Advanced/Metastatic Cholangiocarcinoma Treatment Landscape - Episode 3

An Overview of Treatment Advances in Metastatic Cholangiocarcinoma

A comprehensive review of chemotherapy and targeted agents available to treat cholangiocarcinoma throughout various lines of therapy.

Transcript:

Anthony B. El-Khoueiry, MD: I’d like to walk you through the therapeutic approach to advanced cholangiocarcinoma. If we think about first-line therapy, the combination of gemcitabine and cisplatin has been the standard of care for several years. In the last few weeks, we saw a press release reporting that the TOPAZ-1 clinical trial—which examined gemcitabine-cisplatin plus durvalumab, the anti–PD-L1 antibody vs gemcitabine-cisplatin alone—met its primary end point. We haven’t seen the data, but this trial seems to have been closed by the data-safety monitoring committee because of a survival benefit. It was felt to be unethical to continue with the trial. We’re excited and looking forward to the results of this trial, which may lead to the approval of durvalumab with chemotherapy as the new first-line standard. But today the standard continues to be gemcitabine and cisplatin.

In the second line, there are multiple options, and the second-line choice may be influenced by the molecular makeup of the tumor. Hopefully, the patient has had molecular profiling of their tumor before or during first-line treatment. If the patient has no targetable alterations—we’ll come back to this in a minute—the current standard of care, based on the ABC-06 trial, is the combination of 5-FU [5-fluorouracil] and oxaliplatin: FOLFOX [5-fluorouracil, leucovorin, oxaliplatin]. This was compared with active symptom control and showed a modest benefit in PFS [progression-free survival] and OS [overall survival]. Unfortunately, the responses are very rare, and the duration of benefits seems to be rare. We’re still talking about an immediate PFS of less than 4 months in general with this option. But if there are no targetable alterations, FOLFOX [5-fluorouracil, leucovorin, oxaliplatin] is an option. Of course, clinical trials are a great option for second-line cholangiocarcinoma.

Let’s talk about the specific molecular subgroups. If the patient has an FGFRalteration—the most common is theFGFR2 fusion—we have accelerated approval of 2 agents, infigratinib and pemigatinib. Both target FGFR2 alterations, and both are approved oral agents that could be used in the second or third line. The response rates with these agents are from mid 20% to low 30%, and the median PFS is close to 7 months, which is significantly better if you compare it side by side with giving chemotherapy in the second line, where the median PFS is 2 to 4 months. It’s certainly an effective and promising option.

The challenge is that many patients develop resistance. There are established resistance mechanisms that occur, both in FGFRitself and in other parallel pathways. Second-generation agents are being tested in that space. If the patient has an IDH1 mutation, abrocitinib is approved in this space based on the ClarIDHy trial, which was the first molecularly targeted phase 3 study in biliary cancers. This randomized patients in a 2:1 fashion with abrocitinib vs placebo. It allowed crossover. The primary end point was PFS, and it met its primary end point. The PFS with abrocitinib was about 2.7 months vs 1.4 with placebo. The disease control rate was above 50% with abrocitinib compared with mid-20% with placebo.

Later, with longer follow-up, there was a trend in favor of abrocitinib for overall survival, about 10.5 months vs 7 with placebo. An adjusted analysis was done to account for the crossover—because the trial allowed crossover from placebo to abrocitinib—and 70% of the patients did cross over. When accounting for that crossover, and the analysis is adjusted for that, the difference in OS becomes more striking, with a hazard ratio of 0.49 and a median OS of 10.5 months with abrocitinib vs about 5 months with placebo. This is a novel, established option. I spent more time on this because this is a phase 3 trial, and these are final results. With infigratinib and pemigatinib, these are accelerated approvals based on phase 2 data, but they’re consistent data with targeting FGFR.

Lastly, I’ll mention that there are emerging therapies. These are not approved, but there are data for agents that target HER2 [human epidermal growth factor receptor 2], such as the compound known as CW25, as well as the combination of trastuzumab and pertuzumab, which have shown promise in HER2-amplified or HER2-mutated cholangiocarcinoma. This is something to keep in mind and refer to. The same with BRAF. There is a study known as ROAR that looked at the combination of BRAF and neck and showed promising activity in that space. A very small subset of patients may make it to the third line. Clinical trials are a priority in that space. If clinical trials aren’t an option, and if the patient had gemcitabine-cisplatin and then FOLFOX [5-fluorouracil, leucovorin, oxaliplatin], then some of the targeted agents that target FGFR orIDH could be used in third line, along with the other agents that we mentioned targeting HER2 and BRAF.

Transcript edited for clarity.