Practical Toxicity Management Awareness With FGFR Inhibitors Improves Real-World Patient Outcomes

Vivek Subbiah, MD

With the increasing interest in FGFR inhibitors used to treat patients across malignancies, clinicians should understand best practices for closely monitoring and managing highly prevalent on-target toxicities with this class of agents. Doing so will help maintain the efficacy of these agents in a real-world setting and improve patient outcomes, according to Vivek Subbiah, MD.

In a retrospective review, investigators sought to identify the most prevalent adverse effects (AEs) seen in patients receiving FGFR inhibitors for cholangiocarcinoma, for example, and inform clinicians of practical management strategies available to be used in clinic.

Data showed that the most frequently observed on-target toxicities associated with FGFR inhibitors were hyperphosphatemia, dermatologic AEs, ocular toxicities, hand-foot syndrome, and gastrointestinal toxicities. Most of these AEs were found to be manageable with prophylactic measures, dose adjustments or interruptions, or specific alterations to diet. Investigators concluded that proactive monitoring was vital for providing patients with the highest clinical benefit.

“It is important to make sure that we have a comprehensive view of the safety profile of diseases from the real world, because more patients are going to be treated there,” said Subbiah, an associate professor and clinical medical director of the Clinical Center for Targeted Therapy in the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston. “We also publish these articles to make sure that the healthcare team members are continuously educated and trained in the management of these FGFR toxicities.”

In an interview with OncLive®, Subbiah emphasized the need for improved guidance on practical toxicity management for various FGFR-altered malignancies, highlighted best practices for monitoring and managing the most common on-target toxicities associated with FGFR inhibitors, and discussed the key implications of this review for those utilizing FGFR inhibitors.

OncLive: What gaps in knowledge were you seeking to address by conducting this review of FGFR inhibitor–associated AEs?

Subbiah: Genetic alterations in the FGFR family include activating fusions, gene rearrangements, or amplifications and mutations. These are associated with oncogenesis in many malignancies. The oncogenic potential of FGFR alterations has prompted the development of small molecule inhibitors targeting this FGFR pathway in several malignancies, including bladder cancer, colorectal carcinoma, and hematological malignancies. Currently we have 3 FGFR inhibitors approved for various FGFR-driven cancers. Erdafitinib [Balversa] is approved for [patients with] locally advanced metastatic bladder cancer harboring an FGFR2/3alteration that has progressed on platinum-based therapy. Pemigatinib [Pemazyre] and futibatinib [Lytgobi] are approved for previously treated unresectable locally advanced metastatic cholangiocarcinoma with either FGFR2 fusions or other gene rearrangements of the FGFR pathway.

In addition, pemigatinib was also approved for patients with relapsed/refractory lymphoid/myeloid neoplasms. These are a heterogeneous group of hematological malignancies harboring FGFR gene rearrangements. [The approval] was based on [the agent's] promising activity in the [phase 3] FIGHT-203 trial [NCT03011372]. Another drug was approved called infigratinib [Truseltiq] for cholangiocarcinoma. Unfortunately, the distribution of this agent was discontinued based on several factors in March 2023.

There are several other FGFR drugs in clinical development, including derazantinib (ARQ 087) and rogaratinib (BAY1163877). There is also a new FGFR2 selective inhibitor called RLY-4008 [lirafugratinib]. These agents are being investigated in a variety of cancers.

FGFR agents are a new class of drugs, and many clinicians may not be aware of their on-target toxicities. The most encountered on-target toxicities for FGFR inhibitors are hyperphosphatemia, nail problems, eye problems, dermatological problems, and gastrointestinal toxicities. This review article [helps address] the gap in knowledge or clinical practice [of] these AEs, and [informs clinicians of how to] manage specific FGFR inhibitor–

related toxicities.

Could you provide an overview of the types of cancer where FGFR alterations are most prevalent, and how these alterations contribute to oncogenesis?

The more we test, the more [FGFR alterations] we find. FGFR gene rearrangements, fusions, amplifications, and mutations are seen in diverse cancers. interestingly, an analysis of more than 350,000 patients with solid tumors using next-generation sequencing found that FGFR1-4 variants were present in nearly 3% of patient samples and copy number aberrations were present in over 4% of tumor samples. Regarding [the prevalence of specific mutations], FGFR1 was the most frequently mutated gene, followed by FGFR2, at 3.6% and 1.7%, respectively. [This was] followed by FGFR3 and FGFR4, respectively. Interestingly, the cancer with the highest frequency of FGFR alterations is cholangiocarcinoma. Beyond cholangiocarcinoma, we see FGFR alterations in bladder cancers and urinary tract cancers. We see FGFR gene rearrangements in salivary gland cancer, lung cancer, prostate cancer, and many other cancers, although they [are typically present in] less than 1% [of these patients]. One molecular profiling study found FGFR2 alterations in 20 of 158 intrahepatic cholangiocarcinoma samples. Depending on the study, we see that most of these alterations are enriched in bladder and colon carcinomas.

Could you elaborate on the methodology employed to assess and compile FGFR inhibitor–associated AEs, including the sources of data and the selection criteria? How was real-world clinical experience integrated into the review?

This is a unique, hybrid review. We went through all the clinical studies that have been published so far on all the FGFR inhibitors. The clinical studies were reviewed for safety, tolerability, and data to provide an overview of all the AEs. We also investigated the dose adjustments leading to study discontinuation, and all the FDA-approved package inserts and package labels. [Myself and my co-author] Srdan Verstovsek, MD, PhD, led several of the studies with FGFR inhibitors, so we have personal experience treating patients with FGFR inhibitors.

Many of these were real-world studies. We incorporated much of our own personal experience managing the AEs of these patients with FGFR inhibitors so that healthcare providers can closely monitor patients' toxicities and know what to expect. [This includes data from] lab tests, imaging studies or physical exams, as well as detailed documentation of their severity and time of onset.

We want to emphasize that the management of these patients with FGFR inhibitor–related toxicity requires a multidisciplinary team. The patient and their family members [are] most important [to consider]. In addition, collaboration with a multidisciplinary team, including nurses, nurse practitioners, advanced practice providers, pharmacists, and other healthcare professionals, such as ophthalmologists and dermatologists, can facilitate early identification and management of AEs.

What are some of the most encountered on-target toxicities associated with FGFR inhibitors, and how can they be optimally managed?

FGFR inhibitors cause 2 [main eye toxicities], 1 of which is central serous retinopathy. In clinical studies, its [prevalence is] anywhere from 4% to 21%. It also causes blurred vision. This eye disorder usually resolves without intervention when we [withhold the] drug. Otherwise, the dose can be withheld or reduced. It is important to seek an ophthalmologic evaluation especially if the eye issues are symptomatic.

Going from the eye down to the mouth, we see stomatitis. In published studies, its [frequency is] anywhere from 70% to 88%. We manage this through diet and lifestyle modification. Patients have told us that baking soda rinses help a lot, as well as mucosal coating agents and topical anesthetics. Withholding the drug for at least a week can also usually [mitigate] this AE. Another common mouth-related AE is dry mouth. We [emphasize] good oral/dental hygiene, meeting with the dentist regularly, and making sure that they clean the teeth. We've also used systemic and topical delivery stimulants for the dry mouth.

One of the most common AEs across all the FGFR inhibitors is hyperphosphatemia, which is FGFR1 inhibitor–related. It is reported on studies with either pemigatinib, erdafitinib or other drugs like futibatinib. [The incidence of] hyperphosphatemia ranges anywhere from 60% to 81%. Withholding the drug can reduce hypophosphatemia down. What we outline in the article is the [importance of a] low phosphate diet vs a high phosphate diet. Patients can follow a low phosphate diet to make sure that they don't develop hypophosphatemia. We also have phosphate lowering treatments.

Another AE we see is alopecia, which we have successfully [managed using] topical minoxidil. [To treat] dry skin, we ask patients to moisturize often using unscented preparations. Sometimes urea or salicylic-containing preparations help patients. Another gastrointestinal toxicity [associated with this drug class] is diarrhea. We see anywhere from 20% to 50% of patients experiencing low- to moderate-grade diarrhea. Patients can modify their diet with a low-fat, low-phosphate diet to help with the diarrhea. We also [commonly] prescribe loperamide and diphenoxylate-atropine medications to help with this.

One of the most common on-target AEs is hand foot syndrome. This is usually seen in 5% to 20% of patients. To manage this, we avoid exacerbating factors as much as possible. We ask patients to have topical preparations, especially moisturizers, and use heavy creams with urea. Sometimes, if the hand-foot syndrome is moderate to severe, we've even resorted to using both over the counter or prescription topical steroids.

Changes in the nail are definite on-target toxicities of all the FGFR inhibitors. Nails may darken, may develop white streaks and ridges, may become brittle, dry, and cracked, or may lift from the nail bed. We advise patients to take special care of their nails. They should gently trim or file nails without getting too close to the nail bed. We also ask them to avoid obtaining professional manicures or pedicures unless they discuss it with a dermatologist or their physician team beforehand. Moisturizing lotions and creams given by the healthcare team can keep the nails and cuticles very healthy. I have recommended gloves to my patients, especially when working around the house or the yard. We also advise patients to wear heavy moisturizing cream at night under gloves so that it stays in place. Patients should not be using nail strengthening products because they will irritate the skin or nails.

These are some of the practical management tips that we can provide for these toxicities. The key is knowing what the AEs are and proactively managing them so that patients can experience benefit from these therapies.

What are the key implications of this review for clinicians administering FGFR inhibitors?

The main thing is that we want both the physician team and the patient team to know what these AEs are. I encourage everyone in the real world to report AEs to pharmacovigilance systems, such as the FDA Adverse Event Reporting System. This contributes to the overall safety of hundreds [of drugs]. The experience that we have is limited to published clinical studies, the package inserts, and personal experience from our academic centers.

We do not have [data on managing FGFR inhibitor–associated Aes] from the real-world community oncology setting. There may be more lower grade Aes when we treat patients in the community that may not have been reported. Therefore, it is important to follow the real-world data. Again, that is one of the main limitations of this research.

Does this study identify any specific areas or aspects of FGFR inhibitor use that require further investigation or attention?

[Looking ahead, the question is:] can we develop tumor-specific drugs that don't cause these toxicities in normal cells. One advance that we've recently seen is FGFR2-specific inhibition [with RLY-4008]. That can help in patients with cholangiocarcinoma and many other tumor types. RLY-4008 is being investigated in early clinical trials. It selectively inhibits FGFR2, [reducing FGFR1-associated AEs such as] hyperphosphatemia. Still, we see the same hand-foot syndrome and nail toxicities associated with direct on-target FGFR inhibition. Hopefully, with better technologies, we can design drugs specific to cancer cells alone.

We know that FGFR inhibitors do help patients with cancer. However, many patients develop resistance to these first-generation agents and many patients are not able to tolerate them at the full dose. Accordingly, we must dose reduce, and we lose efficacy. Several novel FGFR-targeted drugs are being developed either alone or in combination with standard therapies. We are really looking forward to the trial readouts of these novel FGFR2 agents.

Reference

Subbiah V, Verstovsek S. Clinical development and management of adverse events associated with FGFR inhibitors. Cell Rep Med. 2023;4(10):101204. doi:10.1016/j.xcrm.2023.101204