Erdafitinib, an oral pan-FGFR inhibitor, demonstrated encouraging clinical activity and a manageable safety profile in Asian patients with 

-aberrant advanced cholangiocarcinoma (CCA), according to preliminary results from a phase IIa trial presented at the 2018 ESMO Congress.

In the open-label, multicenter, phase IIa trial (NCT02699606), results showed that the overall response rate (ORR) was 45.5% and the 9-month progression-free survival (PFS) rate was 38%.

The overall prognosis for patients with CCA is poor, and although potentially curative surgical options are available for a small number of patients with early, localized disease, options for those with advanced or metastatic disease have been limited to traditional systemic chemotherapy with gemcitabine and cisplatin.

For some time, investigators have known that FGFR plays a crucial role in tumor cell growth, survival, and migration, as well as in maintaining tumor angiogenesis. However, there has been increasing evidence suggesting that aberrant 

Investigators sought to evaluate the clinical efficacy and safety of erdafitinib in select patients with advanced CCA with 

 gene mutations. To be eligible for enrollment, patients had to be 18 years of age or older, histologically or cytologically confirmed advanced CAA, an ECOG performance status of 0 or 1, and must have failed at least 1 prior line of therapy.

Those who had been treated with chemotherapy, targeted therapies, immunotherapy, or any investigational anticancer agent within the 2 weeks prior to the trial starting were ineligible to enroll, as were those with uncontrolled or history of cardiovascular disease, and those with persistent phosphate greater than the upper limit of normal.

Of the 193 patients who were molecularly screened, 29 patients had 

 alterations. Of those with alterations, 7 patients had 

 fusions, 3 had FGFR2 mutations, and 2 had 

 mutation; these 12 were given erdafitinib at a continuous dose of 8 mg once daily, with 1 patient uptitrated to receive a 9-mg dose. Eleven of the 12 patients were deemed evaluable for response. The median number of treatment cycles was 7.0 (range, 2-19), while the median treatment duration was 6.34 months (1.6-17.5).

All patients received prior systemic therapy; 4 patients (36.4%) were previously exposed to radiotherapy, while 6 (54.5%) underwent prior cancer-associated surgery. Four of the 11 patients received 1 prior chemotherapy, 4 underwent 2 chemotherapies and 3 patients received 3 or more lines of chemotherapy. Eight patients were treated with standard gemcitabine/cisplatin, while 11 patients received a regimen of cisplatin/oxaliplatin/carboplatin-based chemotherapy.

Of these 11 patients, there were 5 confirmed partial responses (PRs) in those with 

 fusions had stable disease. Two patients had progressive disease, both of whom had 

 mutations. The disease control rate (DCR) was 72.7%; it was 81.8% when including unconfirmed complete responses and PRs.

The median duration of response with erdafitinib was 3.94 months (95% CI, 3.65-12.16). The median PFS was 5.59 months (95% CI, 1.87 to not evaluable).

The overall response rate was observed in 5 of 11 patients, as well as a 9-month PFS rate of 38%. Of the 9 patients with 

 alteration, the 9-month PFS rate was 49%, while the ORR and DCR were 66.7% and 100%, respectively.

Investigators monitored serum phosphate concentration as a pharmacodynamic endpoint to facilitate dose adjustment per protocol specification. On cycle 1 day 14, they measured serum phosphate for pharmacodynamic uptitration. Results showed that serum phosphate concentrations from patients with CCA were within the 90% model prediction interval. Serum phosphate concentration fell within the targeted range for most of the patients, supporting the current dosing regimen in this population.

One patient with a confirmed PR to treatment with a 

 fusion confirmed in tumor and cell-free DNA (cfDNA) analysis, was observed to have experienced maximum tumor shrinkage (-46.2%). Further analysis revealed V564L, a secondary 

 kinase domain mutation. Because this gatekeeper mutation had not been observed in the baseline plasma or tumor tissue, investigators postulate that this mutation represents a mechanism of acquired resistance to erdafitinib.

The most common, any grade adverse events (AEs) associated with the treatment were the following: hyperphosphatemia (n = 10), dry mouth (n = 8), stomatitis (n = 8), dry skin (n = 5), nail disorder (n = 4), and hand-foot syndrome (n = 4). AEs that resulted in dose reduction were noted in 5 patients (45.5%), while events that led to dose interruption were observed in all patients (100%).

Three patients (27.3%) experienced serious AEs but were not deemed to be drug-related; these included gastrointestinal hemorrhage (n = 1), pyelonephritis acute (n = 1) and pathological failure (n = 1). Grade 3 or higher AEs were experienced in 6 patients (54.5%), but none of these AEs resulted in treatment discontinuation or death.

Investigators concluded that a larger sample size is needed to further explore safety and effectiveness of erdafitinib in this patient population. Further research is also needed to evaluate the molecular underpinnings of CCA to inform the development of new treatment options.

Chen YY, Park JO, Su WC, et al. Preliminary results of a ph2a study to evaluate the clinical efficacy and safety of erdafitinib in Asian patients with biomarker-selected advanced cholangiocarcinoma (CCA). 

. 2018;29(8). doi: 10.1093/annonc/mdy282.008.

Articles

Erdafitinib, an oral pan-FGFR inhibitor, demonstrated encouraging clinical activity and a manageable safety profile in Asian patients with FGFR-aberrant advanced cholangiocarcinoma.

Erdafitinib Shows Promise in FGFR-Aberrant Cholangiocarcinoma

The selective pan-FGFR kinase inhibitor infigratinib (BGJ398) showed meaningful antitumor activity and a manageable safety profile in patients with previously treated intrahepatic cholangiocarcinoma (IHC) who harbor 

 fusions, according to updated phase II findings presented at the 2018 ESMO Congress.

 fusions or translocations (NCT02150967), the confirmed and unconfirmed overall response rate (ORR) in all 

-fusion—positive patients was 31.0% (95% CI 20.5%-43.1%) and the investigator-assessed confirmed ORR in patients with potential for confirmation was 26.9% (95% CI 16.8%-39.1%).

Approximately 13% to 17% of patients with IHC have 

 fusions, and the majority of the patients enrolled on the trial were female (62.0%) as opposed to male (38.0%). These patients received the ATP-competitive, FGFR1—3-selective oral TKI infigratinib at 125 mg daily for 21 days of a 28-day cycle. Treatment was discontinued if there was unacceptable toxicity, disease progression, investigator discretion, or withdrawal of consent.

Partial responses were confirmed in 18 patients (25.4%), and stable disease was confirmed in 41 patients (57.7%). Progressive disease was observed in 8 patients (11.3%), and there were 0 confirmed complete responses. Tumor response was assessed per RECIST v1.1 criteria using CT or magnetic resonance imaging.

“The vast majority of patients either have response or stable disease. The disease control rate was 80%, so that is quite remarkable for a targeted therapy in this disease,” said lead author Milind Javle, MD, professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, in an interview with OncLive. “Currently, this is the largest trial of patients with 

 fusions, and it also has the longest follow-up.”

Secondary endpoints of disease control rate (DCR), median duration of response (DoR), progression-free survival (PFS), and overall survival (OS) were reported for patients with potential for confirmation. In these patients, DCR was 83.6% (95% CI, 72.5%-91.5%), median duration of response was 5.4 months (95% CI, 3.7-7.4), median PFS was 6.8 months (95% CI, 5.3-7.6), and median OS was 12.5 months (95% CI, 9.9-16.6).

Patients with potential for confirmation were defined as those who completed or discontinued treatment prior to 6 cycles. The endpoints in this population were investigator-assessed.

Safety and pharmacokinetics were also evaluated at secondary endpoints in all patients. Adverse events (AEs) were observed during treatment and for the following 30 days after last dose. Toxicity was manageable with phosphate binders and routine supportive care, investigators noted. Prophylactic use of a phosphate-binding agent was recommended by investigators on the days in which infigratinib was administered. Patients were also instructed to follow a low phosphate diet.

The most common treatment-related AEs (TRAEs) of any grade were hyperphosphatemia (73.2%), fatigue (49.3%), stomatitis (45.1%), alopecia (38.0%), constipation (35.2%), dry eye (32.4%), and dysgeusia (32.4%). Fifty-seven patients (66.2%) experienced grade 3/4 TRAEs, the most common of which were hypophosphatemia (14.1%), hyperphosphatemia (12.7%), hyponatremia (11.3%), and stomatitis (9.9%).

“This study has taught us a lot about this disease,” Javle said. “First, [it taught us] that 

 fusions occur in 15% of patients, but more so in the younger population and often in women. These patients do benefit with targeted FGFR inhibition.”

These findings suggest that infigratinib induces clinically meaningful activity in patients with 

-fusion IHC when given following chemotherapy. Additionally, investigators noted that the findings of this study support 

 as a therapeutic target for this patient population. Investigators concluded that further investigation of infigratinib is warranted.

“The next step here is to see whether we can expand this experience in the first-line setting, where this drug can be given upfront without chemotherapy. I believe that the efficacy will be seen in the first-line setting as well,” Javle suggested.

Javle M, Kelley RK, Roychowdhury S, et al. A phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor (TKI), in patients with previously-treated advanced cholangiocarcinoma containing FGFR2 fusions. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract 3652.

The selective pan-FGFR kinase inhibitor infigratinib showed meaningful antitumor activity and a manageable safety profile in patients with previously treated intrahepatic cholangiocarcinoma who harbor FGFR2 fusions.

Infigratinib Active in Intrahepatic Cholangiocarcinoma

The potent FGFR1-3 inhibitor pemigatinib (INCB054828) showed preliminary efficacy and safety signals in the phase II FIGHT-202 trial (NCT02924376) of patients with previously treated advanced, metastatic or surgically unresectable cholangiocarcinoma. Data from the first 47 patients with 

 translocations enrolled in cohort A were presented at the 2018 ESMO Congress.

“In this interim analysis of patients from cohort A who had at least 8 months of follow-up, pemigatinib was generally well tolerated and demonstrated preliminary efficacy in previously treated patients with cholangiocarcinoma harboring 

 translocations,” principal investigator Antoine Hollebecque, MD, senior medical physician at Institut Gustave Roussy, and co-investigators wrote.

To be eligible for enrollment, patients must have had a histologically or cytologically confirmed CCA and failed ≥1 prior treatment, have radiographically measurable disease, adequate hepatic and renal function, and an ECOG performance status ≤2. Patients were ineligible if they had received previous treatment with select FGFR inhibitors.

 translocations (cohort A, n = 100), other 

 genetic alterations (cohort B, n = 20) and no 

 genetic alterations. Of the 47 patients evaluable in cohort A, 44 patients (94%) had intrahepatic cholangiocarcinoma, 46 (98%) had an ECOG performance status ≤1, and 28 (60%) had received ≥2 prior therapies.

The primary endpoint of this study was overall response rate (ORR) in cohort A, which was 40.4% (95% CI, 26.4%-55.7%). Nineteen patients (40.4%) had a confirmed partial response, while 21 patients (44.7%) had a best response of stable disease.

Secondary endpoints in cohort A included duration of response (DOR), and in cohorts A, B, and C, investigators evaluated disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Median DOR in cohort A was not reached at the time of data cutoff, but investigators noted that the probability of maintaining response ≥6 was 86.2% (95% CI, 55.0%-96.4%). DCR was 85.1% in cohort A, 45.5% in cohort B, and 22.2% in cohort C. Median PFS in cohort A was 9.2 months, 2.1 months in cohort B, and 1.7 months in cohort C. Median OS in cohort A was 15.8 in cohort A, 6.8 months in cohort B, and 4.0 months in cohort C.

The most common treatment-emergent adverse events (TEAEs) in all patients treated with pemigatinib were hyperphosphatemia (60.7%), alopecia (41.6%), diarrhea (39.3%), decreased appetite (37.1%), fatigue (36.0%), and dysgeusia (36.0%). The most frequent grade ≥3 TEAEs were hypophosphatemia (13.5%), abdominal pain (6.7%), arthralgia (6.7%), and fatigue (4.5%).

Although 5 patients experience TEAEs that resulted in a fatal outcome, investigators deemed that those results were not related to pemigatinib. Deaths on the study were attributed to failure to thrive, abdominal distension, sepsis, malignant neoplasm progression, dyspnea, pleural effusions, and cholangitis.

 translocation may be associated with the pathogenesis of cholangiocarcinoma. This led to the rationale to use pemigatinib in a trial that enrolled patients with documented 

Currently, the median OS and PFS rates for patients with cholangiocarcinoma receiving second-line therapy are low, at 7.2 and 3.2 months, respectively. Pemigatinib may offer a second-line option for patients who otherwise have no well-established treatment options after failure of first-line gemcitabine and cisplatin. Additionally, this oral agent has previously shown efficacy in patients with 

“Overall, these results support continued development of pemigatinib as a promising treatment for patients with CCA harboring 

 translocations,” Hollebecque et al noted.

Recruitment is closed, and data on the overall study population will be presented at a later date.

Hollebecque A, Borad M, Sahai V, et al. Interim results of FIGHT-202, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with previously treated advanced/metastatic or surgically unresectable cholangiocarcinoma (CCA) with/without fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations [published online ahead of print October 23, 2018]. 

The potent FGFR1-3 inhibitor pemigatinib showed preliminary efficacy and safety signals in the phase II FIGHT-202 trial (NCT02924376) of patients with previously treated advanced, metastatic or surgically unresectable cholangiocarcinoma.

Pemigatinib Emerging as Potential Second-Line Treatment for Cholangiocarcinoma

 can be targetable in many cancers, particularly in cholangiocarcinoma. FGFR inhibitors are now being tested in clinical trials of patients with these fusions.

“I would say that as far as the landscape of 

 across cancers, we are really only looking at the tip of the iceberg. We really don't know who else is going to have it,” said Sameek Roychowdhury, MD, PhD. “Everyone should be tested for it.”

Findings from 2 studies presented at the 2018 ESMO Congress showed the potential for the FGFR inhibitors infigratinib and pemigatinib in patients with cholangiocarcinoma. Both agents demonstrated favorable safety profiles in their respective studies, as well as signals of antitumor activity. It is still early, however, and the management of adverse events (AEs) is something that needs to be stressed, Roychowdhury said.

: What is the importance of FGFR inhibitors in cholangiocarcinoma?

In an interview with OncLive®, Roychowdhury, an associate professor at The Ohio State University Comprehensive Cancer Center, discussed the potential for FGFR inhibitors in the treatment of patients with cholangiocarcinoma who harbor 

 gene fusions, sometimes called translocations or rearrangements, have emerged as a significant target for therapy, not only in cholangiocarcinoma, but also in other cancer types. The most common gene fusion in cholangiocarcinoma that is intrahepatic is FGFR2, but we have also seen FGFR1 and FGFR3 in other cancer types, such as urothelial carcinoma, pancreatic cancer, and breast cancer. For each of these cancer types, especially cholangiocarcinoma, early trials involving inhibitors of the 

 gene, which is a receptor tyrosine kinase, [have] emerged.

There are about 10 FGFR inhibitors in this clinical space being tested in this population who have 

 fusions. For the most part, we are seeing some promising results. Patients are either having partial responses or rare complete responses. More commonly, we are seeing patients develop stable disease that goes on for quite a long time. We are seeing an improvement in progression-free and probably overall survival. The studies are ongoing.

Should FGFR inhibitors be tested in a tumor-agnostic fashion?

The most common tumor types where we see [

 fusions] are cholangiocarcinoma and urothelial cancer. However, we are seeing this in any solid tumor as a fusion. The frequency of this is low, but it is high enough that it is worthwhile for us to find these patients and offer them therapy, because they have a good chance of benefitting. Over the last couple of years, we have seen patients beyond cholangiocarcinoma and urothelial cancer—including prostate cancer, neuroendocrine tumors, head and neck cancer, breast cancer, and pancreatic cancer&mdash;with 

-driving genetic alterations. Finding these fusions has allowed patients to qualify for an FGFR inhibitor of some kind and benefit [from it]. As we [do genetic testing on] more and more patients, we are going to find more candidates for testing.

As a principle, companies developing and driving FGFR inhibitors are interested in getting these drugs to patients who will benefit. My understanding is that they are interested in patients who have marker-positive cancer, regardless of cancer type. There are definitely disease-specific studies; however, these markers are not limited to patients who have a certain cancer type. We are seeing them in multiple tumor types, and patients are benefitting. The landscape of FGFR drug development isn't limited to 1 or 2 cancer types; any cancer type with a driving alteration in 

We saw some early findings for pemigatinib and infigratinib presented at the 2018 ESMO meeting. Could you share your thoughts on those?

I can see the possibility of a marker-driven approach to therapy as opposed to a disease-driven approach. Two examples in the past 2 years are microsatellite instability—high cancers and immunotherapy, as well as the most recent approval of an NTRK inhibitor for patients who have NTRK fusion–positive tumors. As long as patients are going to benefit, that could be the course that these companies take. Certainly, physicians want to see that as well. We want to see the right patients benefit from the right drug.

These drugs have been in phase I/II expansion studies for solid tumors including cholangiocarcinoma, as well as urothelial cancer. Both are inhibitors of the FGFR kinase and are selective for 

. They are both oral drugs and appear to have some efficacy in patients with 

-positive cancers. As a class of drugs, these 2 have a similar profile of AEs, which includes fatigue, hyperphosphatemia, mucositis, gastrointestinal complaints, and arthralgia. Overall, they are similar, but certainly, as we see more data for efficacy and toxicity, we will learn more. It is still very early, but we are seeing some promising findings.

As a class, [FGFR inhibitors] have had similar AE profiles. Over time, these start to add up. In patients who are benefitting from these therapies, often for months, there is some cumulative fatigue that starts to add up. Is it relative to the benefit? It has been worth it. People's lives are being extended. Down the road, I can see allowing for some more holidays, or breaks, for the therapies to allow them to be more tolerable.

Moving forward, what are the next steps for FGFR inhibitors?

Mucositis is one of the things we have seen, and I borrowed some tricks that we use in other cancer types. I use a steroid mouthwash in patients to quell some of that oral mucositis, and I have started to use that preventatively to either reduce the severity or duration of any mucositis or small mouth sores that we see. That is not a randomized, controlled trial; that is just me trying to do the best I can for supportive care. If they have fewer days of mucositis, that is worth it.

These agents are the first-generation FGFR inhibitors, so I am excited to see both the continued study of their efficacy in patients who have 

 alterations, and I am excited to see new diagnostics to help us identify patients with 

 alterations. I am excited to see that the next generation of drugs [will likely have] more efficacy and potentially reduced AE profiles.

We are benefitting patients now, but we have to be cognizant of what happens when the disease becomes resistant to the therapy. We are very interested in studying drug resistance to these FGFR inhibitors. So much so that about 2 years ago, we started a study of body donations, where we have partnered with patients and their families. Thus far, none of these patients have been cured, but a lot of them have benefitted.

Many of them go on to succumb to their disease, so we previously asked them to donate their bodies for cancer research after death. Over the last 2 years, we have completed 9 autopsies for research with our patient partners to collect the sites of disease. We can look at how the tumor evolved over time to become resistant. We are looking at concepts, including clonal evolution and tumor heterogeneity. Therefore, understanding drug resistance to these novel inhibitors are going to help us strategize the next steps.

Sameek Roychowdhury, MD, PhD, discusses the potential for FGFR inhibitors in the treatment of patients with cholangiocarcinoma who harbor FGFR fusions.

FGFR Inhibition in Cholangiocarcinoma: Update from the 2018 ESMO Congress | Special Issues

Erdafitinib Shows Promise in FGFR-Aberrant Cholangiocarcinoma

Infigratinib Active in Intrahepatic Cholangiocarcinoma

Pemigatinib Emerging as Potential Second-Line Treatment for Cholangiocarcinoma

Cholangiocarcinoma Emerges as Key Target of FGFR Inhibitor Research