Mitesh J. Borad, MD, oncologist, Department of Medical Oncology, Mayo Clinic Comprehensive Cancer Center, discusses the unique mechanism of action of next-generation FGFR inhibitors like KIN-3248 and their potential effect on patient outcomes in cholangiocarcinoma and urothelial cancer.

The next-generation FGFR inhibitor KIN-3248 is of particular interest for intrahepatic cholangiocarcinoma and urothelial cancer, as 

 alterations are common in these tumor types, Borad continues. The safety and preliminary efficacy of this agent is under investigation in the phase 1 KN-4802 trial (NCT05242822) of advanced solid tumors harboring 

 gene alterations. KN-4802 is a two-part study and consists of a dose-escalation followed by a planned dose-expansion cohort. The trial is open to enrollment and is expected to enroll approximately 120 patients.

Researchers hope that these early phase trials will provide a broader array of targeted treatments for patients with these tumor types and address several limitations associated with early FGFR inhibitors.

Acquired resistance to FGFR inhibitors often results from on-target polyclonal mutations, which prevents the agents from binding to the ATP active site and inhibiting the protein, Borad begins. Unlike early FGFR inhibitors, next-generation FGFR inhibitors are designed to bind at non-mutated sites in the ATP-binding pocket, thereby successfully inhibiting the protein, he explains.

Currently, around 30% of patients achieve responses for up to 6 or 7 months with available inhibitors. Future-generation inhibitors may increase the proportion and durability of these responses.

Moreover, current FGFR inhibitors are associated with increased toxicities, as these agents can bind to FGFR1, FGFR2, and FGFR3 receptors. Targeting 

 alterations that are not related to the specific tumor mutation will not confer resistance and instead leads to off-target effects. Therefore, more selective agents are needed to reduce these toxicities in patients with specific alterations or fusions, Borad concludes.

Videos

Mitesh J. Borad, MD, discusses the unique mechanism of action of next-generation FGFR inhibitors like KIN-3248 and their potential effect on patient outcomes in cholangiocarcinoma and urothelial cancer.

Dr. Borad on the Use of Next-Generation FGFR Inhibitors in Cholangiocarcinoma and Urothelial Carcinoma

The next-generation FGFR inhibitor KIN-3248 represents a new class of highly targeted agents that have the potential to increase efficacy and decrease off-target toxicity in the treatment of patients with 

-altered urothelial cancer and cholangiocarcinoma, according to Mitesh J. Borad, MD.

KIN-3248 will be investigated in the phase 1 KN-4802 trial (NCT05242822) in patients with advanced solid tumors harboring 

 gene alterations.1 This inhibitor, as well as agents such as RLY-4008, which is under investigation in patients with 

-altered cholangiocarcinoma, may contribute to an increasingly targeted future treatment paradigm for cancers with 

“Drugs that are more specific, less toxic, more durable, and beneficial to a greater number of patients are what we want to see,” Borad said in an interview with 

 alterations influence treatment strategies in cholangiocarcinoma and urothelial cancer, discussed the FGFR resistance mechanisms that are prompting further research in this area, and highlighted the rationale for the KN-4802 trial.

Borad is an oncologist in the Department of Medical Oncology at Mayo Clinic Comprehensive Cancer Center in Phoenix, Arizona.

 alterations in cholangiocarcinoma and urothelial carcinoma?

: Alterations in the FGFR pathway are prevalent in many solid tumors and some hematological malignancies. Cancers where [

 fusions] are more prevalent include intrahepatic cholangiocarcinoma, where the prevalence is estimated to be in the 10% range. There are also 

 mutations, which are found at a 3% to 4% prevalence mostly in intrahepatic cholangiocarcinoma, with a smaller prevalence in extrahepatic and hilar cholangiocarcinoma.

In bladder cancer, the alterations are mostly in FGFR3, and they’re most commonly mutations, predominantly in exon 7 and exon 10. [The estimates for the prevalence of these mutations in bladder cancer vary, but they range from] 20% to 40%, depending on the subset of bladder cancer, including muscle invasive, non–muscle invasive, luminal, etc. As a broad estimate, 30% [of bladder cancers have 

 mutations]. Those are the 2 cancers where [

 alterations affect the efficacy of standard therapies in these cancers?

This question is still under study in some cancers. For example, in cholangiocarcinoma, it is not well known if [patients who] have these fusions or mutations are more or less responsive to cytotoxic chemotherapies, [or if they will respond to] immunotherapy with the advent of the [phase 3] TOPAZ-1 study [NCT03875235] in biliary cancers. This question will be studied further [to determine] whether these tumors are more or less responsive to standard therapies.

In other cancers, such as lung cancer, where 

 alterations [are present], patients do much better on targeted therapies. That might end up being the case [in cholangiocarcinoma], but this is still under evaluation. In bladder cancer, the data seem to suggest that patients are somewhat less responsive to immunotherapy and perhaps cytotoxic therapies, but larger studies need to tease this out, especially in the frontline settings.

What are some known resistance mechanisms for 

, and what is the current standard of care for patients who develop acquired resistance?

We’ve seen in lung cancer that you can start with the first-generation inhibitors, understand the mechanisms of resistance, and then, when better drugs are subsequently developed, you can prolong responses or sequence drugs as newer-generation inhibitors are brought through the development pipeline. What we understand with FGFR2 and FGFR3 is that the mechanisms of resistance can be on pathway or off pathway.

When they’re on pathway, they may be mutations in FGFR2 or FGFR3, often polyclonal mutations that have many clones in the tumor, each having different mutations. You can often determine this through liquid biopsy analysis. [When you identify on-pathway mutations], you need drugs that can cover many of these different mutations, because there are multiple mechanisms of on-pathway resistance.

There’s no standard yet, but for example, with cholangiocarcinoma, futibatinib [Lytgobi] has been active in the setting where other drugs have previously been used. There are also newer third-generation inhibitors like RLY-4008, which has preliminary data showing activity even in patients who have received futibatinib. The field is rapidly evolving, and we’ll see what the standard ends up being, but it will probably be these later-generation inhibitors.

[Regarding] the off-pathway resistance mechanisms, we don’t fully understand all these yet. They include downstream mutations in the PI3K pathway or the RAS/RAF/MEK/ERK pathway, heat shock protein signaling, autophagy, and other mechanisms.

One next-generation FGFR inhibitor in development is KIN-3248. What sets this agent apart from earlier-generation agents?

One of the main mechanisms of resistance [to these agents] are on-target polyclonal mutations. [In tumors with] these mutations, the drugs in use can’t bind in the ATP pocket and inhibit the protein. Most of these next-generation inhibitors are designed to bind at sites in the ATP pocket that don’t have these mutations, so they can still bind and still have their effect.

[KIN-3248] falls into that next-generation category of inhibitors. It’s still in early phase studies with dose escalation followed by dose-expansion cohorts planned, with [a target enrollment of 120 patients]. The diseases of interest are tumors like intrahepatic cholangiocarcinoma and urothelial cancer, where these alterations [are prevalent].

What patient populations will be enrolled to KN-4802?

Like many targeted therapies being evaluated, we want to focus on patients who have these alterations and keep [the population] broad during dose escalation to arrive at the doses to use in phase 2 studies and potentially pivotal studies. Then, there are expansion cohorts [of patients with] intrahepatic cholangiocarcinoma, [which has] 

 events, and urothelial cancer, [which has] 

Another category will encompass [patients with] other solid tumors. The prevalence [of these mutations in these patients] will be in the low percentage range, but if they’re common tumors, we can still get a fair number of patients in total.

What are the eligibility criteria for this trial, and how will enrollment testing be conducted?

Some patients who will be evaluated [in this trial] will have received other FGFR inhibitors, because many of those are already in clinical use. In cholangiocarcinoma, this includes pemigatinib [Pemazyre] and infigratinib [Truseltiq], which are both FDA approved through accelerated approval mechanisms. In urothelial cancer, there is erdafitinib [Balversa], which is approved through an accelerated approval mechanism [and which is being investigated in ongoing] pivotal trials.

Patients, especially in the US, may have already received these types of drugs and may be evaluated in the context of overcoming resistance. Evaluation in patients who are naïve to this category of therapies may also be of consideration. Those [decisions] would come through further exploration as these trials advance and undergo design changes.

What could next-generation FGFR inhibitors such as KIN-3248 mean for patients with cholangiocarcinoma and urothelial cancer if they become options in the treatment paradigm?

[We want to see] future-generation inhibitors deliver results such as more durable responses. Currently, we can typically achieve responses in the range of 30% with most of the current inhibitors. We’d like to see a larger number of patients respond, and we’d like patients to stay in response longer, beyond the 6- to 7- month range that we get currently. [We want a] higher proportion of responses and more durable responses.

Secondly, we’d like to see fewer toxicities. The current inhibitors hit FGFR1, FGFR2, and FGFR3. Depending on [the agent’s] target, some of those other 

 alterations may be off target. [We need] more specific inhibitors. [In patients with] 

 alterations, we primarily want to hit FGFR3. [In patients with] 

 fusions, we don’t want to hit the other 

 alterations because they don’t typically contribute to resistance, and patients will just experience toxicity.

What other intriguing next-generation FGFR inhibitors are in development?

RLY-4008 is an allosteric inhibitor of FGFR2, so it doesn’t use the kinase pocket as its mechanism of action. Preliminary results have already been presented at the 2022 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. [Continued findings in this area will be of interest] regarding therapeutic activity in this class.

What is your main message for colleagues regarding ongoing research developing more effective targeted therapies for patients with 

[We need to increase our] ability to identify these patients. If you haven’t profiled them, you will not see [who has these alterations] and you may just use the more empiric therapies that are otherwise available. Genomic profiling will be key and doing it earlier in the treatment process will allow time for the testing to be done and for the results to become available so that at the juncture of acting upon it, you already have the data in hand. My single most important message to colleagues is to always keep testing in mind in all your patients, if feasible.

A study to evaluate KIN-3248 in participants with advanced tumors harboring FGFR2 and//or FGFR3 gene alterations. ClinicalTrials.gov. Updated December 13, 2022. Accessed January 5, 2022. 

https://clinicaltrials.gov/ct2/show/NCT05242822

Articles

Mitesh J. Borad, MD, explains how FGFR alterations influence treatment strategies in cholangiocarcinoma and urothelial cancer, discusses the FGFR resistance mechanisms that are prompting further research in this area, and highlights the rationale for the KN-4802 trial. 

Developmental FGFR Inhibitors Are Active in FGFR+ Cholangiocarcinoma and Urothelial Carcinoma

Novel irreversibly binding FGFR inhibitors on the horizon in cholangiocarcinoma and urothelial carcinoma may be key for overcoming resistance to first-generation agents, according to Sameek Roychowdhury, MD, PhD.

One small molecule pan-FGFR inhibitor currently under investigation is KIN-3248. A phase 1 trial (NCT05242822) is ongoing to investigate the agent’s safety, tolerability, pharmacokinetics, and preliminary efficacy in adult patients with intrahepatic cholangiocarcinoma, urothelial carcinoma, and other solid tumors harboring 

“Hopefully, we can understand which mutations and genes can benefit from these novel drugs and bring them forward for those patients,” Roychowdhury said.

, Roychowdhury discussed the rationale for targeting 

 mutations in cholangiocarcinoma and urothelial carcinoma, the potential efficacy of irreversible pan-FGFR inhibitors in these populations, and how continued research in this area may yield more personalized therapeutic approaches for patients with 

Roychowdhury is an assistant professor in the Department of Internal Medicine and the Department of Pharmacology at The Ohio State University and a member of the Translational Therapeutics Program at The Ohio State University Comprehensive Cancer Center–James in Columbus.

: Could you elaborate on the prevalence of 

 mutations in intrahepatic cholangiocarcinoma and urothelial carcinoma?

: The gain-of-function activating mutations in FGFR receptors are common in intrahepatic cholangiocarcinoma and urothelial or bladder cancer. In intrahepatic cholangiocarcinoma, we tend to see more of the FGFR2 variety, in anywhere from 10% to 15% of that subset. In bladder cancer, we tend to see more FGFR3, in around 15% to 20% of that subset.

In bladder cancer, we tend to see more of point mutations, or single nucleotide changes, whereas in cholangiocarcinoma, we tend to see more fusions or rearrangements of FGFR2. However, for both cancers, we can see other varieties of FGFR receptor type, as well as the type of mutation that could be gain-of-function.

How does the presence of these mutations affect the efficacy of standard therapies?

 alterations, whether they are fusions or point mutations in cholangiocarcinoma and bladder cancer, helps us identify a subset of patients that is likely to benefit from an FGFR-targeted kinase inhibitor. Patients who don’t have these 

 activating mutations are probably not going to benefit at all. Only the subset of patients [with these mutations is likely to benefit].

In cholangiocarcinoma, anywhere from 70% to 80% of patients have clinical benefit; whether it’s a partial response [PR] or stable disease [SD], they’re experiencing disease control and clinical benefit. For bladder cancer, we’re seeing a benefit rate of around 40%, with patients having PRs and SD.

What are some known resistance mechanisms for FGFR inhibitors, and what is the current standard of care for patients with acquired resistance?

When this defined group of patients receives FGFR kinase inhibitors as targeted therapy, we unfortunately see progression of their cancer and acquired resistance. We are beginning to see secondary mutations, more so in the patients with cholangiocarcinoma than in the patients with bladder cancer. That is 1 class of resistance mechanism.

In each instance, for cholangiocarcinoma, or liver cancer, and bladder cancer, the average time to progression is around 6 months. Some patients may progress before [6 months], at around 6 months, or sometimes [after 6 months], having longer duration of benefit. The mutations tend to interfere with how the drug interacts with the kinase part of the receptor.

We’ve also seen other mechanisms, mutations, genes, and pathways that tend to [activate] downstream of the receptor. We often see evidence of MAPK or PI3K activation downstream after FGFR resistance develops.

Could you provide some background on irreversible small molecule pan-FGFR inhibitors, such as KIN-3248? What sets these agents apart from other inhibitors, and what have been observed with them so far?

The first-generation inhibitors of FGFR kinases are irreversibly binding. Some FGFR kinase inhibitors are being studied or will soon be studied in clinical trials. Some of these have covalent binding, meaning once they bind with the receptor, that bond cannot be broken. This potentially allows for greater inhibition of the kinase and target, preventing it from cycling on and off, and could be beneficial as a means of overcoming resistance to the other first-generation drugs. We’ll be excited to see the current and upcoming data for some of the irreversibly binding drugs.

We’re also beginning to see other drugs that have a new design. We are considering the known acquired resistance mutations and finding a way for the new class of drugs to still bind and inhibit the enzyme and receptor activation. Those are potentially opportunities for new therapies and hope for these patients. We’re looking forward to offering these agents to patients.

What are the eligibility criteria for the trials investigating small molecule pan-FGFR inhibitors?

The unique eligibility criteria for some of the current FGFR inhibitors that are in clinical trials, aside from the usual criteria of the patient’s wellness, are about molecular eligibility. Patients need to have evidence, usually through genetic testing, of an activating gain-of-function 

 mutation, including gene fusions and point mutations.

We’re now beginning to understand that there are additional gain-of-function mutations, such as the extracellular domain mutations, that are small deletions. Some of these are known because of what we’ve learned from other hereditary disorders involving FGFR, where there’s gain-of-function mutations in the extracellular domain, as well as in the transmembrane domain. The current studies can include all these patients.

If the data with these FGFR inhibition studies prove to be positive, what could those findings mean for the cholangiocarcinoma and urothelial cancer treatment paradigms?

As we begin to see second-generation drugs for FGFR, one of our challenges and opportunities will be to sort out which patient needs which drug. We could be in a [position to choose] which therapy might benefit one patient with one resistance mutation, vs another patient who has a different resistance profile.

In gastrointestinal stromal cell tumors, as well as in chronic myeloid leukemia, when secondary mutations arise, we can select the appropriate kinase inhibitor or other second-class drug. Right now, we’re talking about kinase inhibitors. But there are potentially other ways to target FGFR, for example, antibody-mediated approaches. Having more therapies in the pipeline is always beneficial to our patients, and [we need] more choices so we can take care of them in a better way.

What other planned research with FGFR inhibitors in this area would you like to highlight?

We’ve learned that though cholangiocarcinoma and bladder cancer have these gain-of-function 

 alterations, other cancer types harbor similar 

 gain-of-function activating mutations. The challenge is, they’re not as common. Working together with the pharmaceutical industry and their efforts for FGFR [is important for determining] how we make sure we reach these patients and identify which patient subsets are going to respond and benefit.

In my experience, we’ve been lucky enough to treat many patients with pancreatic cancer with 

 fusions. Compared with [patients with] cholangiocarcinoma, they’ve done quite well, with astounding responses that are far more durable than what we see in cholangiocarcinoma. However, [these responses are] quite rare. That’ll be one of our upcoming challenges for the field of FGFR drug development: How do we advance beyond cholangiocarcinoma and urothelial carcinoma? Certainly, we’re bringing new generations of drugs to those 2 diseases, but how do we make sure we can reach all patients who can benefit?

What should your colleagues take away from this research?

 receptor alterations. There are some known gain-of-function fusions and mutations, but we’re beginning to see that there are other gain-of-function mutations that are less common. Whenever you see an 

 mutation, look closely to see if you can get [that patient] matched to a clinical trial that accepts that mutation or type of mutation. Keep an eye out for these patients.

A study to evaluate KIN-3248 in participants with advanced tumors harboring FGFR2 and//or FGFR3 gene alterations. ClinicalTrials.gov. Updated November 9, 2022. Accessed December 2, 2022. 

Sameek Roychowdhury, MD, PhD, discusses the rationale for targeting FGFR mutations in cholangiocarcinoma and urothelial carcinoma, the potential efficacy of irreversible pan-FGFR inhibitors in these populations, and how continued research in this area may yield more personalized therapeutic approaches for patients with FGFR mutations. 

Resistance Mechanisms Spur Innovative Research in FGFR-Mutant Liver and Bladder Cancer 

Benjamin Miron, MD, fellow, Hematology/Oncology, Fox Chase Cancer Center, discusses mechanisms of resistance to FGFR inhibitors in cholangiocarcinoma.

Treatment with FGFR inhibitors can lead to the emergence of several mutations that promote resistance, Miron says. Although there is not much known about these mutations, data from the use of FGFR inhibitors in biliary cancers have shed some light on some resistance mechanisms, Miron explains. These resistance mutations are similar to those that have been observed with other TKIs, such as EGFR inhibitors, Miron adds.

There are currently no approved agents that can target resistance mechanisms to FGFR inhibitors; however, drugs are under development to fill this unmet need, Miron adds. Without approved drugs, the current standard for patients who develop such mutations during treatment with an FGFR inhibitor is to switch therapies or to enroll to a clinical trial, Miron concludes.

Benjamin Miron, MD, discusses mechanisms of resistance to FGFR inhibitors in cholangiocarcinoma.


Dr. Miron on Resistance Mechanisms to FGFR Inhibitors in Cholangiocarcinoma

Early sensitivity to FGFR inhibition has improved outcomes for patients across tumor histologies; however, kinase domain mutations limit extended efficacy for select patients including those with intrahepatic cholangiocarcinoma or urothelial cancer. Primary and acquired mutations associated with clinical resistance highlight the need for therapeutic development to focus on preventing the activation of these oncogenic driver alterations.

“Alterations in the FGFR pathway are prevalent in many solid tumors, [as well as] some hematological malignancies,” Mitesh J. Borad, MD, said in an interview with 

. “One cancer where [FGFR2 fusions are] more prevalent [include] intrahepatic cholangiocarcinoma, where the prevalence is estimated in the 10% range in the intrahepatic subtype. There are also 

 mutations, which are found in [approximately] 3% to 4% of [tumors], mostly in the intrahepatic [subtype]. In bladder cancer, the alterations are mostly with 

, and they’re most commonly mutations in exon 7 and exon 10.” Borad noted that there have been varying estimates reported in the 20% to 40% range depending on the subset of bladder cancer. Borad is a medical oncologist at Mayo Clinic Comprehensive Cancer Center in Phoenix, Arizona.

Identifying patients with these mutations has presented significant improvements in clinical outcomes, according to Sameek Roychowdhury, MD, PhD.

“When we identify gain-of-function, activating 

 alterations, whether it be a fusion or a point mutation in cholangiocarcinoma or bladder cancer, that helps us identify a subset of patients who are likely to benefit from an FGFR-targeted kinase inhibitor,” Roychowdhury said in an interview with 

, adding that patients without the mutations may not experience any benefit. Roychowdhury is an assistant professor in the Department of Internal Medicine and the Department of Pharmacology at The Ohio State University in Columbus.

Patients with intrahepatic cholangiocarcinoma or urothelial carcinoma represent 2 populations with approved FGFR inhibitors targeting 

 Approvals of agents such as infigratinib (Truseltiq) and pemigatinib (Pemazyre) for patients with cholangiocarcinoma with an 

 rearrangement or fusion have shown overall response rates of 23% and 36%, respectively, with median durations of response ranging from 5 to 9 months, respectively.

 Nearly all patients (98%) treated had intrahepatic cholangiocarcinoma.

Erdafitinib (Balversa) in advanced or metastatic urothelial carcinoma with 

 alterations demonstrated an overall response rate of 40% with a median duration of 5.6 months according to updated data from the BCL2001 trial (NCT02365597) published in 

Although overall response rates are below 40% for the approved indications, clinical benefit has been seen in other end points. “In cholangiocarcinoma, we are seeing anywhere from 70% to 80% of patients having some kind of clinical benefit,

 whether it’s a partial response or stable disease, they’re experiencing disease control. In bladder cancer, we’re seeing a benefit rate of approximately 40%,

 where patients are having partial responses and stable disease.”

Primary and acquired mutations observed with first-generation FGFR inhibitors have prompted investigators to pinpoint opportunities to react or circumvent their development. “Just like we’ve seen in lung cancer, where you start with the first-generation inhibitors, you understand the mechanisms of resistance, and then subsequently better drugs are developed and you can prolong that response or you can [begin to] sequence drugs as newer generation inhibitors are brought through the development pipeline,” Borad said. “What we understand with FGFR2 and FGFR3 is that the mechanisms of resistance can be on pathway or off pathway. When they’re on pathway, they may be mutations in 

 themselves, often polyclonal mutations where you have many clones in the tumor, each having different mutations. You can often determine this is happening by liquid biopsy analysis. When [this occurs] you need drugs that can cover a lot of these different mutations because there’s multiple mechanisms of pathway resistance.”

Gatekeeper and molecular brake mutations, such as V565F and N550H, respectively, have demonstrated an ability to escape inhibition with available FGFR inhibitors. Further, acquired bypass resistance mechanisms result in limited long-term efficacy for patients with cholangiocarcinoma and urothelial cancer.

“The average time to progression is approximately 6 months,” Roychowdhury said. “The [emerging] mutations tend to interfere with how the [FGFR inhibitor] interacts with the kinase part of the receptor. But we’ve also seen other mechanisms [arise]—mutations and other genes and pathways—that tend to be downstream of the receptor. We often see evidence of MAPK or PI3K activation downstream after FGFR resistance develops.”

An all-encompassing approach to blocking outgrowth activity of 

 resistance clones and mutations, investigators have initiated a phase 1 study (NCT05242822) to evaluate the preliminary efficacy of KIN-3248, a next-generation pan-FGFR inhibitor in individuals with advanced solid tumors harboring 

 The first patient in the trial was dosed in April 2022.

KIN-3248 was designed to treat patients with intrahepatic cholangiocarcinoma, UC, and other solid tumors. In preclinical studies, KIN-3248 demonstrated activity across a range of mutations that drive primary disease and acquired resistance to other FGFR inhibitors. For example, the agent has shown that it can inhibit the activation of the FGFR-MAPK pathway in cells that express 

KN-4802 is a multicenter, open-label, 2-part study that aims to enroll approximately 120 patients with advancedstage solid tumors.

 mutations by previous genomic analysis of tumor tissue or circulating tumor DNA. Patients can be naïve to, or pretreated with, FGFR inhibitors.

“With targeted therapies, you want to focus on those patients who have these alterations and keep [the populations] somewhat broad during dose escalation to arrive at the doses you would use in phase 2 studies and potentially pivotal studies,” Borad explained of the primary solid tumor population. “There are expansion cohorts in intrahepatic cholangiocarcinoma, where you have the FGFR2 events and urothelial cancer, where you have the FGFR3 events—predominantly mutations—and then a category that would encompass other solid tumors where prevalence may be in the low percentage range.”

Part A will determine the recommended dose and will include 6 dose levels: 5 mg, 10, mg, 20 mg, 30 mg, 40, mg, and 50 mg. KIN-3248 is taken orally once daily.

Once the maximum tolerated dose (MTD) is established, the dose-expansion phase of the trial will examine the safety and efficacy of the agent.

Primary end points in the dose-escalation portion include incidence of DLTs and to identify the MTD and/or recommended phase 2 dose (RP2D), with secondary end points including pharmacokinetics assessing maximum plasma concentration. Once the MTD and/or RP2D is established, the dose-expansion phase of the trial will examine the safety and efficacy of the agent.

Primary end points in the dose-expansion part include objective response rate, disease control rate, duration of response, and progression-free survival. Exploratory end points include overall survival, exposure-safety and exposure-efficacy relationships, and durability of stable disease.

Patients must have measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function to enroll. Patients with clinically active or clinically progressive brain metastases are not eligible for enrollment.

Roychowdhury noted that “paying close attention to FGFR alterations” is a key takeaway for clinicians seeing patients with cholangiocarcinoma or urothelial carcinoma. “There are some known gain-of-function fusions and mutations, but I think we’re beginning to see that there are other gain-of-function mutations that are not that common,” he said. “Whenever you do see an 

 mutation, look closely to see if you can get the match to a clinical trial that accepts that type of mutation. Keep an eye out for these patients.”

Krook MA, Reeser JW, Ernst G, et al. Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance. 

. 2021;124(5):880-892. doi:10.1038/s41416-020-01157-0

Goyal L, Perez CA, Kato S, et al. Design and rationale of a f irst-in-human (FIH) phase 1/1b study evaluating KIN-3248, a next-generation, irreversible (irrev), pan-FGFR inhibitor (FGFRi), in adult patients with solid tumors harboring FGFR2 and/or FGFR3 gene alterations (NCT05242822). 

. 2022;40(suppl 16):TPS9601. doi:10.1200/JCO.2022.40.16_suppl.TPS9601

FDA grants accelerated approval to infigratinib for metastatic cholangiocarcinoma. FDA. May 28, 2021. Accessed August 31, 2022. bit.ly/3eiyI7J

FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. FDA. Updated April 20, 2020. Accessed August 31, 2022. bit.ly/3RpMdAS

FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma. April 12, 2019. Accessed August 31, 2022. bit.ly/3R6elcy

Javle MM, Roychowdhury S, Kelley RK, et al. Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement. 

. 2021;39(suppl 3):265. doi:10.1200/ JCO.2021.39.3_suppl.265

Siefker-Radtke A, Necchi A, Park SH, et al; BCL2001 Study Group. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study. 

. 2022;23(2):248-258. doi:10.1016/S14702045(21)00660-4

Franovic A, Mohan A, Uryu, et al. Activity of KIN-3248, a next-generation pan-FGFR inhibitor, against acquired FGFR-gatekeeper and molecular-brake drug resistance mutations. 

. 2022;40(suppl 4):461. doi:10.1200/JCO.2022.40.4_suppl.461

Kinnate Biopharma Inc. announces first patient dosed in phase 1 clinical trial of its FGFR inhibitor product candidate, KIN-3248. News release. Kinnate Biopharma Inc. April 18, 2022. Accessed September 1, 2022. bit.ly/3wRTlhD

A study to evaluate KIN-3248 in participants with advanced tumors harboring FGFR2 and//or FGFR3 gene alterations. ClinicalTrials.gov. Updated August 11, 2022. Accessed September 1, 2022. https://clinicaltrials.gov/ct2/show/ NCT05242822

Early sensitivity to FGFR inhibition has improved outcomes for patients across tumor histologies; however, kinase domain mutations limit extended efficacy for select patients including those with intrahepatic cholangiocarcinoma or urothelial cancer. 

Pan-FGFR Inhibitor Seeks to Overcome Resistance Hurdles in Cholangiocarcinoma and Urothelial Carcinoma

Sameek Roychowdhury, MD, PhD, medical oncologist, assistant professor, the Department of Internal Medicine and the Department of Pharmacology, The Ohio State University, discusses the prevalence of 

 mutations in intrahepatic cholangiocarcinoma (ICC).

 mutations, which activate the FGFR receptor and cause abnormal signaling that affects cell growth, are most common in ICC, plus urothelial or bladder cancers, Roychowdhury says. Specifically, 

 mutations tend to be more common in ICC, ranging from 10% to 15% of patients in that subset, Roychowdhury adds. However, 

 mutations are more common in bladder cancer, appearing in 15% to 20% of that subset of patients, Roychowdhury explains.

 point mutations tend to occur more often in bladder cancer, whereas in ICC, 

 gene fusions or rearrangements are typical, Roychowdhury continues. Despite these tendencies, a variety of 

 mutations can present in these cancers, Roychowdhury concludes.

Sameek Roychowdhury, MD, PhD, discusses the prevalence of FGFR mutations in intrahepatic cholangiocarcinoma.

Novel Therapeutic Approaches to Target FGFR Mutations in Solid Tumors | Supplements and Featured Publications

Dr. Borad on the Use of Next-Generation FGFR Inhibitors in Cholangiocarcinoma and Urothelial Carcinoma

Developmental FGFR Inhibitors Are Active in FGFR+ Cholangiocarcinoma and Urothelial Carcinoma

Resistance Mechanisms Spur Innovative Research in FGFR-Mutant Liver and Bladder Cancer

Dr. Miron on Resistance Mechanisms to FGFR Inhibitors in Cholangiocarcinoma

Pan-FGFR Inhibitor Seeks to Overcome Resistance Hurdles in Cholangiocarcinoma and Urothelial Carcinoma

Dr. Roychowdhury on FGFR Mutations in Intrahepatic Cholangiocarcinoma