Ghassan K. Abou-Alfa, MD, discusses the design and aim of the PROOF trial in advanced cholangiocarcinoma.
In the phase 3 PROOF trial (NCT03773302), investigators are evaluating the efficacy and safety of the selective pan-FGFR kinase inhibitor infigratinib versus standard gemcitabine and cisplatin as frontline therapy in patients with unresectable, recurrent, or metastatic cholangiocarcinoma who harbor FGFR2 gene fusions and translocations, explained lead study author, Ghassan K. Abou-Alfa, MD.
The ongoing trial is enrolling an expected 384 patients and randomizing them 2:1 to receive 125 mg of oral infigratinib once daily for 21 days of a 28-day cycle versus 1000 mg/m2 of intravenous gemcitabine and 25 mg/m2 of cisplatin on days 1 and 8 of a 21-day cycle.
Progression-free survival (PFS) will serve as the primary end point of the trial with key secondary end points of overall survival (OS) and objective response rate (ORR).
Notably, patients who are randomized to gemcitabine and cisplatin will be able to crossover to infigratinib if they experience disease progression, or if they can’t tolerate the chemotherapy.
“We’re not only assessing whether the drug works. We’re also looking at the timing of therapy,” said Abou-Alfa. “Some patients will get [infigratinib] right from the get-go, and others will get gemcitabine/cisplatin for a certain period of time before crossing over to receive infigratinib. That’s a very important component of the study that we should all pay attention to.”
Prior data from a phase 2 trial (NCT02150967) which evaluated infigratinib as second-line therapy in previously treated patients with advanced FGFR2-altered cholangiocarcinoma had shown an investigator-assessed confirmed ORR of 26.9% (95% CI 16.8%-39.1%). Additional results showed a median PFS of 6.8 months (95% CI, 5.3-7.6) and a median OS of 12.5 months (95% CI, 9.9-16.6).
In an interview with OncLive, Abou-Alfa, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the design and aim of the PROOF trial in advanced cholangiocarcinoma.
OncLive: Could you provide some background on the research that led to the PROOF trial?
Abou-Alfa: It’s a really great pleasure to talk on behalf of my colleagues about what’s going on in the field of cholangiocarcinoma, specifically with regard to the PROOF study, which is evaluating infigratinib versus gemcitabine and cisplatin as first-line therapy in patients with advanced cholangiocarcinoma. The study is restricted to patients with FGFR2 gene fusions and translocations.
My colleague Milind Javle, MD, of The University of Texas MD Anderson Cancer Center, reported data on infigratinib, which was previously known as BGJ398, at the [2017 ASCO Annual Meeting]. The results, which were published in the Journal of Clinical Oncology, evaluated infigratinib as second-line therapy for patients with FGFR-altered advanced cholangiocarcinoma.
What are some of the key inclusion and exclusion criteria of the PROOF trial?
Patients have to have a confirmed diagnosis of cholangiocarcinoma and a confirmed FGFR2 gene fusion, which is a very important component of the trial. It’s of critical importance to know what the next-generation sequencing (NGS) of the tumor is from day 0.
We know sometimes NGS can take some time and since [infigratinib] is being administered as a first-line therapy, that could be a potential limitation to get patients on the study. However, we are able to get fast results with fluorescence in situ hybridization testing at Mayo Clinic within a week. I’ve used [that modality] in practice. The team at Mayo Clinic has been amazing in getting us those results as soon as possible.
Additionally, the patient should have recovered from any prior interventions, with the exception of prior systemic therapy, which patients were not allowed to have received. Of course, patients have to have an ECOG performance status of 0 or 1 and [adequate] organ function. We exclude patients who had prior FGFR inhibitors and prior liver transplant.
How is the trial designed?
We stratify patients by whether patients had locally advanced or metastatic disease, by geography, and by prior adjuvant or neoadjuvant therapy. Patients were randomized 2:1 to 125 mg of oral infigratinib daily for 21 days out of a 28-day cycle versus gemcitabine and cisplatin at the standard dose [that was evaluated in the] ABC-01 study: 1000 mg/m2 and 25 mg/m2, respectively.
An important point is that patients in the gemcitabine/cisplatin arm can crossover to infigratinib if they experience disease progression, or if they can’t tolerate the chemotherapy. The crossover design [prompted us to] make PFS a primary end point of the trial. We’ll also be looking at OS, and response rate as secondary end points.
What is the status of the trial?
We’re still accruing patients to the trial worldwide. I’m honored to co-lead this effort at Memorial Sloan Kettering Cancer Center and The University of Texas MD Anderson Cancer Center with my colleague Jaffer Ajani, MD. Our [goal] is complete accrual. If you don’t have access, don’t [rush] to gemcitabine and cisplatin. Give us a call or any of your colleagues who are close by who have the study open before you put patients on therapy.
Pending positive results from the trial, what do you see the biggest impact being?
We have to see whether the drug works. We always like to measure OS and PFS, as well as response rates. The results will help us understand sequencing. At the moment, we already have an FDA-approved drug on the market, which is pemigatinib (Pemazyre) for patients with FGFR2-altered cholangiocarcoma. I led the effort with pemigatinib, data for which were published in Lancet Oncology.
[Pemigatinib] is available not necessarily as a first-line therapy. As such, it’s important to think about the PROOF study in terms of efficacy and sequencing. Of note, pemigatinib is also being evaluated in another study versus gemcitabine/cisplatin.
1. Abou-Alfa GK, Borbath I, Cohn A, et al. Infigratinib versus gemcitabine plus cisplatin as first-line therapy in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/rearrangements: phase 3 PROOF trial. 2020 ESMO World Congress on Gastrointestinal Cancer; July 1-4, 2020; Abstract P-144.
2. 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. Ann Oncol. 2018;29(8):viii720. doi:10.1093/annonc/mdy424.030