FGFR2 Is Promising Second-Line Target in Cholangiocarcinoma

Treatment with pemigatinib resulted in a durable objective response rate in 35.5% of patients with previously treated, locally advanced or metastatic cholangiocarcinoma who harbored an FGFR2 fusion or rearrangement.

Arndt Vogel, MD, PhD

Treatment with pemigatinib, a selective oral inhibitor of FGFR1, 2, and 3 resulted in a durable objective response rate (ORR) in 35.5% of patients with previously treated, locally advanced or metastatic cholangiocarcinoma who harbored an FGFR2 fusion or rearrangement, according to results from the phase II FIGHT-202 trial.

These findings indicate a potential paradigm shift in those with these alterations, according to Arndt Vogel, MD, PhD, lead investigator of the trial.

Approximately 15% of patients with cholangiocarcinoma harbor alterations in FGFR2, making pemigatinib a viable treatment option for patients in need of an otherwise undefined second-line treatment.

“Historically, response rates in this setting have been 6% to 7%,” said Vogel in an interview with OncLive during the 2019 ESMO Congress. In this study, the response rate in [patients with FGFR2 fusions/rearrangements] was 35.5%, which is really remarkable.”

In addition, patients with FGFR2 fusions/rearrangements (arm A; n = 107) experienced a median duration of response (DOR) of 7.5 months. Investigators also evaluated the agent in patients with other FGF/FGFR alterations (arm B; n = 20) and no FGF/FGFR alterations (arm C; n = 18), but no responses were reported.

Notably, the higher ORR in arm A translated to a longer median progression-free survival (PFS) and interim overall survival (OS) compared with 2.1 months and 1.7 months in arms B and C, respectively.

In terms of adverse events (AEs), investigators noted a 60% incidence of low-grade hyperphosphatemia and a 23% incidence of hypophosphatemia. Hyperphosphatemia was managed with low phosphate intake and dose reductions or interruptions. Additional AEs were mostly managed with dose reductions, and 9% of patients discontinued treatment.

According to these data, investigators have launched a phase III study comparing pemigatinib with the current frontline standard of gemcitabine and cisplatin in patients with FGFR2 fusions/rearrangements.

In the interview, Vogel, a professor of gastrointestinal oncology at Hannover Medical School in Germany, discussed the design of the phase II FIGHT-202 trial in cholangiocarcinoma and the significance of the findings for the field.

OncLive: What are the current therapies that are available for patients with cholangiocarcinoma?

Vogel: The established frontline chemotherapy is gemcitabine and cisplatin; we do not really have a lot of good data for second-line therapy. Recently, the phase III ABC-06 trial was published; that research indicated that there's some clinical benefit to treating patients with second-line FOLFOX. However, the median PFS was just around 3 months and the median OS was 6 months. There’s clearly a high unmet need for patients with more advanced disease. [We need] more therapeutic options in the second- and third-line settings that can result in prolonged disease control.

Could you provide a rationale for the FIGHT-202 trial?

Cholangiocarcinoma is a rare disease, and it has a very poor prognosis. At the moment, we only have data for the frontline use of gemcitabine and cisplatin. However, we also have data indicating that there are many druggable genetic alterations in cholangiocarcinoma, one of which is FGFR2 fusions and rearrangements. These [alterations] can be found in around 15% of patients. We know from preclinical work that these fusions and rearrangements usually result in the activation of a pathway that is likely the main driver of these cancers. Therefore, there was a clear hypothesis that inhibition of this pathway in patients with this driver will result in clinical benefit.

Could you discuss the design of the trial?

This was a large phase II study, which included a large prescreening effort. More than 1000 patients were screened to identify candidates for the trial. There were some patients who already had their next-generation sequencing report in hand; these patients were also included in the study. Around 140 patients were allocated into 3 groups. The largest was arm A, which included patients with [FGFR2] fusions and rearrangements who we believed would have the largest clinical benefit. Twenty patients with FGF/FGFR genetic alterations were enrolled in arm B to see whether there were any responses. Preclinical evidence suggested that the [FGFR pathway] may be involved in cholangiocarcinoma, [even in patients] who don’t have a [FGF/FGFR] genetic alteration. Therefore, patients without FGF/FGFR alterations were also included in the study, in arm C.

How was pemigatinib administered in the trial?

Pemigatinib is a specific FGFR1, 2, and 3 inhibitor; it has a very clear safety profile. It's an oral drug, and in this trial, it was given on a 3-week schedule, 2 weeks on, 1 week off, which was very tolerable for patients. Based on the data we have seen from the study, there is efficacy.

What were the findings?

The primary endpoint of the trial was ORR in patients with gene fusions or rearrangements. In this study, two-thirds of patients had received 1 prior line of therapy, and one-third had received at least 1 prior line of therapy, so this was a very advanced patient population. Importantly, we saw complete responses in addition to partial responses. Additionally, the responses were durable, at more than 6 months by definition. The median DOR was 7.5 months; we also saw a disease-control rate of 82%, which was remarkable. The [primary endpoint] was clearly positive and translated into a PFS and OS benefit. According to this single-arm, phase II trial, there’s a clear indication of efficacy [with pemigatinib].

Was the safety profile consistent with expectations?

Yes. The safety profile was in line with what we would expect from this class of drugs and was easily manageable. The most notable AE was hyperphosphatemia, which is related to the inhibition of the FGFR1 receptor in the renal tubule; it’s usually activated by FGF23, which is important for phosphate secretion. If we block this pathway, we see this hyperphosphatemia.

Other AEs included skin toxicity. Arthralgia was observed as well. It's also important to note that serous retinal detachment occurred in 4% of patients; however, [these events were] low-grade and resolved either on their own or after dose discontinuation or interruption. The risk-benefit balance [with pemigatinib] was clearly favorable.

What are the next steps for this research?

The next step is a phase III study. Companies have now decided they want to [evaluate this agent] in the first-line setting, which is probably reasonable. In this study, the ORR did not differ with regard to line of therapy. FGFR2 fusions and rearrangements are clear drivers of cholangiocarcinoma. The tumor tries to change, and just a few point mutations are necessary to induce quiet resistance. From this perspective, it’ll be important to treat patients with a low tumor burden. If we're getting these patients into a response [in the frontline setting that compares favorably] to what we have seen in the second- and third-line settings, the remaining tumor burden would be pretty low; that might help extend disease control.

Should FGFR2 fusions and rearrangements be tested for upfront?

We already do that, but it’s not only about FGFR2 fusions. At the 2019 ESMO Congress, we also heard about the use of IDH inhibitors in cholangiocarcinoma. There's some excitement in this disease because we have so many genetic alterations. We’ve now seen phase II data showing that BRAF, NTRK, IDH1/2, and FGFR fusions are druggable, and [the right targeted agent can induce] responses and clinically meaningful benefit.

Pending further study, how could these results impact practice?

If these studies are positive, they will be practice-changing; there's no question about it. We should not forget that we are talking about a rare disease and a small subgroup of patients. These phase III studies [in the frontline setting] have 400 to 500 patients, so they will take some time and effort to complete. In the second-line setting, it's a little bit easier because most patients want to start treatment immediately. When it comes to screening efforts, you have to do genetic testing, which will take time, before patients can be included in the trial. That may lead to us losing eligible patients who may just want to begin treatment.

Is there anything else you would like to emphasize about these findings?

These results are really exciting. For many years, cholangiocarcinoma was a difficult-to-treat disease. [Our standard of care] was gemcitabine for several years and then gemcitabine and cisplatin. For us, it was difficult to start an academic trial since there was usually no funding. Now, we have ideas about how we can improve [outcomes] with these targeted therapies. We’re seeing that pharmaceutical companies are now interested in cholangiocarcinoma, which is really great.

Vogel A, Sahai V, Hollebecque A, et al. FIGHT-202: a phase 2 study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA). Presented at: 2019 ESMO Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA40.