Uveitis Caused by New Anticancer Drugs (Molecular Targeted Therapies)

Molecular targeted drugs for the skin cancer malignant melanoma
• Dabrafenib (Tafinlar®)
• Trametinib (Mekinist®)
These can also cause uveitis as a side effect.

Blurred vision
Distorted vision
Trouble seeing clearly
Reduced visual acuity
Eye redness

Some patients develop symptoms such as these and visit an eye doctor.

Uveitis (an Eye Side Effect) Caused by New Anticancer Drugs Called Molecular Targeted Therapies

What Are Molecular Targeted Drugs?

As immunology research has advanced, it has become possible to identify the genes and proteins that drive cancer progression.
It is also possible to tell that a cancer is progressing because of a particular gene mutation.

Drugs that act on the genes and proteins of cancer cells are called “molecular targeted drugs.”

Cancer progresses when abnormal cell proliferation occurs.
(That is, cancer cells multiply quickly.)

Anticancer drugs used in chemotherapy also damage normal cells that multiply quickly.
As a result, they caused serious side effects, such as:
• Hair loss
• Nausea
• Decreased white blood cell count

and others.

By targeting molecules involved in cell proliferation, these side effects can be reduced¹.

Malignant Melanoma and New Treatments

Malignant melanoma is a type of skin cancer in which
the cells that produce melanin pigment, called melanocytes, become cancerous.

Genes determine the specific molecules and proteins in the body.
Among them, it has become possible to identify molecules involved in the growth of cancer cells.

“Gene mutations” that make cancer cells grow faster have also been identified.

Genetic testing is now available.

Drugs have been developed that can be used in patients in whom a specific gene mutation is confirmed^2,3.

These are called “molecular targeted drugs.”

• Dabrafenib (Tafinlar®): BRAF inhibitor
• Trametinib (Mekinist®): MEK inhibitor

Dr. Caroline Robert, Head of Dermatology at the Institut Gustave Roussy, a cancer research institute based in Paris, stated: “This analysis showed that with first-line treatment using Tafinlar® and Mekinist® in combination, about one in five patients had their disease controlled for five years, and about one in three were still alive after five years. Patients with metastatic malignant melanoma have long been considered to have a poor prognosis, but there are now more reasons for hope. This analysis has high clinical significance and should have a positive effect on patient survival. These results show that molecular targeted therapy can bring long-term survival and lasting improvement in outcomes.”

From the Novartis website

• Dabrafenib (Tafinlar®)　
• Trametinib (Mekinist®)　
Novartis Pharma:
https://www.product.gan-kisho.novartis.co.jp/tafinlar-mekinist-info

* The following combination therapies with molecular targeted drugs are also available.

• Encorafenib (Braftovi®)
• Binimetinib (Mektovi®)　
Ono Pharmaceutical:
https://www.ono-oncology.jp/medical/products/mektovi/action

• Vemurafenib (Zelboraf®)
• Cobimetinib (Cotellic®)
In the evaluation under the Patient Access Scheme (PAS),
cost-effectiveness did not meet the criteria, and the combination is classified as “not recommended.”
https://www.cotellic.com

The Eye’s “Immune Privilege”: A Mechanism That Protects the Eyeball from Inflammation

Unlike many other organs, the eyeball is a closed organ.

It has a function that protects the eye by mounting an immune response to inflammation from outside:
the “immunologically privileged site.”

Cells sensitized to a foreign substance (“antigen”) that enters the eye are carried from the lymph nodes to the spleen, where they form a population of cells that suppresses inflammation.
These cells return to the eye and are known to mount a protective response against the specific antigen⁴:
ACAID (Anterior Chamber-associated Immune Deviation)

An intact blood-retinal barrier is essential.

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What Is the Blood-Retinal Barrier?

A fundus photograph clearly shows the blood vessels of the retina.
The retina looks orange because the color of the choroid, a tissue rich in blood vessels located behind it, shows through.

There is a barrier that keeps the blood flowing through the vessels from leaking out, and it allows the retina to function normally.
This is called the blood-retinal barrier.

It is known that this barrier is disrupted when the eye inflammation “uveitis” is occurring⁵.

The onset and progression of diabetic retinopathy are also caused by breakdown of the blood-retinal barrier⁶.

Uveitis During Treatment with the Molecular Targeted Drugs Tafinlar® and Mekinist®

Tafinlar® (dabrafenib) and Mekinist® (trametinib) act on molecules involved in cell proliferation (MAP kinases).

They also act on the proliferation of vascular endothelial cells, which line the inside of blood vessels, and are known to impair their function.

Damage to the blood-retinal barrier is thought to break down the eye’s “immune privilege”:
and trigger the inflammatory reaction known as uveitis^7-10.

• Branch retinal vein occlusion (BRVO)
• Central serous chorioretinopathy（Central serous chorioretinopathy, CSC）
is also an important side effect of these molecular targeted drugs^{11, 12}.

Early Symptoms of Uveitis and Retinal Disease

• Blurred vision
• Red eyes
• Vision that is poorer than usual
• Changes in the visual field
• Distorted vision, and others

If you have any symptoms, please see an eye doctor.

References

1. Sullivan, R., LoRusso, P., Boerner, S., Dummer, R., 2015. Achievements and Challenges of Molecular Targeted Therapy in Melanoma. American Society of Clinical Oncology Educational Book 177–186. https://doi.org/10.14694/EdBook_AM.2015.35.177
2. Menzies, A.M., Long, G.V., Murali, R., 2012. Dabrafenib and its potential for the treatment of metastatic melanoma. Drug Des Devel Ther 6, 391–405. https://doi.org/10.2147/DDDT.S38998
3. Patel, H., Yacoub, N., Mishra, R., White, A., Yuan, L., Alanazi, S., Garrett, J.T., 2020. Current Advances in the Treatment of BRAF-Mutant Melanoma. Cancers 12, 482. https://doi.org/10.3390/cancers12020482
4. Taylor, A.W., 2009. Ocular immune privilege. Eye 23, 1885–1889. https://doi.org/10.1038/eye.2008.382
5. de Smet, M.D., Taylor, S.R.J., Bodaghi, B., Miserocchi, E., Murray, P.I., Pleyer, U., Zierhut, M., Barisani-Asenbauer, T., LeHoang, P., Lightman, S., 2011. Understanding uveitis: the impact of research on visual outcomes. Prog Retin Eye Res 30, 452–470. https://doi.org/10.1016/j.preteyeres.2011.06.005
6. Kinuthia, U.M., Wolf, A., Langmann, T., 2020. Microglia and Inflammatory Responses in Diabetic Retinopathy. Front Immunol 11, 564077. https://doi.org/10.3389/fimmu.2020.564077
7. Joshi, L., Karydis, A., Gemenetzi, M., Shao, E.H., Taylor, S.R.J., 2013. Uveitis as a Result of MAP Kinase Pathway Inhibition. Case Rep Ophthalmol 4, 279–282. https://doi.org/10.1159/000357060
8. Rueda-Rueda, T., Sánchez-Vicente, J.L., Moruno-Rodríguez, A., Molina-Socola, F.E., Martínez-Borrego, A.C., López-Herrero, F., 2018. Uveitis and serous retinal detachment secondary to systemic dabrafenib and trametinib. Arch Soc Esp Oftalmol (Engl Ed) 93, 458–462. https://doi.org/10.1016/j.oftal.2018.01.008
9. Draganova, D., Kerger, J., Caspers, L., Willermain, F., 2015. Severe bilateral panuveitis during melanoma treatment by Dabrafenib and Trametinib. J Ophthal Inflamm Infect 5, 17. https://doi.org/10.1186/s12348-015-0049-9
10. Sarny, S., Neumayer, M., Kofler, J., El-Shabrawi, Y., 2017. Ocular toxicity due to Trametinib and Dabrafenib. BMC Ophthalmology 17, 146. https://doi.org/10.1186/s12886-017-0541-0
11. van der Noll, R., Leijen, S., Neuteboom, G.H.G., Beijnen, J.H., Schellens, J.H.M., 2013. Effect of inhibition of the FGFR-MAPK signaling pathway on the development of ocular toxicities. Cancer Treat Rev 39, 664–672. https://doi.org/10.1016/j.ctrv.2013.01.003
12. Niro, A., Strippoli, S., Alessio, G., Sborgia, L., Recchimurzo, N., Guida, M., 2015. Ocular Toxicity in Metastatic Melanoma Patients Treated With Mitogen-Activated Protein Kinase Kinase Inhibitors: A Case Series. American Journal of Ophthalmology 160, 959-967.e1. https://doi.org/10.1016/j.ajo.2015.07.035

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