Mitesh J. Borad, MD, oncologist, Department of Medical Oncology, Mayo Clinic Comprehensive Cancer Center, discusses key findings from the phase 1/2 ReFocus trial (NCT04526106) in 

The ReFocus trial evaluated the novel FGFR2 inhibitor RLY-4008 in patients with 

-altered solid tumors. Within the cholangiocarcinoma cohort, patients were either FGFR inhibitor naïve or FGFR inhibitor refractory. The phase 1 portion aimed to determine the recommended phase 2 dose (RP2D) and proof of mechanism of RLY-4008, as well as the agent’s safety, pharmacokinetics, pharmacodynamics, and initial efficacy. Efficacy data were reported for patients who received daily doses of less than 70 mg of RLY-4008 vs RLY-4008 at 70 mg or higher across all 3 of the dosing schedules, Borad states.

Preliminary results from the study showed that the 11 FGFR inhibitor–naïve patients with 

 fusion–positive cholangiocarcinoma achieved an overall response rate (ORR) of 73% with 70 mg or more of RLY-4008, Borad reports. This included 8 partial responses (PR) and 3 patients with stable disease (SD). Responses were also shown to be durable, with a median duration of response (DOR) of 11.2 months, Borad adds. The 6-month progression-free survival and disease control rates (DCRs) were both 100%.

Conversely, the ORR in patients in this population who received less than 70 mg of RLY-4008 (n = 14) was 36%, Borad states. There were 5 PRs, 6 patients with SD, and 3 patients with progressive disease (PD). The median DOR in this population was 5.6 months, the 6-month PFS rate was 70%, and the DCR was 79%.

RLY-4008 also demonstrated clinical activity in patients with 

 fusion–positive cholangiocarcinoma who were pretreated with FGFR inhibitors (n = 50), Borad notes. This difficult-to-treat population is known to experience poorer outcomes due to the development of resistance mechanisms and lack of effective therapeutics, he explains.

Patients in this population who received at least 70 mg of RLY-4008 (n = 14) experienced an ORR of 21%, with 3 PRs, 10 patients achieving SD, and 1 with PD, Borad continues. The median DOR was 5.6 months, the 6-month PFS rate was 43%, and the DCR was 93%. Individuals who received less than 70 mg of RLY-4008 (n = 36) had an ORR of 11%, including 4, 23, and 7 patients achieving PR, SD, or PD, respectively. Median DOR was 6 months; the 6-month PFS rate and DCR was 33% and 75%, respectively, Borad details.

Based on these data, 70 mg was selected as the RP2D, Borad says. The ongoing phase 2 dose expansion portion of the study will determine the agent’s efficacy in 

Dr Borad reports receiving research funding from Relay Therapeutics.

Videos

Mitesh Borad, MD,  key findings from the phase 1/2 ReFocus trial in FGFR2-altered cholangiocarcinoma.


Dr Borad on the Initial Efficacy of RLY-4008 in FGFR2 Fusion–Positive Cholangiocarcinoma 

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.

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

Mitesh Borad, MD, professor of Medicine, Mayo Clinic School of Medicine, program leader, Gene and Virus Therapy Program, director, Cancer Cell, Gene, and Virus (CGV) Therapy Lab, director, Liver and Biliary Cancer Research Program, Mayo Clinic, discusses the next steps for investigating RLY-4008 in cholangiocarcinoma harboring 

Data from the phase 1/2 ReFocus trial (NCT04526106) presented at the 2022 ESMO Congress showed that RLY-4008 elicited an objective response rate of 88.2% in 17 patients with FGFR inhibitor–naïve cholangiocarcinoma who received the oral agent at the recommended phase 2 dose of 70 mg once daily.

A key next step for research will involve evaluating RLY-4008 in a larger cohort of patients, Borad says. Given the smaller cohort of patients examined thus far in the ReFocus trial, additional data from a larger population can shed additional light on response rates initially observed with the agent, Borad adds. Getting additional data on the agent in future studies will be vital, Borad concludes.

Mitesh Borad, MD, discusses the next steps for investigating RLY-4008 in cholangiocarcinoma harboring FGFR2 fusion or rearrangement.   


Dr. Borad on the Next Steps for Research Evaluating RLY-4008 in FGFR2+ Cholangiocarcinoma

Cholangiocarcinoma (CCA) is a rare and often overlooked cancer that forms in the bile duct. Rare in that it affects fewer than 10,000 people in the U.S.,

but overlooked likely because of its non-specific symptoms – including abdominal pain, night sweats, fatigue, jaundice, general discomfort and weakness – which can make it difficult for physicians to identify.

 Too often, CCA becomes a diagnosis of exclusion, only determined after physicians undergo rigorous processes to rule out other potential explanations to reach a diagnosis. As such, CCA is often diagnosed at an advanced stage when curative modalities such as surgery are not feasible and the prognosis is poor.

Given the non-specific nature of symptoms associated with the diagnosis of CCA, other than jaundice, early detection is uncommon. In my own practice, I have found that a growing number of patients are being incidentally diagnosed by the presence of lesions, which are identified through imaging in the absence of other typical CCA symptoms.

Historically, the only potentially curative treatment for CCA has been surgery, but even after surgery, relapse rates are high, and patients have a median survival of only about 12 months.

 More recently, technological interventions are making it possible to more efficiently evaluate CCA by allowing researchers to look closely inside each person’s tumors to see exactly which mutations are present.

This type of testing, called molecular profiling, pinpoints driver mutations, or genomic abnormalities.

Molecular profiling can help detect these abnormalities earlier on in disease progression.

For example, FGFR2 fusion or rearrangement is observed in 10 – 15% of patients whose CCA originates in the bile ducts within the liver, known as intrahepatic CCA.

While a variety of molecular profiling methods are now available, next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) are among the most common. NGS allows us to analyze a tissue sample for multiple alterations at the same time, while FISH tests are conducted to identify one specific, predetermined alteration at a time.

Molecular profiling isn’t consistently conducted, and it often isn’t even considered until after first-line chemotherapy has failed. Knowing that, I encourage patients within my practice to undergo molecular profiling early on in a patient’s CCA diagnosis, and I urge my hepatology and gastroenterology colleagues to do the same.

It is critical that physicians understand the importance of early molecular profiling when it comes to treating patients with CCA. More broadly, molecular profiling has helped scientists and physicians better understand how cancer can start, grow and spread in the body.

For more information on FGFR2 fusions and next generation sequencing in cholangiocarcinoma, visit 

Disclosures: Dr. Borad reports financial ties to Incyte, ADC Therapeutics, Exelixis Pharmaceuticals, G1 Therapeutics, Immunovative Therapies, Inspyr Therapeutics, Lynx Group, OncBioMune Pharmaceuticals, Western Oncolytics

Key Statistics for Bile Duct Cancer. American Cancer Society. 

https://www.cancer.org/cancer/bile-duct-cancer/about/key-statistics.html

Banales JM, et al. Nat Rev Gastroenterol Hepatol. 2016;13:261‒280.

Uhlig J, et al. Ann Surg Oncol. 2019;26:1993–2000.

Bridgewater J, et al. J Hepatol. 2014;60(6):1268-1289.

Lowery M, et al. Clin Cancer Res. 2018;24(17):4154-4161.

Graham RP, et al. Hum Pathol. 2014;45:1630‒1638.

Farshidfar F, et al. Cell Rep. 2017;18(11):2780–2794.

Damodaran S, Berger MF, Roychowdhury S. Am Soc Clin Oncol Educ Book. 2015;e175-e182.

Hu L, Ru K, Zhang L, et al. Biomark Res. 2014;2(1):3.

Articles

The Critical Role of Molecular Profiling in Cholangiocarcinoma

Mitesh J. Borad, MD, associate professor of medicine, consultant, Division of Hematology/Oncology, Mayo Clinic, discusses the results of the SARAH and SIRveNIB studies in patients with hepatocellular carcinoma.

The SARAH study was conducted in Europe and looked at Y-90 radioembolization versus sorafenib (Nexavar). The study was conducted to determine whether radioembolization was better than sorafenib. Findings from the trial showed that radioembolization was not superior. Upon further inspection, the data reveal that radioembolization was not significantly inferior to sorafenib. Borad states that similar results may be achieved with lower toxicities.

The SIRveNIB study was a similar study that was conducted in Asia that asked the same question of whether radioembolization was better than sorafenib. It also resulted in a negative finding, but Borad says that it may be able to be used in appropriately selected patient populations to avoid the toxicities of sorafenib.

Mitesh J. Borad, MD

Articles

Dr Borad on the Initial Efficacy of RLY-4008 in FGFR2 Fusion–Positive Cholangiocarcinoma

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

Dr. Borad on the Next Steps for Research Evaluating RLY-4008 in FGFR2+ Cholangiocarcinoma

The Critical Role of Molecular Profiling in Cholangiocarcinoma

Dr. Borad on the SARAH and SIRveNIB Studies in Hepatocellular Carcinoma