Management of Adverse Events Associated With FGFR Inhibitors

Vivek Subbiah, MD, Sarah Cannon Research Institute, Nashville, Tennessee, discusses the management of adverse events associated with FGFR inhibitors for urothelial carcinoma and cholangiocarcinoma.

Dr Subbiah highlights methods for treating ocular, dermatological, and gastrointestinal toxicities in patients treated with FGFR inhibitors. He concludes, “The key is proactive monitoring to ensure the optimal clinical benefit from these precision medicine agents”

Transcript:

Hello. I'm Vivek Subbiah, Chief of Early Phase Drug Development, Sarah Cannon Research Institute, Nashville, Tennessee. It is my pleasure and honor to talk to you all about clinical development and management of adverse events associated with FGFR inhibitors. Why do we need to know about the adverse events about on FGFR inhibitors?

Genetic alterations in the fibroblast growth factor receptor gene family—that include activating gene fusions, rearrangements, amplifications, and mutations—are associated with oncogenesis of a variety of tumor types. The oncogenic potential of FGFR alterations has prompted the clinical development of several FGFR inhibitors, what we call pan-FGFR inhibitors. They include for the treatment of urothelial carcinoma and cholangiocarcinoma.

To date, we have 3 FDA-approved drugs for targeting FGFR-altered malignancies. Erdafitinib is approved for the treatment of locally advanced metastatic urothelial cancer that harbor FGFR2 or FGFR3 alterations and has progressed on platinum-based therapy. Pemigatinib and futibatinib are approved for previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or other rearrangements. Futibatinib is approved only for intrahepatic cholangiocarcinoma. Interestingly, in August 2022, pemigatinib was additionally approved for the treatment of relapsed refractory myeloid lymphoid neoplasm (MLN) with FGFR1 gene rearrangement based on promising and durable clinical activity of the study known as the FIGHT-203 study.

Interestingly, another drug, infigratinib, was also approved by the US FDA for the treatment of cholangiocarcinoma harboring FGFR2 alterations. However, the distribution of infigratinib was discontinued. In addition to that, there are several drugs targeting the FGFR pathway in clinical trial development like the derazantinib and rogaratinib. Most recently, a specific FGFR2-selective inhibitor, lirafugratinib, RLY-4008, which are being investigated in histology-specific and a tissue-agnostic setting. For any therapeutic agent, demonstrated efficacy must be balanced against on-target associated toxicity to optimize clinical benefit.

With FGFR inhibitors, we commonly encounter what we call as on-target toxicities that include hyperphosphatemia. When we start FGFR inhibitors, the on-target toxicity is hyperphosphatemia. Patients have many issues: eye issues, dermatological issues, gastrointestinal side effects as well, like diarrhea, nausea, etc. It is important for us to closely monitor and address these adverse events associated with FGFR inhibitors in the clinical setting. There always remains an unmet need for practical insights into adverse event management in the real-world setting.

What we provided in this review, published in Cell Reports Medicine, is a comprehensive review for best practices for proactively monitoring and managing adverse events related to FGFR-targeted agents. Again, this is primarily based on patients we treated on clinical trials and also real-world clinical experience in reviews of literature and prescribing information.

Hyperphosphatemia can be managed by careful monitoring with dose reduction or interruption of the FGFR inhibitor. Prophylactic, a low-phosphate diet. In fact, in the supplementary section, we've detailed on what are the low-phosphate diets, and also we detailed on phosphate-lowering therapies. This is important because this is a quality of life issue, and hyperphosphatemia can be managed very effectively, with these guidelines.

One of the other adverse events that we see is eye toxicities. Ocular adverse events are managed by withholding or adjusting the dose of the FGFR agent. It is important to have a good ophthalmologist as a colleague for consulting and referring these patients. We also talk about how to monitor these ocular related adverse events from FGFR inhibitors.

What's the next adverse event? Dermatological adverse events. Mainly, what we've seen is alopecia, hair loss, which can be managed with a drug like minoxidil. We see a lot of dry skin with FGFR inhibitors. This is similar to several of the tyrosine kinase inhibitors, and we usually prescribe liberal moisturizers to help with dry skin. One of the challenges with all the FGFR inhibitors has been the hand-foot syndrome [palmar-plantar erythrodysesthesia]. Hand-foot syndrome can be prevented essentially by lifestyle changes and with moisturizing creams, urea, and salicylic acid. In the review we give a detailed guideline on how to manage and prevent this hand-foot syndrome from happening because this is a huge quality of life issue for these patients.

Among the gastrointestinal adverse events, diarrhea is usually managed by drugs like loperamide. We see mouth sores with FGFR inhibitors. Mouth sores can be managed by baking soda, rinses with baking soda, mucosal-coating agents, topical anesthetics. We also see dry mouth. Dry mouth is usually managed, again, by baking soda rinses, also salvatory substitutes, and sometimes we have used even salvatory stimulants.

In summary, most of the FGFR–inhibitor-associated adverse events are manageable in most patients, especially if you can proactively take prophylactic measures and treat them. The key is proactive monitoring to ensure the optimal clinical benefit from these precision medicine agents. Thank you so much.

Source:

Subbiah V and Verstovsek S. Clinical development and management of adverse events associated with FGFR inhibitors. Cell Rep Med. 2023;4(10). doi:10.119j.xcrm.2023.101204