Infigratinib in Patients With FGFR2 Fusion-Positive Cholangiocarcinoma

Clinical Summary: 

• Design/Context: The phase 3 PROOF 301 trial assessed infigratinib in patients with FGFR2 fusion-positive advanced cholangiocarcinoma.
• Key Outcomes: The study faced major accrual limitations despite extensive international screening efforts, limiting interpretation of efficacy outcomes.
• Clinical Relevance: These findings underscore the need for innovative trial designs and alternative end points to accelerate development of targeted therapies in rare molecularly defined cancers.

Ghassan Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, New York, New York, discusses results from the phase 3 PROOF 301 trial evaluating infigratinib in patients with FGFR2 fusion-positive cholangiocarcinoma. 

The study highlights the challenges of conducting large randomized trials in rare molecular subsets and raises important questions about trial design and end points in precision oncology.

Transcript: 

Hello everybody, this is Ghassan Abu-Alfa from Memorial Sloan Kettering Cancer Center in New York. It’s a delight, and also a great awakening, to talk about the infigratinib study.

If you recall, this was a phase 3 clinical trial of infigratinib, anti-FGFR2, versus gemcitabine plus cisplatin, at that time was the standard-of-care therapy, there was no immunotherapy yet. This was in patients with advanced cholangiocarcinoma with FGFR2 fusion or rearrangement. 

At that time, there was a lot of excitement about anti-FGFR2 therapy and for that reason we built the study as a first-line therapy trial with a 2:1 randomization for patients to receive infigratinib versus gemcitabine plus cisplatin. Why 2:1? Because there was a lot of excitement to get the drug available for patients with FGFR2 fusion disease, and that made total sense. The primary end point was progression-free survival within the limited cohort that we were studying, especially because we wanted to make sure there was an opportunity for crossover as well. Secondary end points included overall survival and other variables.

Now, why are we talking about the study? Because it was really an exciting effort that we did proudly and collaboratively. This was an effort where we at Memorial Sloan Kettering agreed with our colleagues at MD Anderson that if we each did separate studies, neither would accrue adequately, so Dr Javle and myself joined hands on this study, together with a superb group from all over the world. And if anything, our effort sadly did not pan out as we had hoped.

Over more than 40 months, that’s more than 3 years, a total of 1,127 patients were screened from 120 sites, this really highlights how extensive and expensive this study was, and only 48 patients were randomized to the infigratinib arm and 19 to chemotherapy, despite a target accrual of 300 patients.

Of course, it really does not make sense to comment heavily on the efficacy outcomes because the data were simply not mature due to the lack of accrual. Nonetheless, progression-free survival between the 2 arms was fairly similar, 7.4 months for infigratinib and 8 months for gemcitabine plus cisplatin. However, we still felt strongly about presenting and publishing this study because it was an important opportunity to complete the evaluation of infigratinib.

This is where we really thank the sponsor, because they fully agreed with us that we were obligated to publish the study, because we owe it to our patients. At the same time, and perhaps more importantly, this study serves as an awakening for all investigators, sponsors, and potentially regulatory bodies to revisit how we design studies for rare cancers with rare genetic alterations. Here, we have a rare cancer like cholangiocarcinoma with a rare genomic alteration such as FGFR2 fusion, and we attempted a very large randomized study of 300 patients, which, as we saw, failed to accrue. 

As such, we think this study should prompt reconsideration of whether overall survival in very large randomized studies should always remain the required primary end point in these settings. Perhaps we should revisit the use of other end points, such as response rate or progression-free survival, to help bring these promising drugs to patients faster rather than later.

Thank you very much for listening.

Source:

Abou-Alfa GK, Borbath I, Roychowdhury S, et al. Phase III trial of infigratinib versus gemcitabine/cisplatin in adults with advanced cholangiocarcinoma with FGFR2 gene fusion or rearrangement: Results and reflections on early termination of PROOF 301. ESMO Open. Published online: March 17, 2026. doi: 10.1016/j.esmoop.2026.106306