Dr Baretti on Entinostat Plus Nivolumab in Advanced PDAC

Marina Baretti, MD, assistant professor, Johns Hopkins School of Medicine, discusses results and from a single-center, open-label, phase 2 trial (NCT03250273) evaluating entinostat in combination with nivolumab (Opdivo) for the treatment of patients with advanced pancreatic ductal adenocarcinoma (PDAC).

The study aimed to address the immune-suppressive nature of the tumor microenvironment (TME) in PDAC, which poses challenges for immune checkpoint inhibitor therapy in this patient population. Patients received 5 mg of oral entinostat once per week during a 14-day lead-in period, followed by 5 mg of entinostat in combination with 240 mg of nivolumab once every 2 weeks.

Results presented at the 2024 AACR Annual Meeting showed that patients with advanced PDAC treated with the combination (n = 27) experienced an overall response rate (ORR) per RECIST v1.1 criteria of 11% (95% CI, 2.4%-29.2%) and a disease control rate of 18.5% (95% CI, 6.3%-38.1%). The median duration of response was 10.2 months. The most common any-grade treatment-related adverse effects (TRAEs) in the safety population (n = 30) included fatigue (67%), anorexia (50%), nausea (33%), anemia (30%, decreased lymphocyte count (27%), vomiting (20%), and hyponatremia (17%).

Based on the ORR observed during the study, investigators plan to revisit preclinical models to explore different timing and dosing of entinostat, Baretti says. Other types of combinations utilizing entinostat could also be explored, as researchers look to answer other questions regarding how the agent could modulate the TME in PDAC, she expands. She notes that reprogramming of dendritic cells has been observed with entinostat. Therefore, combining the agent with other drugs that more heavily rely on the function of dendritic cells could be another possible avenue of investigation, she concludes.

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Marina Baretti, MD, on results from a phase 2 study of entinostat in combination with nivolumab for the treatment of advanced pancreatic ductal adenocarcinoma. 

Marina Baretti, MD, discusses some common adverse effects associated with FGFR inhibition in cholangiocarcinoma.

Dr Baretti on Mitigating Toxicities Associated With FGFR Inhibition in Cholangiocarcinoma  

Marina Baretti, MD, assistant professor, oncology, Johns Hopkins Medicine, discusses some common adverse effects (AEs) associated with FGFR inhibition in patients with cholangiocarcinoma, as well as strategies to mitigate these AEsin clinical practice.

As a drug class, FGFR inhibitors exhibit a distinctive toxicity profile, Baretti begins. The most commonly observed AEs associated with these agents are hyperphosphatemia, or elevated phosphate levels; gastrointestinal complications, such as diarrhea; and dermatological toxicities ranging from hair loss to nail and skin toxicity, Baretti reports. Additionally, ocular toxicity, though rare, has been observed in patients who have received these agents, she adds. Addressing FGFR inhibitor–associated hyperphosphatemia was initially challenging for many clinicians, but accumulated experience with FGFR inhibitors has provided valuable insights into the management of this toxicity, Baretti says. Educating patients on the importance of adopting a low-phosphate diet and the potential use of hydration or phosphate binder medicationshas proven effective in most cases, Baretti states. These strategies can eliminate the need for dose reductions or interruptions, she explains.

Similar proactive strategies, such as comprehensive patient education on symptom recognition, hygiene, and guidelines for prompt health-care provider communication, apply to the management of nail and skin toxicities, Baretti continues. Ocular toxicities are best addressed through routine eye evaluations at baseline and at regular intervals throughout the treatment course, Baretti advises. Additional eye assessments may be prompted by any patient-reported vision changes. Proactive management ensures the safe handling of these AEs and can also reduce their severity to baseline conditions, she emphasizes.

Overall, a proactive approach to patient and caregiver education, combined with timely interventions, is the recommended strategy for addressing AEs and minimizing the need for reductions or interruptions of FGFR inhibitor doses,Baretti says. This, in turn, contributes to improved treatment outcomes for patients with cholangiocarcinoma who harbor 

Marina Baretti, MD, discusses some common adverse effects associated with FGFR inhibition in patients with cholangiocarcinoma, as well as strategies to mitigate these AEs in clinical practice.

Dr Baretti on Mitigating Toxicities Associated With FGFR Inhibition in Cholangiocarcinoma

Marina Baretti, MD, discusses mechanisms of resistance in intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions or rearrangements.

Dr Baretti on the Mechanisms of Resistance Associated With FGFR2+ Cholangiocarcinoma

Marina Baretti, MD, assistant professor, oncology, Johns Hopkins Medicine, discusses innate and acquired mechanisms of resistance in patients with unresectable, advanced, or metastatic intrahepatic cholangiocarcinoma harboring 

Although previous data have demonstrated the efficacy of approved FGFR-targeted agents, such as pemigatinib (Pemazyre) and infigratinib (Truseltiq), in this patient population, a subset of patients will not initially respond to these therapies, Baretti begins. Moreover, the emergence of acquired resistance mechanisms can cause the efficacy of these agents to diminish over time, she states. Therefore, it is imperative to improve the identification of predictive biomarkers for response and resistance. Regarding innate resistance, growing evidence suggests that responses to FGFR inhibitors could be influenced by concurrent genetic alterations beyond 

 alterations, Baretti explains. Initial data from the phase 2 FIGHT-202 study (NCT02924376) suggest that patients with mutations in tumor suppressor genes might benefit less from treatment with pemigatinib, she adds.

Similarly, subgroup analyses have shown futibatinib (Lytgobi) have not shown differences in outcomes based on the presence of concurrent 

 gene mutations; however, data suggest that patients with mutations in other genes may experience less benefit with the agent, Baretti expands. She notes that these subgroup analyses include a limited number of patients, meaning it can be challenging to discern whether these effects should be attributed to the drug or are constrained by small sample sizes, she imparts.

As clinical experience with these FGFR-targeted agents increases, it's crucial to investigate how the spectrum of mutations influences the efficacy of these agents, Baretti notes. The emergence of secondary resistance is another challenge seen with the use of targeted therapy. The molecular basis for this acquired, on-target resistance has been well-documented, she says. Prolonged treatment with an FGFR inhibitor can cause a point mutation in the 

 kinase domain, resulting in a conformational change that impedes proper drug binding, Baretti states. Secondary resistance is polyclonal, reflecting the heterogeneity of cholangiocarcinoma, she adds.

Leveraging liquid biopsies, such as circulating tumor DNA, can improve understanding of these secondary resistance mechanisms, Baretti continues. Current data suggests that various FGFR inhibitors may have distinct activity profiles against common secondary mutations, she says. For example, futibatinib appears to maintain efficacy against a variety of secondary point mutations; however, its activity can be limited by gatekeeper mutations, Baretti adds. Efforts are underway to overcome this challenge through the development of next-generation FGFR inhibitors, Baretti concludes.

Marina Baretti, MD, discusses innate and acquired mechanisms of resistance in patients with unresectable, advanced, or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions or rearrangements.


Marina Baretti, MD, discusses the evolving utility of FGFR inhibitors in intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions or other rearrangements.

Dr Baretti on the Utility of FGFR Inhibitors in FGFR2+ Intrahepatic Cholangiocarcinoma

Marina Baretti, MD, assistant professor, oncology, Johns Hopkins University, Johns Hopkins Hospital, discusses the evolving utility of FGFR inhibitors in the treatment of patients with unresectable, advanced, or metastatic intrahepatic cholangiocarcinoma harboring 

The oncology field has made notable progress in transitioning molecularly targeted therapies from experimental stages to clinical application, Baretti begins. Infigratinib (Truseltiq) was among the initial medications 

+ cholangiocarcinoma in 2021 based on findings from a phase 2 study (NCT02150967). However, the commercialization of infigratinib was discontinued by the manufacturing company in 2022,rendering the agent currently unavailable, Baretti emphasizes. However, 2 other agents are available for patients with cholangiocarcinoma: pemigatinib (Pemazyre) and futibatinib (Lytgobi).

 for patients with advanced, metastatic, or surgically unresectable cholangiocarcinomas carrying 

 fusions based on findings from the phase 2 FIGHT-202 study (NCT02924376), she expands. The study enrolled pretreated patients whose disease had progressed following 1 or more prior lines of therapy and produced highly encouraging results with pemigatinib. These positive outcomes includedimproved median progression-free survival (PFS) and overall survival (OS) with pemigatinib compared with historical data from chemotherapy-based therapies in the second-line setting and beyond, Baretti explains.

+ cholangiocarcinoma. Futibatinib acts as an irreversible inhibitor by binding to the FGFR ATP binding pocket, Baretti states. Notably, futibatinib was evaluated in a phase 1/2 study (NCT02052778) in a global population of patients with advanced solid tumors harboring 

fusions or rearrangements. This trial exhibited positive results in the cholangiocarcinoma cohort, and the PFS and OS data with futibatinib in this cohort outperformed historical data with chemotherapy in patients with cholangiocarcinoma, she adds.

The spectrum of FGFR-targeted therapies continues to expand rapidly, with some novel agents under current investigation, Baretti continues. Yet, questions remain about the optimal sequential use of these targeted agents in clinical practice, she concludes.

Marina Baretti, MD, discusses the evolving utility of FGFR inhibitors in the treatment of patients with unresectable, advanced, or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions or other rearrangements.


Marina Baretti, MD

Articles

Dr Baretti on Entinostat Plus Nivolumab in Advanced PDAC

Dr Baretti on Mitigating Toxicities Associated With FGFR Inhibition in Cholangiocarcinoma

Dr Baretti on the Mechanisms of Resistance Associated With FGFR2+ Cholangiocarcinoma

Dr Baretti on the Utility of FGFR Inhibitors in FGFR2+ Intrahepatic Cholangiocarcinoma