FOENIX Update: A New Era in Cholangiocarcinoma Precision Medicine

Data from the final analysis of a trial examining the FGFR1-4 inhibitor futibatinib (TAS-120) bear out its durability, efficacy, and tolerability among patients with the rare cancer intrahepatic cholangiocarcinoma (iCCA). The findings confirm results seen in the primary analysis and show outcomes that exceed historical standards.

Patients with iCCA, particularly those whose disease progresses following first-line chemotherapy, have limited overall treatment options¹ and a notoriously poor survival rate.² Data presented at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting put the 5-year survival rate at 24%³. However, data presented at the 2022 ASCO Annual Meeting show that patients may soon have a new agent to fight this rare cancer in futibatinib (Taiho Oncology), an FGFR inhibitor.

Lipika Goyal, MD, an assistant professor of medicine at Harvard Medical School and a medical oncologist at Mass General Cancer Center in Boston, Massachusetts, presented the final data analysis of the phase 2 FOENIX-CCA2 trial (NCT02052778)on futibatinibat the meeting.⁴ Goyal explained that median overall survival (OS) for iCCA also is short, at just over 6 months with second-line chemotherapy with a FOLFOX (folinic acid, fluorouracil, and oxaliplatin) regimen and close to 1 year with first-line gemcitabine and cisplatin, or gemcitabine, cisplatin, and durvalumab.

Approximately 8000 patients receive a CCA diagnosis each year,⁵ but patients with FGFR2 gene rearrangements, including fusions, especially stand to benefit from futibatinib, as this genetic mutation is seen more often in those living with iCCA.¹ The mutation occurs at a rate of 9% to 14% in the 40% to 50% of patients with iCCA and actionable targets, said Goyal.

The FDA accepted futibatinib for priority review on March 30, 2022.⁶ At that time, Volker Wacheck, MD, vice president of clinical development at Taiho Oncology, Inc, noted: “Given the lack of an accepted standard chemotherapy following the failure of first-line treatment, futibatinib could represent a significant opportunity for a targeted therapy in this subset of patients with CCA, which has driven our pursuit with this investigational compound.”

Futibatinib received a breakthrough therapy designation from the FDA on April 1, 2021,7 and the Prescription Drug User Fee Act date is set for September 30, 2022.¹

The final analysis from FOENIX-CCA2, which investigated the use of futibatinib among 103 patients with unresectable or metastatic iCCA and an FGFR2 fusion or rearrangement, confirms the efficacy, safety, and durability of the highly selective, irreversible FGFR1-4 inhibitor, echoing data presented at the 2020 and 2021 meetings.2-4 The primary data cutoff was October 1, 2020, and final data cutoff was May 29, 2021, with these newest data including 8 more months of efficacy and safety information, including mature OS data.

All patients in the open-label single-arm study had progressive disease (PD) after at least 1 systemic treatment—with 53% having received 2 or more prior lines—consisting of gemcitabine and platinum-based chemotherapy. The investigators evaluated outcomes from a 20-mg once-daily oral dosage of futibatinib given continuously until PD or intolerability in 21-day cycles. Prior therapy with FGFR inhibitors was not allowed. The primary end point was objective response rate (ORR), with a target ORR of 20%; secondary end points were duration of response (DOR), disease control rate, progression-free survival (PFS), OS, safety, and patient-reported outcomes.² The median follow-up was 25 months, and patients underwent a median of 13 cycles of treatment.

“A unique aspect of this agent is that it binds covalently and therefore irreversibly to a cysteine residue in the P loop of the FGFR kinase domain,” Goyal noted. “By contrast, most other FGFR inhibitors approved or being investigated are reversible and ATP competitive.”

In an interview with Evidence-Based Oncology®, Wacheck, who is also an oncologist and clinical pharmacologist, and head of the global development program for futibatinib, elaborated on the drug’s mechanism of action.

“It is also less sensitive with respect to any mutation in the kinase domain that might emerge after prolonged treatment with an FGFR inhibitor because that cysteine residue is only very rarely subject to any of those acquired mutations,” he said. “We have some preclinical data suggesting that this might be a mechanism [for] how we can delay with this molecule the resistance, or the emergence of resistance, due to kinase domain mutations.”

The final analysis shows the following results compared with those of the primary analysis^2,4:

• 93% of patients discontinued treatment vs 70% from the primary analysis
• ORR and DCR remained unchanged, at 41.7% and 82.5%, respectively
• Median DOR was 9.5 vs 9.7 months
• Median time to response was 2.6 months
• 74% vs 72% of responses lasted 6 months or longer
• Median PFS was 8.9 vs 9.0 months
• 12-month PFS rate was 35.4%
• 6-month PFS rate was 65%
• Mature OS rate was 20 months
• 12-month OS rate was 73%
• 6-month OS rate was 88%
• 19% of responses lasted at least 12 months

These objective responses were seen independent of age, sex, region of residence, and number of prior treatment lines. In addition, Goyal highlighted the fact that 42 patients had a confirmed partial response and 1 had a confirmed complete response, as well as that 95% of those with stable disease “had some degree of target lesion shrinkage.”

Much of futibatinib’s success lies in its ability to delay the resistance often seen with other FGFR2 inhibitors, Wacheck emphasized, resistance that stems from the constant onslaught of mutations.

“Some of those mutations in the kinase domain can lead to resistance, particularly to ATP-competitive inhibitors,” he noted. “What we also see in the literature is that also so-called bypass mechanism. Pathways that initially might not be the driver of disease more and more become important for the progression of the disease.”

FOENIX-CCA2 was also among the first FGFR inhibitor studies to report on patient quality of life. EuroQol-5D findings showed that the 89% of patients who provided data were able to maintain their quality of life during treatment.

Adverse effects from futibatinib remained consistent from the primary to the secondary analysis, with the most common being hyperphosphatemia, alopecia, and dry mouth, at 85%, 33%, and 30% in both analyses, respectively, of grade 1/2.2,4 No new safety signals were identified, and there were no treatment-related deaths.

Hyperphosphatemia, which leads to an imbalance between phosphorus and calcium homeostasis in a patient,⁸ is one of the exclusion criteria for clinical trials of FGFR inhibitors, Wacheck noted. This is because this drug class is increasing phosphate levels in patients, which is a known on-target effect.

Also reported during the session, for the first time, were the results of the exploratory biomarker analysis on circulating tumor DNA (ctDNA) for FGFR2. Ninety-two percent of patients provided these data, Goyal said, with 83% having FGFR2 fusions and rearrangements. This equated to an 87% positive percentage agreement from baseline to ctDNA analysis for the tissue samples collected at both time points.

Wacheck also noted that more data are needed before the day-to-day use of ctDNA to optimize the use of futibatinib in patients. He added that there is great potential for its use “as an interesting alternative for patients” in instances of a lack of available tissue or when rebiopsy is not an option.

“Overall, these results represent another example of the promise of precision medicine in iCCA and establish futibatinib as effective for and well tolerated by patients with advanced FGFR2 fusion- or rearrangement-positive disease,” Goyal concluded.

At present, the phase 3 FOENIX-CCA3 trial (NCT04093362) is evaluating futibatinib vs gemcitabine and cisplatin in the first line in patients with CCA and FGFR2 rearrangements.⁹

Two other FGFR inhibitors are approved for use in a second-line setting for patients with CCA and FGFR2 fusion/rearrangement. However, according to data presented during the ASCO meeting by Marina Baretti, MD, an assistant professor of oncology at Johns Hopkins Medicine in Baltimore, Maryland, the use of futibatinib vs pemigatinib (approved in 2020) and infigratinib (approved in 2021) leads to superior outcomes in overall response rate, median DOR, and median PFS.¹⁰

References

1. Taiho Oncology announces updated efficacy and safety data for futibatinib in cholangiocarcinoma at 2022 ASCO Annual Meeting. News release. Taiho Oncology. June 3, 2022. Accessed June 4, 2022.

https://www.taihooncology.com/us/news/2022-06-03_asco_2022_press_release/

2. Goyal L, Meric-Bernstam F, Hollebecque A, et al. Primary results of phase 2 FOENIX-CCA2: the irreversible FGFR1-4 inhibitor futibatinib in intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions/rearrangements. Cancer Res. 2021;81(suppl 13):CT010. doi:10.1158/1538-7445.AM2021-CT010

3. Goyal L, Meric-Bernstam F, Hollebecque A, et al. FOENIX-CCA2: a phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements. J Clin Oncol. 2020;38(suppl 15):108. doi:10.1200/JCO.2020.38.15_suppl.108

4. Goyal L, Meric-Bernstam F, Hollebecque A, et al. Updated results of the FOENIX-CCA2 trial: efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/rearrangements. Abstract presented at: 2022 ASCO Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract 4009. Accessed June 4, 2022. https://meetings.asco.org/2022-asco-annual-meeting/14271?presentation=208022#208022

5. Caffrey M. Clinical, scientific updates at CCF 2022 highlight advances in cholangiocarcinoma. The American Journal of Managed Care®. February 27, 2022. Accessed June 4, 2022.

https://www.ajmc.com/view/clinical-scientific-updates-at-ccf-2022-highlight-advances-in-cholangiocarcinoma

6.FDA accepts futibatinib for priority review for FGFR2 rearrangements and fusions in cholangiocarcinoma. The American Journal of Managed Care®. March 30, 2022. Accessed June 4, 2022. https://www.ajmc.com/view/fda-accepts-futibatinib-for-priority-review-fgfr2-rearrangements-and-fusions-in-cholangiocarcinoma

7. FDA grants breakthrough therapy designation for Taiho Oncology’s futibatinib for treatment of advanced cholangiocarcinoma. News release. Taiho Oncology, Inc. April 1, 2021. Accessed June 4, 2022. https://www.prnewswire.com/news-releases/fda-grants-breakthrough-therapy-designation-for-taiho-oncologys-futibatinib-for-treatment-of-advanced-cholangiocarcinoma-301260615.html

8. Lewis JL. Hyperphosphatemia. Merck Manual. Updated September 2021. Accessed June 4, 2022.

https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/electrolyte-disorders/hyperphosphatemia

9. Futibatinib versus gemcitabine-cisplatin chemotherapy as first-line treatment of patients with advanced cholangiocarcinoma harboring FGFR2 gene rearrangements (FOENIX-CCA3). ClinicalTrials.gov. Updated May 18, 2022. Accessed June 4, 2022.

https://clinicaltrials.gov/ct2/show/NCT04093362

10. Baretti M. Can we begin to predict responders to targeted therapy in gastrointestinal cancer? Presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022; Chicago, IL. Accessed June 4, 2022. https://meetings.asco.org/2022-asco-annual-meeting/14271?presentation=209415#209415