Evaluating Treatment Options and the Multidisciplinary Care of Ocular Toxicities of MEK Inhibitors

Ocular toxicities associated with conventional cytotoxic chemotherapy and novel targeted therapies utilized in cancer care continue to evolve.

The authors of “Ocular Toxicities of MEK inhibitors in Patients with Cancer: A Systemic Review and Meta-Analysis” provide a comprehensive analysis of 17 randomized clinical trials. Because the RAS-MAPK activation pathway is a common mutation in multiple malignancies, MEK inhibitor use continues to expand in treatment recommendations. Recent advancements include the BRAF/MEK inhibitor combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) receiving FDA approval for a tissue-agnostic indication in solid tumors harboring a BRAF V600E mutation.¹ Other examples of expanding use of MEK inhibitors beyond BRAF V600E mutations include binimetinib (Mektovi) for NRAS-mutated melanoma and neurofibromatosis type 1–associated tumors, particularly progressive low-grade gliomas and plexiform neurofibromas.^2,3

With this increasing clinical presence, clinicians need to be cognizant of these unique risks of therapy and appropriate monitoring strategies to mitigate toxicities.

Results from this meta-analysis report an increased risk of ocular adverse effects (AEs) specifically blurred vision, chorioretinopathy, and retinal detachment when MEK inhibitors are combined with additional targeted or traditional chemotherapy. Most of these ocular AEs are National Cancer Institute Common Terminology Criteria for Adverse Events grade 1 or 2 in severity. Grading of ocular AEs—given the diversity of toxicities—can be challenging; notably, improvements have been made in the classification of retinal vascular disorders, MEK inhibitor–associated retinopathy, and blurred vision with Common Terminology Criteria for Adverse Events version 5.0.

Many patients are asymptomatic or present with mild symptoms depending on the ocular AEs, which can create challenges for clinicians in early clinical intervention. In the setting of suspected MEK inhibitor–associated retinopathy, MEK inhibitors can cause transient, dose, and time-dependent retinopathy. Elimination half-lives of MEK inhibitors vary (approximately 3.5 hours for binimetinib, 44 hours for cobimetinib [Cotellic], and 4.8 days for trametinib), so the timing of ocular AEs may differ. Interestingly, some patients experience these events immediately following the initiation of therapy, and the duration of therapy does not influence the development of ocular sequelae.⁴ Adherence to product recommendations for dose reductions or discontinuations (temporary/permanent) based on toxicity is advised.

In many cases, MEK inhibitors can be safely resumed following the resolution of symptoms at a reduced dose without provoking repeat ocular AEs. These descriptive findings on ocular toxicity imply that there is a threshold for provocation in a dose-dependent manner and that alternative dosing strategies may be beneficial in patients with high baseline risks of ocular complications. The traditional paradigm in clinical trial design and drug development is to utilize anticancer drugs at maximum tolerated doses, so rarely do phase 3 trials incorporate multiple dosing strategies when seeking new indications of use.

However, there appears to be renewed interest in shifting to seeking minimum effective doses, particularly in targeted therapies.⁵ A recent example of this strategy is with sotorasib (Lumakras), which received FDA accelerated approval for KRAS G12C non–small cell lung cancer.⁶ The FDA issued a postmarketing requirement to evaluate 960 mg vs 240 mg daily dosing to assess objective response rates with less toxicity (CodeBreaK201; NCT04933695). Because KRAS and MEK share the common pathway target of MAPK, further clinical investigation and use of MEK inhibitors would benefit from learning this lesson and exploring optimized dosing strategies to minimize common toxicities like those outlined in this manuscript.

In 2006, van Heeckeren et al wrote a brilliantly titled editorial, “Promise of NewVascular-Disrupting Agents Balanced With Cardiac Toxicity: Is It Time for Oncologists to Get to Know Their Cardiologists?” following the emergence of VEGF targeted therapies.⁷ With the expanding use of MEK inhibitors and recent FDA approvals that include belantamab mafodotin-blmf (Blenrep), tisotumab vedotin-tftv (Tivdak), and mirvetuximab soravtansine-gynx (Elahere), we have reached the era where oncologists should “get to know” their ophthalmologists.

We would advocate for the development of collaborative practice partnerships due to the challenges of fragmented cancer care. With some novel agents requiring ophthalmic exams, including visual acuity and slip lamp exams at baseline and prior to each dose and the coordination of multiple eye drops (lubrication, corticosteroids, vasoconstrictor), these proposed partnerships to manage ocular AEs should be multidisciplinary. The establishment of integrated communication would foster improved coordination of patient care. For example, if a patient were to experience loss of vision or other visual disturbance while receiving a MEK inhibitor, it can be challenging to receive an ophthalmological evaluation within 24 hours as recommended. These proposed partnerships between oncology and ophthalmology could expedite consultations.

Clearly, all healthcare professionals need to be vigilant in their patient education sessions regarding the risk of ocular AEs and management strategies.

DISCLOSURES: DeRemer has nothing to disclose; Doonan receives research funding from Curis, Inc.

AFFILIATIONS: David L. DeRemer, PharmD, BCOP;^1,2 Bently P. Doonan, MD, MS^2,3

¹Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville
²University of Florida Health Cancer Center, Gainesville
³Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville; University of Florida Health Cancer Center, Gainesville

CORRESPONDING AUTHOR(S):

David L. DeRemer, Pharm.D., BCOP, FCCP, FHOPA
Clinical Professor
Assistant Director, Experimental Therapeutics Group
University of Florida College of Pharmacy
University of Florida Health Cancer Center
Office: 352-294-8891
Email: dderemer@cop.ufl.edu
ORCID: 0000-0002-2207-9552

Bently P. Doonan, MD, MS
Assistant Professor
University of Florida College of Medicine
Division of Hematology and Oncology
University of Florida Health Cancer Center
Email: Bently.Doonan@medicine@ufl.edu
ORCID: 0000-0001-5401-2910

References

1. FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation. FDA. June 23, 2022. Accessed February 9, 2023. https://bit.ly/3HYXkhe
2. Dummer R, Schadendorf D, Ascierto PA, et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(4):435-445. doi:10.1016/S1470-2045(17)30180-8
3. Klesse LJ, Jordan JT, Radtke HB, et al. The use of MEK inhibitors in neurofibromatosis type 1-associated tumors and management of toxicities. Oncologist. 2020;25(7):e1109-e1116. doi:10.1634/theoncologist.2020-0069
4. Arora S, Surakiatchanukul T, Arora T, et al. Retinal toxicities of systemic anticancer drugs. Surv Ophthalmol. 2022;67(1):97-148. doi:10.1016/j.survophthal.2021.05.007
5. Piccart MJ, Hilbers FS, Bliss JM, et al. Road map to safe and well-designed de-escalation trials of systemic adjuvant therapy for solid tumors. J Clin Oncol. 2020;38(34):4120-4129. doi:10.1200/JCO.20.01382
6. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. FDA. May 28, 2021. Accessed February 13. 2023. https://bit.ly/3YEj1Kk
7. van Heeckeren WJ, Bhakta S, Ortiz J et al. Promise of new vascular-disrupting agents balanced with cardiac toxicity: is it time for oncologists to get to know their cardiologists? J Clin Oncol. 2006;24(10):1485-1488. doi:10.1200/JCO.2005.04.8801