The Role of Molecular Therapy in Intrahepatic Cholangiocarcinoma

Gregory Gores, MD

Gregory Gores, MD

Two fibroblast growth factor receptor (FGFR) inhibitors TAS-120 and BGJ398, are under investigation for targeted treatment of patients with intrahepatic cholangiocarcinoma (iCCA) who harborFGFR2mutations, said Gregory Gores, MD. Oncologists treating this disease are excited about the results, which may begin to serve an unmet need for approved agents that can be used in the community setting.

The ongoing phase II FOENIX-101 trial, which plans to enroll 100 patients withFGFR2aberrations and locally advanced or metastatic iCCA, is exploring the use of TAS-120 in this population of patients (NCT02052778). The qualifications for this trial include prior treatment with gemcitabine plus platinum-based chemotherapy. The study’s primary endpoint is objective response rate (ORR) and no data have been reported thus far.

The study of BGJ398, however, has demonstrated meaningful clinical activity in the 66 patients enrolled in the phase II study. The drug showed an ORR of 14.8%, which was increased to 18.8% in patients withFGFR2fusions, and a median progression-free survival (PFS) of 5.8 months. The trial is actively recruiting more patients withFGFR2gene fusions or translocations or otherFGFRgenetic alterations (NCT02150967).¹

A promising IDH1 inhibitor ivosidenib (Tibsovo) is also in development to target patients with isocitrate dehydrogenase-1 (IDH1) mutations. Ivosidenib showed a significant improvement in PFS compared with placebo, meeting its primary endpoint. The data were presented at the 2019 ESMO Congress showing a 63% reduction in the risk of progression or death.²

As more treatments for molecularly targeted subpopulations of patients with iCCA are developed, the need for the molecular testing in these patients is increased to identify these patients who can benefit from such targeted treatments, Gores highlighted.

In an interview withTargeted Oncology, Gores, professor of medicine, University of Minnesota, explained the role of molecular therapy and the use of genetic testing to guide treatment of iCCA.

TARGETED ONCOLOGY:Can you provide an overview of your presentation on pathogenesis and systemic management of iCCA and the role of molecularly-targeted therapy?

Gores: I reviewed the genetic aberrations that occur in iCCA, specifically the ones that can be targeted. In particular, there has been a lot of interest in the fibroblast growth factor receptor-2 (FGFR2) fusions and the targeted therapies for theseFGFR2fusion driver genes. The molecular alterations are complex but occur in up to 15% of patients with iCCA. The updated data using targeted therapies have given an efficacy signal and also have demonstrated that there are resistance mechanisms. Different agents are now being tested to avoid the resistance mechanisms and see if they confer greater efficacy and those trials are ongoing.

The other genetic aberration that is of great interest is isocitrate dehydrogenase (IDH)-1 mutations. These aberrations can also be targeted with relatively non-toxic therapy. There are approved agents for the treatment of leukemia, and they're clinically available. A recent trial was conducted, and although the results have not been released, they suggest that the trial met the PFS endpoint. We're anticipating the results of that study.

There are a few other aberrations likeBRAFandNRTKmutations, which can be treated, although they are less common in iCCA.

TARGETED ONCOLOGY:What role does genetic testing play in treatment of this disease?

Gores: Unlike many other cancers, genetic sequencing in iCCA treatment is important. There are many targetable mutations that one could identify such asFGFR2fusions,IDHmutations,BRAFmutations, andNRTKmutations. There are also patients with microsatellite instability who can have dramatic responses to checkpoint inhibitors.

TARGETED ONCOLOGY:What targeted therapies are available for treatment of iCCA?

Gores: For iCCA, the standard of care is gemcitabine (Gemzar) and cisplatin.

For theFGFR2aberrations, there are 2 published data sets on using BGJ398. There was a surprising disease control rate in this subgroup of patients. The drug was reasonably tolerated. But there were a number of escape mutations that occurred within the kinase finding pocket and those are called gatekeeper mutations. BGJ398 is a reversible inhibitor.

There are now irreversible inhibitors such as TAS-120, which is in clinical trials and it's been demonstrated in humans that TAS-120 is able to inhibit FGFR2 kinase proteins, despite these gatekeeper mutations. There's a lot of interest and anticipation of these newer agents for this subgroup of patients with iCCA.

For theIDH1mutation, we're all waiting for data to published, or at least for it to become public so it can be evaluated, and learn more about the efficacy and the potency of these agents.

TARGETED ONCOLOGY:Are there any new agents under investigation in this space?

Gores: There are several IDH1 inhibitors available, and there are 4 or 5 different companies with FGFR2-targeted therapies. There a lot of activity going on for those 2 subgroups. This is an active field and people should be aware of what’s going on.

As long as we're talking about targeted therapy, the immunotherapy results have been disappointing in patients who don't have microsatellite instability. The response rates may be as low as 6% in one study.

References

1. Javle M, Lowery M, Shroff RT, et al. Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma.J Clin Oncol. 2018;36(3):276-282. doi: 10.1200/JCO.2017.75.5009.
2. Abou-Alfa GK, Maraculla TM, Javle M, et al. ClarIDHy: A global, phase 3, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. Presented at: 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA10_PR.