Infigratinib Represents New Option for FGFR2+ Cholangiocarcinoma, as Efforts Shift to Target Other FGFR Alterations

Sameek Roychowdhury, MD, PhD

Infigratinib (Truseltiq) represents a strong option for previously treated patients with locally advanced or metastatic cholangiocarcinoma whose tumors harbor FGFR2 fusions or rearrangements, according to Sameek Roychowdhury, MD, PhD, who added that the next steps for research will be focused on further leveraging the activity observed with the agent, and gaining a better understanding on other alterations within the FGFR pathway to develop additional targeted options for rarer subsets.

Results from a multicenter, open-label, single-arm, phase 2 study (NCT02150967) showed that at a median follow-up of 10.6 months (range, 6.2-15.6), the FGFR inhibitor infigratinib elicited an objective response rate of 23.1% (95% CI 15.6%-32.2%), with 1 confirmed complete response and 24 partial responses (PRs).¹ Results from the trial supported the May 2021 FDA approval of infigratinib for use in patients with previously treated locally advanced or metastatic cholangiocarcinoma harboring an FGFR2 fusion or rearrangement.²

“There are going to be more novel genetic alterations in FGFR [to examine]. We are studying one right now,” Roychowdhury said. “As such, there are going to be more patients [beyond] those who have cholangiocarcinoma, [those with] other cancer types, who have other mechanisms to activate the FGFR [pathway] and could derive benefit from FGFR inhibitors.”

In an interview with OncLive®, Roychowdhury, medical oncologist, assistant professor in the Department of Internal Medicine and the Department of Pharmacology at The Ohio State University, discussed the efficacy and safety data reported with infigratinib in FGFR2-positive cholangiocarcinoma, nuances to treatment with the agent, and ongoing research efforts to further improve outcomes in this population.

OncLive®: Could you provide some background information on infigratinib and what sets it apart from other agents utilized in cholangiocarcinoma, such as pemigatinib (Pemazyre)?

Roychowdhury: We have learned that a fraction, about 15%, of patients who have intrahepatic cholangiocarcinoma will have FGFR2 gene rearrangements, sometimes referred to as fusions. Several companies over the past 7 years have developed and studied FGFR inhibitors, [which are] small molecule inhibitors for patients with FGFR-altered cancers. Over the years, [these agents have been investigated in] all solid tumors [as part of] the first phase 1 trials.

Then, disease-focused clinical trials [were done] for cholangiocarcinoma and urothelial cancer. We have seen several drug approvals, the first [being] erdafitinib [Balversa] for [patients with] urothelial cancer with FGFR alterations, followed by pemigatinib [Pemazyre], which was examined [in patients with] cholangiocarcinoma harboring FGFR2 [alterations]. Most recently, we saw data become mature and [support] the FDA approval of infigratinib for [patients with] FGFR2-positive cholangiocarcinoma.

We are seeing that many patients can benefit [from infigratinib]. We have seen a safety profile that is unique to the class of FGFR kinase inhibitors. We are excited to now be able to offer these agents to patients with FGFR-positive cholangiocarcinoma.

[These advancements have] also placed a greater emphasis on the need to diagnose these patients early on, to ensure they receive adequate genetic testing that can find FGFR alterations in cholangiocarcinoma. In addition to FGFR [inhibitors], these patients could benefit from other targeted therapies. As such, comprehensive genetic testing for cholangiocarcinoma is important.

One important pearl [of wisdom] about cholangiocarcinoma is that many times, it can present as something [like] poorly differentiated cancer, and as such, the pathologist will not [diagnose the patient with] cholangiocarcinoma. A lot of times, however, cholangiocarcinoma is just that: poorly differentiated. The clinical presentation of having a large dominant liver mass, a few smaller liver lesions, an elevated CA 19-9, and no pancreas lesions is cholangiocarcinoma. We want to ensure that these patients undergo genetic testing so that we can make the [correct] diagnosis and offer them appropriate treatments.

Shifting specifically to the pivotal phase 2 trial examining infigratinib, what was the objective of this research, and what was found?

The study was meant to identify patients with FGFR-altered cancers. Most patients had FGFR2 alterations. This was a single-arm, open-label study, and all patients received infigratinib. We were looking specifically at the overall response rate and the disease control rate [achieved with the agent].

We were quite impressed to see that many of our patients benefitted [from the agent, with] some [achieving] stable disease and a smaller number of patients [achieving] PRs. Interestingly, even stable disease can be very durable. I have patients with durable disease, who, in some cases, do better or live longer than those who achieved PRs [to treatment]. The depth of their response is not necessarily predictive of their overall survival. Now, we are really excited to see that patients are also benefitting [from this drug] outside of the clinical trial.

Did the number of prior lines of therapy received have an impact on benefit derived with the agent?

The patients in the study had to have received at least 1 prior line of therapy, which was usually some [type] of platinum- or gemcitabine-based chemotherapy, which is a standard of care for cholangiocarcinoma. Some patients may have received up to 3 or 4 prior lines of therapy.

Following the principles of oncology practice, the number of lines of therapy [received] can predict someone's ability to get through more therapy. Certainly, more lines of therapy can make it harder for [a patient] to benefit and tolerate therapy. However, the good news is that even patients who have received many lines of prior therapy can still derive benefit from infigratinib, or [other] FGFR inhibitors, so we are fortunate to see that.

What has been learned about time to response with infigratinib?

One of the important nuances [to be aware of] is that sometimes the response to therapy can be slow. After 2 months of therapy is when we typically will consider a new CAT scan as part of a clinical trial or standard practice. [However,] we might not see many changes by 2 months. By waiting a little bit longer, [like] 4 or 6 months, we may start to see a slow change in response. It may not meet the criteria for PR, but we do see slow responses with [infigratinib in patients with cholangiocarcinoma], which probably has something to do with the biology of FGFR-positive liver cancers.

What does the safety profile of the agent look like? What should your colleagues be aware of when using this drug?

Many of the patients experienced a similar toxicities [to what has been seen with other FGFR inhibitors]. Some of the unique adverse effects [AEs] experienced with FGFR inhibitors include hyperphosphatemia, which is an expected on-target effect since the drug inhibits FGFR2, but it also inhibits FGFR1 and FGFR3. It is thought that FGFR1 effects the body's management of phosphorus, so we see and expect an elevation of phosphate levels. We recommend managing [that effect] with phosphate binders.

In the study, we [also saw] patients with hypophosphatemia, where [phosphate levels were] low; that's an AE [that can result from the overutilization of] phosphate binders, which drive phosphate [levels] down. It is not a problem to worry about and can be easily fixed by adjusting the phosphate binder. Some of the other unique AEs [experienced with] this drug class include mucositis, dry eyes, and paronychia, which is brittleness and tenderness of the nails. These are chronic accumulative AEs can be managed with dose reductions.

Unfortunately, some of those AEs do not go away completely, but they are not life threatening. [These toxicities] do have quite a bit of an effect on quality of life, but sometimes we are just happy to be able to control the liver cancer for 18 months and some nail damage [can be tolerated]. Perhaps we will [continue to] learn a little bit more [about this as we get more experience]. These are the first drugs [to target] FGFR. We are [continually] learning to [more effectively] manage these AEs. Maybe we will be able to reduce some of these [toxicities] moving forward if we learn and study [them] further.

Could you expand on what management looks like for those AEs in practice? Do some of them, such as the eye toxicities, require multidisciplinary care?

We do expect to see some eye toxicities, such as dry eyes. We can see fluid or swelling behind the retina. Regular exams with the ophthalmologist are recommended to help observe these AEs. Some of [these toxicities] do not come with [visible] symptoms, so [patients] may have fluid behind the retina and that may [not be observable] as opposed to the expectation of blurred vision. Many of these can be managed with dose reductions. Having a low threshold to reduce these doses is a good idea, so that we can minimize some of the toxicities. However, regular eye exams are recommended for most of the FGFR inhibitors that are approved [for use] today.

What has been the impact of the FDA approval of infigratinib on the cholangiocarcinoma treatment paradigm? What should be understood about the indication?

Having more options for our patients with cholangiocarcinoma is always a great thing. We have seen a growth in drug development in this area of both FGFR-positive cholangiocarcinoma as well as other cancers with FGFR positivity. We are also still learning about genetic changes in FGFR that can activate FGFR signaling.

A recent paper published in Cancer Discovery [looked at] some mutations that are part of the extracellular domain of FGFR, and I have had several patients with similar mutations who respond to FGFR inhibitors. These [subsets] are not included in the FDA labels with regard to urothelial carcinoma or cholangiocarcinoma. As such, it is important for us to see these patients and get them on clinical trials to collect [the necessary] data [on the benefit of these agents].

We have more to learn about FGFR genetics, we have more patients who can benefit [from these inhibitors], and thankfully, many new companies are entering the space. [Bearing in mind] the patients who have their cancer progress, we have now cataloged over 15 mutations that are acquired and can render the cancer resistant to these first-generation FGFR drugs. The more people who get in this game to help us to develop better drugs, the better [outcomes] our patients will [have]. A healthy amount of competition in the marketplace is good for all of us—patients, doctors, and the field overall. We are glad to see a lot of interest in FGFR drug development.

Regarding next steps for this agent, do you foresee it moving into the first-line setting? Is that under investigation now?

Several clinical trials are happening right now in cholangiocarcinoma that are looking at the comparison of gemcitabine and platinum-based chemotherapy vs an FGFR inhibitor. We look forward to seeing readouts of [those efforts to gain insight into] which [therapy] we should be utilized first.

Another twist to that idea is whether we should we be considering chemotherapy and a kinase inhibitor together, or whether should we be considering them in a cyclical way, so alternating therapy as a way to forestall drug resistance and to potentially limit the amount of cumulative toxicity from one [approach] or the other. If you cycle back and forth between a chemotherapy and a targeted inhibitor, you could try to limit some of the cumulative toxicities, such as cytopenia and other [AEs] that come with FGFR inhibitors. These are all really exciting [areas of exploration] for the next couple years.

What is your take-home message regarding this research?

First, besides FGFR2, we do know that there are other activating alterations in FGFR receptors like FGFR1 and FGFR3, and this is not limited to fusions. Whenever you see a patient with cancer involving the liver and you see something related to FGFR, [it is important] to ask yourself whether that is a driver mutation.

In the next couple years, we would like to see some of these patients who have received a standard-of-care FGFR inhibitor, such as infigratinib or pemigatinib, get referred to tertiary medical centers because we have a number of FGFR inhibitors that are second generation. We need to get these patients onto those clinical trials. We need better options; [these patients] eventually experience progression of their cancer.

[Because this is] a rare cancer, the number of patients who are [eligible] for such studies is small. As such, we need everyone's help to get patients onto these new clinical trials so that we can bring more therapies [into the armamentarium, and provide even better] standard-of-care [approaches to this population].

References

1. Javle M, Roychowdhury S, Kelley RK, et al. Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study. Lancet Gastroenterol Hepatol. 2021;6(10):803-815. doi:10.1016/S2468-1253(21)00196-5
2. Bridgebio pharma’s affiliate qed therapeutics and partner helsinn group announce fda approval of truseltiq (infigratinib) for patients with cholangiocarcinoma. News release. BridgeBio Pharma, Inc. May 28, 2021. Accessed November 9, 2021. https://bit.ly/3wE320C