patient medical records were reviewed. All patients received at least one dose of selinexor in combination with multiple standard chemotherapy or immunotherapy agents in our cohort of patients with advanced malignancies. A total of 34 (19.54%) patients experienced 37 ocular adverse events. The most frequently reported ocular symptom was blurred vision, which was reported in 22 (12.64%) patients. The most frequently reported treatment‐related adverse event was dry eye syndrome reported in 21 (12.1%) patients, and 19 (10.9%) of them were diagnosed with mild dry eye. The second most common treatment‐related adverse event was the progression of age‐related nuclear sclerosis (cataract) reported in 7 (4.0%) patients. None of the ocular adverse events required therapy discontinuation.
Conclusion
Our findings highlight that ocular adverse events associated with oral selinexor were mild. The most frequently reported ocular treatment‐related adverse events were mild dry eye and progression of age‐related nuclear sclerosis. None of the ocular adverse events required therapy discontinuation.
Implications for Practice
Patients receiving selinexor in combination with multiple standard chemotherapy or immunotherapy agents were reviewed, with a total of 34 patients experiencing 37 ocular adverse events. Findings highlight that ocular adverse events associated with oral selinexor were mild. The most frequently reported ocular treatment‐related adverse events were mild dry eye and progression of age‐related nuclear sclerosis. None of the ocular adverse events required therapy discontinuation.
Keywords: Ocular side effect of selinexor, Ocular treatment‐related adverse events, Selinexor (KPT‐330), Selective inhibitor of XPO1, Selinexor in combination with multiple standard chemotherapy or immunotherapy agents
Short abstract
XPO1 inhibitors are associated with distinct adverse events. This article focuses on ocular adverse events in patients with advanced malignancies treated with selinexor.
Background
Selinexor (KPT‐330; XPOVIO, Karyopharm Therapeutics Inc., Newton, MA) is the first and only orally bioavailable, selective inhibitor of XPO1‐mediated nuclear export approved by the U.S. Food and Drug Administration (FDA). Selinexor induces apoptosis of cancer cells by the nuclear retention of tumor suppressor proteins and the expression of the glucocorticoid receptor, in addition to inhibition of translation of oncoprotein mRNAs [1, 2, 3, 4, 5, 6].
Responses to selinexor have been reported in patients with multiple myeloma, mantle cell, diffuse large B cell lymphomas, chronic lymphocytic leukemia, Richter's syndrome, and acute myeloblastic leukemia. In addition, response has been reported in solid malignant tumors such as colon, cervical, sarcoma, melanoma, head and neck cancers, Ewing sarcoma, prostate, ovarian, squamous, and high‐grade malignant gliomas [4, 7, 8, 9, 10, 11].
XPO1 inhibitors work through discrete mechanisms that are distinctly different from conventional cytotoxic chemotherapy. KPT‐330 works by suppression of XPO1‐mediated nuclear export and forces nuclear retention, thus presenting a unique therapeutic strategy pathway that is needed for inhibit tumor growth. Unfortunately, these agents are associated with distinct adverse effect profiles, including ocular adverse events. In general, ocular adverse events are usually mild, whereas serious and disabling ocular adverse events are rare.
The most reported nonocular side effects of selinexor are nausea, vomiting, diarrhea, anorexia, dysgeusia, fatigue, thrombocytopenia, neutropenia, anemia, and hyponatremia. It is always critical to delineate whether the symptoms were caused by and related to the cancer itself, paraneoplastic syndrome, or anticancer treatment [12].
We reviewed medical records of patients treated with selinexor with a goal to quantify the occurrence of ocular adverse events in our investigator‐initiated trial.
Materials and Methods
We retrospectively reviewed the medical records of 174 patients with advanced malignancies who were treated at the comprehensive cancer center in the U.S. between July 2015 and July 2020 and received at least one dose of selinexor in combination with multiple standard chemotherapy or immunotherapy agents. The treatment regimens included selinexor and paclitaxel; selinexor and eribulin; selinexor, carboplatin, and paclitaxel; selinexor and pembrolizumab; and selinexor and nivolumab. All reported ocular adverse events were assessed. The severity of the events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 [13].
Results
A total of 174 patient medical records were reviewed. All patients received at least one dose of selinexor between July 2015 and July 2020. The exposure to selinexor dosing ranged from 1 to 76 cycles with a median of 38.5 cycles. In total, 34 (19.5%) patients reported 37 events of ocular complaints. The majority of patients reported only one event, and three patients reported two events. Reported ocular symptoms included change in vision, light sensitivity, conjunctival irritation, increased tearing, and flashes of light. The most frequently reported ocular symptom was blurred vision, which was reported in 22 (12.6%) patients. Ocular side effects were graded according to National Cancer Institute CTCAE version 4.03 [13]; there were three events with grade 2 and 34 events with grade 1, and no events were grade 3.
Mild age‐related nuclear sclerosis (cataract) was reported in 29 (16.66%) patients, with three (1.72%) patients having baseline history of cataract extraction and posterior chamber intraocular implant. The most commonly reported treatment‐related adverse events were the progression of age‐related nuclear sclerosis (cataract), which was reported in seven (4.0%) patients. Three of these patients (1.7%) had grade 2 age‐related nuclear sclerosis; these patients were symptomatic, but it did not affect the activities of daily living (ADL). On the other hand, four (2.3%) patients had grade 3 age‐related nuclear sclerosis that was visually significant and affected ADL. Cataract extraction with intraocular lens placement was recommended. The second most frequently reported treatment‐related ocular adverse events were dry eye syndrome, reported in 21 (12.1%) patients (19 [10.9%] of them were diagnosed with mild dry eye) and punctate epithelial erosions grade 1, with one patient reporting keratoconjunctivitis sicca at baseline. Symptoms of dry eye were treated with lubricant preservative‐free artificial tears in 19 (10.9%) of patients. Only two (1.1%) patients were diagnosed with moderate to severe dry eye grade 2–3, requiring a short course of topical corticosteroids, topical cyclosporine, and a mandate referral to a cornea specialist for further management. Five (2.9%) patients were diagnosed with mild meibomian gland dysfunction treated with daily lid scrubs, warm water, and antibiotic eye ointment. One (0.6%) patient presented with a new episode of flickering of vision and was found to have an epiretinal membrane, posterior vitreous detachment, and possible vasogenic phenomenon. One (0.6%) patient experienced flashes of light but had no signs of retinal or vitreous detachment; no treatment was needed. Two (1.1%) patients reported primary open‐angle glaucoma. None of the ocular adverse events reported during the selinexor treatment required therapy discontinuation or dose reduction (Table 1). We did not observe dose‐dependent ocular toxicity, as there was no difference between patients who received 1 dose or 76 doses of selinexor. Although the standard chemotherapy or immunotherapy agents used may cause similar treatment‐related ocular side effects, this was not found to be the case in our cohort [14, 15, 16, 17, 18].
Table 1.
Selinexor treatment‐related ocular adverse events
| Selinexor treatment‐related ocular adverse events; grade | n (%) | Treatment |
|---|---|---|
| Cataract | ||
| Grade 1 | 29 (16.66) | Observation |
| Grade 2–3 | 7 (4) a | Cataract extraction and IOL implant |
| Dry eye | 21 (12.1) | |
| Grade 1 | 19 (10.9) | PFAT |
| Grade 2–3 | 2 (1.1) |
PFAT Topical corticosteroids Topical cyclosporine Mandatory referral to cornea specialist |
| Meibomian gland dysfunction | 5 |
Lid hygiene Erythromycin eye ointment PFAT |
| Primary open‐angle glaucoma | 2 | Antiglaucoma drops |
| Flickering of vision | 1 | Observation |
| Flashes of light | 1 | Observation |
Total number of patients was 174; 37 events were reported.
Cataract grade 2: 3 (1.7%); grade 3: 4 (2.3%).
Abbreviations: IOL, intraocular lens; PFAT, preservative‐free artificial tears.
Discussion
Selinexor has a unique mechanism, as it works by turning off oncogenic signals by XPO1 inhibition and forcing the restoration of the highly effective tumor‐suppressing pathways that lead to the selective eradication of gnomically damaged (i.e., neoplastic) cells by apoptosis. In addition, selinexor can restore tumor cell sensitivity to chemotherapeutic or targeted agents, which makes it an ideal agent for combination therapy with standard chemotherapeutic agents or selective targeted therapy.
In preclinical studies, ocular symptoms were reported by several patients. The most common ocular symptom was blurred vision, thought to be related to dehydration. Visual acuity changes were documented as mild and generally resolved spontaneously or were correctable with new glasses prescriptions. None of the ocular symptoms have been progressive and rarely required therapy discontinuation. Many the patients were reported to have preexisting ophthalmological disorders detected during pretreatment ophthalmology screening examinations. Data from a phase I clinical and observational trial reported blurred vision in 18 (21%) patients [19]. The preliminary data from this study, as of April 2020, suggest that ocular adverse events are negligible. One hundred eighty‐four patients were enrolled in the preclinical study; 4 (2.17%) patients had cataracts (grade 1, n = 1; grade 2, n = 2; and grade 3, n = 1), and 12 (6.52%) patients with grade 1 blurry vision, which did not result in progressive symptoms. Based on the above data and effective with Amendment Version 19, a recommendation has been made that ophthalmology examinations will only be performed as clinically indicated in the study.
Bahlis et al. reported ocular adverse events with blurred vision in eight patients (19%) and cataract in five (12%) out of 42 patients treated with selinexor plus low‐dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma [20]. Based on the phase III BOSTON trial, on December 18, 2020, the FDA approved selinexor in combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who had previously received at least one and at most three prior therapies. Of a total of 194 patients, cataract was reported in 42 (22%) patients, and seven (9%) patients had grade 3–4 [21].
Our study has some limitations: selinexor was not always a single agent and was mostly given in combination with multiple standard chemotherapy or immunotherapy and, this might be challenging for analysis of toxicity (Table 2).
Table 2.
Common ocular adverse event of chemotherapy and immunotherapy used in combination therapy
| Chemotherapy and immunotherapy | Common ocular adverse events |
|---|---|
| Paclitaxel [22, 23] |
Transient scintillating scotomas Cystoid macular edema |
| Eribulin | No reported ocular adverse events |
| Carboplatin [24, 25] |
Eyelid edema Drug‐induced conjunctivitis Ischemic retinopathy and hemorrhage Optic nerve edema |
| Pembrolizumab and nivolumab [6, 26, 27, 28, 29, 30] |
Myasthenia gravis and thyroid eye disease Ocular inflammation (uveitis, iritis) Punctate inner choroidopathy/multifocal choroiditis, white dot Exacerbation of paraneoplastic syndromes |
In summary, our study findings correlate with the results of prior studies. The most common symptom was blurred vision. Age‐related nuclear sclerosis (cataract) and dry eye were the most common treatment‐related ocular adverse events, although percentage and severity differ across different studies. Cataract had been reported as the most common side effect; however, many of patients had baseline cataract, and only seven patients developed progression. Another important point to highlight is that steroid is known to increase the risk of cataracts; this may explain the higher percentage of cataract reported by Bahlis et al. Our study showed other ocular adverse events: dry eye and meibomian gland dysfunction. There was no clear evidence that these ocular adverse events were dose dependent.
Most of our patients had preexisting ophthalmological disorders that may progress after treatment initiation, such as age‐related nuclear sclerosis (cataract).
Conclusion
Our findings highlight that oral selinexor associated ocular adverse events were mild. The most frequently reported ocular treatment‐related adverse events were progression of age‐related nuclear sclerosis and mild dry eye. None of the ocular adverse events required therapy discontinuation. This showed further safety.
Author Contributions
Conception/design: Nagham Al‐Zubidi, Aung Naing
Provision of study material or patients: Nagham Al‐Zubidi, Dan S. Gombos, David S. Hong, Vivek Subbiah, Siqing Fu, Jordi Rodon Ahnert, Sarina A. Piha‐Paul, Apostolia M. Tsimberidou, Daniel D. Karp, Funda Meric Bernstam, Aung Naing
Collection and/or assembly of data: Nagham Al‐Zubidi, Aung Naing
Data analysis and interpretation: Nagham Al‐Zubidi, Aung Naing
Manuscript writing: Nagham Al‐Zubidi, Aung Naing
Final approval of manuscript: Nagham Al‐Zubidi, Dan S. Gombos, David S. Hong, Vivek Subbiah, Siqing Fu, Jordi Rodon Ahnert, Sarina A. Piha‐Paul, Apostolia M. Tsimberidou, Daniel D. Karp, Funda Meric Bernstam, Aung Naing
Disclosures
Dan S. Gombos: Abbvie (C/A, H); David S. Hong: Alpha Insights, Amgen, Axiom, Adaptimmune, Baxter, Bayer, eCancer, Genentech, GLG, Group H, Guidepoint, Infinity, Liberium, Medscape, Numab, Oncology Education Project Association, Pfizer, Prime Oncology, Takeda, Trieza Therapeutics, WebMD (C/A), AbbVie, Adaptimmune, Aldi‐Norte, Amgen, AstraZeneca, Bayer, Bristol‐Myers Squibb, Daiichi‐Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, GlaxoSmithKline, Ignyta, Infinity, Kite, Kyowa, Eli Lilly & Co., LOXO, Merck, MedImmune, Mirati, miRNA, Molecular Templates, Mologen, Novartis, Pfizer, Seattle Genetics, Takeda, Turning Point Therapeutics (RF), Molecular Match (Advisor), OncoResponse (Founder), Presagia Inc. (Advisor) (OI), Bayer, Genmab, (travel, accommodations, expenses); Vivek Subbiah: Helsinn, LOXO Oncology/Eli Lilly & Co., R‐Pharma US, INCYTE, QED Pharma, Medimmune, Novartis (C/A), Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa‐Sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, Medimmune, Altum, Dragonfly Therapeutics, Takeda, Turning Point Therapeutics, Boston Pharmaceuticals (RF), Novartis, Pharmamar, Helsinn, Incyte (travel); Siqing Fu: AstraZeneca, Abbisko, Anaeropharma Science, Arrien Pharmaceuticals, BeiGene, BioAtla, LLC, Boehringer Ingelheim, Eli Lilly & Co., Hookipa Biotech, Huya Bioscience International, IMV, Inc., Innovent Biologics, Co., Ltd., Lyvgen Biopharm, Co., Ltd., MacroGenics, Medivir AB, Millennium Pharmaceuticals, Inc., Nerviano Medical Sciences, NeuPharma, inc., Novartis, OncoMed Pharmaceuticals, Parexel International, LLC, Sellas Life Sciences Group, Soricimed Biopharma, Inc., Tolero Pharmaceuticals, NovoCure, Turnstone Biologics, Taiho Oncology, Abbisko (other); Jordi Rodon Ahnert: Bayer, Novartis, Blueprint Pharmaceuticals, Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun‐Biotech, Takeda‐Millenium, GlaxoSmithKline, Ipsen (RF), Novartis, Eli Lilly & Co., Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceuticals/Klus Pharma, Spectrum Pharmaceuticals, Inc., Pfizer, Roche Pharmaceuticals, Ellipses Pharma, Certera, Bayer, Molecular Partners, NovellusDX, IONCTURA SA (H), Merck Sharp & Dohme, Kelun Pharmaceuticals/Klus Pharma, Bayer, Jansen, Molecular Partners, SOLTI, Elsevier, GlaxoSmithKline (other); Sarina A. Piha‐Paul: AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc, Boehringer Ingelheim, Bristol‐Myers Squibb, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd, Curis, Inc., Daiichi Sankyo, Eli Lilly & Co., ENB Therapeutics, Five Prime Therapeutics, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Medimmune, LLC., Medivation, Inc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Principia Biopharma, Inc., Puma Biotechnology, Inc., Rapt Therapeutics, Inc., Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, Inc., TransThera Bio (RF—institution); Apostolia M. Tsimberidou: Covance, Genentech, Tempus (C/A), Immatics, Tempus, OBI Pharma, EMD Serono, Baxalta, ONYX, Bayer, Boston Biomedical, Placon Therapeutics, Karus Therapeutics, Tvardi Therapeutics (RF—institution); Daniel D. Karp: Phosplatin Therapeutics, Pfizer, Arcu, Arqule, Bristol‐Myers Squibb, Eli Lilly & Co., Five Prime Therapeutics, GlaxoSmithKline, Genmab, Holy Stone Healthcare Co., Ipsen, Mirati Therapeutics, Inc., Novartis, Onco Response, Red Hill Biopharma Ltd., Rgenix, Sanofi‐Aventis, Xencor, Astellas, Janssen, Affigen, Black Beret Life Sciences, (RF—institution); Funda Meric Bernstam: Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman‐La Roche Ltd., Genentech Inc., IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks (C/A), Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis Sponsored Research Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Millennium Pharmaceuticals Inc., Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co. (advisory committee), Chugai Biopharmaceuticals, Mayo Clinic (H); Aung Naing: CytomX Therapeutics, Novartis, Genome & Company, OncoSec KEYNOTE‐695, STCube (C/A), EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly & Co., Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol‐Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Kymab, PsiOxus, Arcus Biosciences, NeoimmuneTech, ImmuneOncia, Surface Oncology (RF—institution), Immune Deficiency Foundation, Jeffery Modell Foundation and Chao Physician‐Scientist, Baxalta (RF—spouse), Takeda, CSL, Behring, Horizon, Pharming (SAB), ARMO BioSciences (travel and accommodation). Nagham Al‐Zubidi indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Acknowledgments
This study was funded by Karyopharm Pharmaceutical, Inc.
Disclosures of potential conflicts of interest may be found at the end of this article.
No part of this article may be reproduced, stored, or transmitted in any form or for any means without the prior permission in writing from the copyright holder. For information on purchasing reprints contact commercialreprints@wiley.com. For permission information contact permissions@wiley.com.
Footnotes
For Further Reading: Yvette L. Kasamon, Lauren S. L. Price, Olanrewaju O. Okusanya et al. FDA Approval Summary: Selinexor for Relapsed or Refractory Diffuse Large B‐Cell Lymphoma. The Oncologist First published 15 June 2021.
Implications for Practice: Selinexor is a new potential option for adults with relapsed or refractory diffuse large B‐cell lymphoma, not otherwise specified, in the third‐line setting or beyond. Toxicities are typically manageable, but can be difficult to tolerate and necessitate close monitoring and supportive care.
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