Comprehensive Genomic Testing Alters the Rapidly Evolving Cholangiocarcinoma Treatment Landscape

The role of comprehensive genomic testing in patients with cholangiocarcinoma has become more pronounced as more is learned about the biology of the disease and as more agents are being developed to target associated alterations, according to Daniel Lin, MD, MS.

“What we've seen in many gastrointestinal cancers, and biliary cancer is a good example, is the key role that comprehensive genomic testing can play for patients [in that it can be used] to guide their treatment [decisions] and to expand their options,” Lin said.

Fifteen to 20% of all patients with biliary tract cancers have tumors that harbor IDH mutations, while 10% to 15% of tumors harbor FGFR mutations.¹ In recent years, many options targeting these alterations have emerged in the pipeline and impacted the outcomes of these patients.

For example, ivosidenib (Tibsovo) resulted in improved progression-free survival (PFS; HR, 0.37; 95% CI, 0.25-0.54) and overall survival (OS) after adjustment for crossover (HR, 0.49; 95% CI, 0.34-0.70) in previously treated patients with IDH1-mutated cholangiocarcinoma, according to data from the pivotal phase 3 ClarIDHy trial (NCT02989857).²

For previously treated patients with cholangiocarcinoma and FGFR2 fusions or rearrangements, infigratinib elicited an overall response rate of 23.1%, with a median duration of response of 5.0 months and a median PFS of 7.3 months.³ “For patients who have been previously exposed to chemotherapy who harbor this alteration, this is another clinically meaningful therapy,” noted Lin. Other FGFR inhibitors under exploration includepemigatinib (Pemazyre) and futibatinib.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on Gastrointestinal Malignancies, Lin, a medical oncologist and assistant professor at the Sidney Kimmel Cancer Center of Jefferson Health, discussed pivotal trials examining important targeted agents for patients with cholangiocarcinoma and the importance of comprehensive genomic testing to guide treatment decisions.

OncLive®: How would you say findings from the phase 3 ClarIDHy trial have impacted clinical practice?

Lin: With the ClarIDHy trial, and also with the infigratinib trial and all the FGFR inhibitor trials, is that comprehensive genomic testing can make a huge difference for patients [with biliary cancers] in terms of expanding options and finding meaningful therapies. ClarIDHy, [which examined] the IDH1 inhibitor ivosidenib, clearly demonstrated an improvement in both PFS as well as OS in patients with IDH1 mutations who were previously exposed to chemotherapy, after you accounted for all the crossover that occurred. [Ivosidenib] is certainly a clinically meaningful treatment option to offer for patients with cholangiocarcinoma with an IDH1 alteration.

With regard to the phase 2 trial with infigratinib, what stood out to you from those data?

The same theme in that patients with this specific alteration had very good disease control rate [DCR]. In this particular study, the ORR was approximately 25%, and the median PFS was about 7 months. As we've seen in most of the FGFR inhibitor trials, manageable toxicities [have been observed] with this [agent].

Infigratinib is not the only FGFR inhibitor under exploration; pemigatinib and futibatinib are also being examined in these patients. How do these agents compare with one another?

The key takeaways when you're comparing all those trials, is that the pemigatinib trial had a little bit more [patients who were in the] second line as opposed to third line, compared with the futibatinib and infigratinib trials. Really, when we look at cross-trial comparisons, which generally we are told not to do but we do it anyway, we found that the DCRs are fairly similar, so a little over 80% across these trials. The median PFS seems to always fall around 7 months, maybe slightly less in terms of the response rate for the infigratinib trial, but it stacked up pretty well, in comparison. With all the FGFR inhibitors, it's going to be interesting [to see] where they fall in terms of the treatment landscape.

Do you recommend comprehensive sequencing over single-gene testing for IDH1 and FGFR mutations? What advantages does the former have over the latter?

Yes. With comprehensive sequencing, the advantages would be that we not only are looking for specific alterations, but what is especially relevant, is looking to see whether there are any other alterations of interest, particularly if they open access to other clinical trials for these patients.

For example, in some of my patients, I sometimes can come across CDK-related alterations. Another relevant [alteration] in terms of biliary cancers, for which we don't necessarily have large phase data but they will still be clinically meaningful, are BRAF mutations. BRAF inhibition, as well as ErbB2 and HER2 alterations, can open possibilities for targeted anti-HER2 therapy.

References

1. Lowery MA, Ptashkin R, Jordan E, et al. Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: potential targets for intervention. Clin Cancer Res. 2018;24(17):4154-4161. doi:1158/1078-0432.CCR-18-0078

2. Zhu AX, Macarulla T, Javle MM, et al. Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. J Clin Oncol. 2021;39(suppl 3):266. doi:10.1200/JCO.2021.39.3_suppl.266

3. Javle MM, Roychowdhury S, Kelley RK, et al. Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement. J Clin Oncol. 2021;39(suppl 3):265. doi:10.1200/JCO.2021.39.3_suppl.265