With inhibitors of fibroblast growth factor receptor 2 (FGFR2) fusion and other genetic alterations now in clinical trials for cholangiocarcinoma, there is interest in better understanding what FGFR2 genetic alterations mean for patients. In particular, little is known about the effects of FGFR2 fusion status on response to chemotherapy. Ghassan K. Abou-Alfa, MD, MBA, of Memorial Sloan Kettering Cancer Center (MSK), New York, was a member of the team that led an examination of the MSK database of patients with advanced intrahepatic cholangiocarcinoma and FGFR2 fusion. The aim was to better understand the clinical importance of this somatic alteration independent of any therapy.
Ghassan K. Abou-Alfa, MD, MBA
“Within the context of the retrospective and limited-data nature of this analysis, we concluded that overall survival was longer for patients with intrahepatic cholangiocarcinoma and FGFR2 fusions or rearrangements, compared to those without. Progression-free survival was similar; however, after the second line of therapy (which did not contain an FGFR2 inhibitor), a clear improvement in progression-free survival was seen for patients with fusions/rearrangements, similar to what has been noted in the literature,” Dr. Abou-Alfa said at the 2021 Gastrointestinal Cancers Symposium.1
FGFR2 fusions or rearrangements may be oncogenic drivers, which occur in almost 10% to 15% of patients with intrahepatic cholangiocarcinoma. The standard of care for advanced cholangiocarcinoma is gemcitabine and cisplatin, based on the ABC-02 study,2 with median survival of almost 1 year and progression-free survival of about 8 months. Second-line
systemic chemotherapy is associated with a median overall survival of around 13 months, he said.3
FGFR2 Fusions/Rearrangements in 11% of Patients
THE MSK team was able to overlay genomic profiling data with clinical data to facilitate a meaningful understanding of patient outcomes and to suggest potential therapeutic options. As noted, the patients in this analysis had not received an anti-FGFR2 agent.
The investigators employed clinical and genomic data from 132 de-identified patients. Patients were categorized according to FGFR2 status obtained from next-generation sequencing in the MSK IMPACT trial, which showed 115 (87.5%) without alterations, 15 (11%) with an FGFR2 fusion or rearrangement, and 2 (1.5%) with other FGFR2 alterations (who were not further analyzed due to the low number of patients). Clinical data included disease history and exposure to prior lines of systemic chemotherapy in the advanced setting. Only patients with complete data for prior lines of chemotherapy were analyzed.
“There was no difference in most demographic and clinical characteristics, except … those with fusions/rearrangements were rather younger, mostly female, and had received at least three lines of therapy,” Dr. Abou-Alfa reported.
Survival May Be Longer With FGFR2 Fusion/Alteration
Median overall survival since diagnosis was numerically longer in patients with FGFR2 fusions/rearrangements, compared with no alterations: 31.3 months vs 21.8 months. The difference was more pronounced after the start of second-line therapy: 23.2 months vs 8.7 months.
Progression-free survival was essentially the same for those with fusions/rearrangements vs those without: 6.2 vs 7.2 months, irrespective of the type of treatment (platinum-based, non–platinum-based, other). Although median progression-free survival following second-line therapy was numerically longer (5.6 months vs 3.7 months, respectively), Dr. Abou-Alfa noted that because of the small sample size, this finding should be approached with caution.
In the discussion period, Dr. Abou-Alfa commented: “The finding of more disease at a younger age [58 vs 64], and in more women than men, needs further analysis for confirmation. But what we are more intrigued by is the improved overall survival in patients with FGFR2 fusions or alterations. Could it be that these patients just get more treatment? We don’t know, but we do know that it’s very important to test every patient.”
Genomic testing currently takes anywhere from 3 to 8 weeks—a pace that he sees as slow, especially considering that targeted agents are now in front-line trials. He told attendees: “We need to know FGFR2, IDH1, and HER2 status from the start, as targeted drugs are becoming available. We need to work together to get information earlier in the game.”
DISCLOSURE: Dr. Abou-Alfa has received institutional research funding from Arcus, Agios, Astra Zeneca, Bayer, BioNtech, BMS, Celgene, Flatiron, Genentech/Roche, Genoscience, Incyte, Polaris, Puma, QED, Sillajen, Yiviva; and served in a consulting or advisory role for Agios, Astra Zeneca, Alnylam, Autem, Bayer, Beigene, Berry Genomics, Celgene, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Incyte, Ipsen, Legend Biotech, Loxo, Merck, MINA, QED, Redhill, Rafael, Silenseed, Sillajen, Sobi, Surface Oncology, Therabionics, Twoxar, Vector, Yiviva.
1. Abou-Alfa GK, Bibeau K, Schultz N, et al: Effect of FGFR2 alterations on survival in patients receiving systemic chemotherapy for intrahepatic cholangiocarcinoma. 2021 Gastrointestinal Cancers Symposium. Abstract 303. Presented January 15, 2021.
2. Valle J, Wasan H, Palmer DH, et al: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362:1273-1281, 2010.
3. Lowery MA, Goff LW, Keenan BP, et al: Second-line chemotherapy in advanced biliary cancers: A retrospective, multicenter analysis of outcomes. Cancer 125:4426-4434, 2019.