Novel Targeted Therapies Show Promise in Cholangiocarcinoma

Ghassan Abou-Alfa, MD, MBA

Advancements in precision medicine are driving a shift away from classification of cholangiocarcinoma (CCA) based on anatomical location toward categories based on molecular profile, paving the way for the development of new therapies, according to gastrointestinal (GI) cancer experts.

During a recent OncLive Peer Exchange^® roundtable, experts discussed novel targeted agents for CCAs progressing through the pipeline, such as infigratinib (BGJ398) and pemigatinib, which are selective pan-inhibitors of FGFR fusions/translocations being evaluated in phase III trials.^1,2

Another ongoing phase III trial in advanced CCA is investigating ivosidenib (Tibsovo), an IDH1 inhibitor that is FDA approved for acute myeloid leukemia.^3,4 Moderator Ghassan K. Abou-Alfa, MD, MBA, a lead investigator for the study, recently presented interim findings at European Society for Medical Oncology (ESMO) Congress 2019.⁴

These investigational efforts underscore the need for oncologists and their patients with advanced or metastatic CCA to learn about available phase III trials and request genetic testing at diagnosis to determine their eligibility.

Geographic Patterns Vary

A rare malignancy, CAA originates in the bile ducts and is typically classified as intrahepatic (iCCA) or extrahepatic (eCCA) according to site of origin within the biliary tree.⁵ The extrahepatic type is further subcategorized into perihilar or distal tumors based on location in the bile ducts.

Panelist Martin E. Gutierrez, MD, said that CCA accounts for approximately 3% of all GI malignancies diagnosed in the United States6 and estimated an overall incidence of 1 to 3 cases per 100,000 per year. “[There are] probably around…42,000 cases of CCA in the United States at any given time,” he said.

Most Western countries have a similarly low incidence of CCA. Study findings suggest, however, that the incidence is up to 40 times greater in Southeast Asian countries such as China and Thailand.⁷ Clusters of CCA have also been observed in limited regions of other countries, including Japan and northern India.⁷ Although most CCAs arise sporadically, Abou-Alfa said the elevated incidence in Asian countries is due primarily to liver fluke infection.⁷

Diagnostic difficulties make it difficult to determine the true incidence of CCA,⁸ which appears to be increasing worldwide.^6,9 The rise is driven primarily by an increase in cases of iCCA, because cases of the more prevalent eCCA have actually declined or remained stable.^6,9 A recent analysis of data from the United States Cancer Registry determined that new iCCA diagnoses rose almost 10% annually between 2010 and 2015 compared with an annual increase of 1.60% in new eCCA diagnoses between 2009 and 2015.⁶

It is unclear whether the trend in iCCA incidence results from increased exposure to known risk factors or changes in classification or coding.⁹ Andrew Zhu, MD, PhD, explained that iCCA has historically been prone to misdiagnosis as cancer of unknown primary (CUP). “As we’re getting better with our diagnostic tools, we realize at least a portion of those are actually not true known primary [cancers],” he said. Zhu was involved in a 2016 study of US trends in CCA incidence that showed diagnoses of CUP with CCA features decreased sharply as iCCA cases increased over a 40-year period.⁸

Andrea Wang-Gillam, MD, PhD, mentioned that a mixed phenotype of iCCA has histological features of hepatocellular carcinoma (HCC) and iCCA. The reported incidence of combined HCC-CCA varies across studies, from 0.4% to 14.2%.¹⁰ “The CCA is more aggressive, so we generally treat it as part of a CCA,” she said.

Diagnosing CCA subtype based on anatomical location can also lead to misdiagnosis, Abou-Alfa said. He cited the difficulty in distinguishing between iCCA and perihilar CCA as an example. The panelists agreed that as more is learned about the molecular differences between CCA subtypes, less emphasis will be placed on anatomical location and more on molecular signature, improving diagnostic accuracy.

Gene Targets Surface

Study findings have identified several potentially targetable genetic alterations in CCA. A recent study using next-generation sequencing to analyze 195 CCA samples (78% iCCA and 22% eCCA) found that almost half contained at least 1 potentially actionable genetic abberation.¹¹ The genetic profile varies between iCCA and eCCA¹² and between infectious and noninfectious CCA.¹³

The prevalence of genetic alterations varies among studies, but data suggest that KRAS mutations, HER2 amplification, and TP53 mutations are more common in eCCA than iCCA, whereas FGFR^1-3 aberrations, IDH1/2 mutations, and EGFR overexpression are more common in iCCA than eCCA.^7,12

The distribution of BRAF, PI3KCA, CDKN2A, and ARID1A aberrations and MET overexpression is fairly even between the CCA subtypes.^7,12,14 “The IDH1 mutations and the FGFR2 fusion are mutually exclusive. In other words, if you see the IDH mutation in patients…usually you don’t see the FGFR2 fusion and vice versa,” Zhu said.

Although agents targeting either FGFR or IDH1 alterations are furthest along in development, Abou-Alfa said, clinical trials may be available for other genetic targets, such as HER2 amplification, ROS1 rearrangement or BRAF mutations. “So it’s really important to make sure that we get as much information as possible,” he said

Wang-Gillam said her institution typically performs next-generation sequencing at diagnosis for all patients with CCA whenever adequate tissue is available. Gutierrez said insurance is more likely to cover sequencing for microsatellite instability, a biomarker used to determine eligibility for pembrolizumab (Keytruda), giving him an opportunity to simultaneously screen for IDH1 and FGFR2.

Teresa Macarulla, MD, said many hospitals in Spain are small and lack the resources to perform molecular analysis routinely for patients with CCA. “We try to convince these oncologists that they have to refer patients—especially those with iCCA—to bigger institutions…to find this targetable alteration and include patients in clinical trials.”

IDH1/2 Inhibitors

Multiple studies have established IDH-mutated tumors as a subtype of iCCA, Zhu said. “This mutation actually occurs much less frequently in eCCA,” he said. IDH2 mutations occur in 3% to 4% of iCCA tumors⁷, and data consistently show the rate of IDH2 mutations in eCCA is “probably in the neighborhood of 15% to 20%,” said Zhu.

Zhu and Abou-Alfa were investigators for a phase I dose-escalation study that assessed ivosidenib monotherapy in 73 patients with previously treated, IDH1-mutated, advanced CAA.¹⁵ Median progression-free survival (PFS) was 3.8 months (95% CI, 3.6-7.3), which Zhu described as reasonable. All responses were partial responses. “Interestingly, if you look at the tail of the curve, there seemed to be patients who were doing very well for a prolonged period of time,” he said. Abou- Alfa added that ivosidenib was very well tolerated, with GI adverse events (AEs) being the most common.

The panel discussed how the mechanism of ivosidenib lends itself to stabilizing tumor growth rather than tumor shrinkage. Macarulla said arresting tumor growth in the second or third line of therapy with minimal serious AEs is good news for patients and could allow them to receive other treatments that might act synergistically with ivosidenib.

The positive findings led to the phase III ClarIDHy trial (NCT02989857), which randomly assigned patients with IDH1-mutated unresectable or metastatic CCA 2:1 to ivosidenib or placebo.⁴ Patients had received 1 or 2 prior regimens. Interim data for 185 patients were presented at ESMO Congress 2019.

“At the time of disease progression… patients randomized to placebo were allowed to cross over,” said Zhu, a study investigator. “We were able to demonstrate that the risks of progression or death were reduced significantly by this very well-tolerated IDH-specific inhibitor.”

Median PFS was 2.7 months in the ivosidenib arm versus 1.4 months in the placebo arm, which met the primary end point (HR, 0.37; 95% CI, 0.25-0.54; P <.001).⁴ No significant difference was observed between the cohorts in overall survival (OS), which Gutierrez implied could be because 57% of patients in the placebo arm crossed over to the ivosidenib arm.

Macarulla, who joined Abou-Alfa and Zhu as an investigator for ClarIDHy, pointed out that the study is the first phase III trial of a targeted therapy to show a clinical benefit in patients with IDH1-mutated CAA. The most common treatment- related AEs (TRAEs) in the ivosidenib arm were nausea (32.1%), diarrhea (28.8%), fatigue, (23.7%), cough (19.2%), abdominal pain and ascites (18.6% each), decreased appetite (17.3%), and anemia and vomiting (16.0% each).⁴

FGFR2 Inhibitors

Infigratinib

FGFR2 alterations are found in 13% to 17% of patients with iCCA and rarely in patients with eCCA.^7,16 Infigratinib is a kinase inhibitor selective for FGFR1-3 that showed promising activity against FGFR2-positive iCCA in a phase II multicenter trial (NCT02150967). Investigators, which included Abou-Alfa, Macarulla, and Zhu, presented updated findings in March 2019 for a cohort of 71 previously treated patients who had an FGFR2 fusion, mutation, or amplification.¹⁷ In patients who received 2 or more prior lines of therapy who Zhu said lacked additional treatment options, infigratinib produced “a very impressive overall response rate [ORR] approaching 20%.”¹⁷ In patients who received no more than 1 prior therapy, the ORR was 40%. Median PFS for the overall population was 6.8 months (95% CI, 5.3-7.6), and median OS was 12.5 months (95% CI, 9.9-16.6).¹⁷ Generally, nontargeted therapies are associated with single-digit response rates and a median PFS of 3 months in patients with advanced CAA.¹⁶

Some safety concerns arose, which Gutierrez described as on-target effects of infigratinib. The most frequent TRAE was hyperphosphatemia, which occurred in 73.2% of patients.¹⁷ Gutierrez said hyperphosphatemia was easily managed with treatment interruption, use of phosphate- lowering agents, and diet control. “Then you can usually continue treating those patients,” he said.

Other common TRAEs (all grades) included fatigue (49%), stomatitis (45%), alopecia (38%), and constipation (35%).¹⁷ The most common grade 3/4 TRAEs were hypophosphatemia (14.1%), hyperphosphatemia (12.7%), and hyponatremia (11.3%).¹⁷ He added that a small number of patients also experienced eye toxicities.

Wang-Gillam recommended checking patients phosphate levels regularly. “When it’s high, you can give diuretics to counteract poor diet control; if it is low, you replace it. It doesn’t really come as a barrier for patients to continue treatment if you manage it well,” she said.

The phase III PROOF trial (NCT03773302) recently began recruiting and is comparing single-agent infigratinib versus gemcitabine plus cisplatin as first-line therapy for patients with advanced, metastatic, or inoperable CCA and an FGFR alteration.² The study will allow patients with disease progression after 8 cycles of chemotherapy to cross over to the infigratinib arm. Zhu said the trial “has a very strong scientific rationale” and that he strongly encouraged clinicians to consider recommending it to patients.

Pemigatinib

The panel also discussed data from FIGHT-202 (NCT02924376), a phase II trial of pemigatinib, another novel pan-FGFR1-3 inhibitor; trial findings have resulted in a priority review designation from the FDA with adecision deadline of May 30, 2020.¹⁸ The study included 146 patients with previously treated locally advanced or metastatic CAA. The ORR in the cohort of 107 patients with an FGFR2 rearrangement/fusion was 35.5% (95% CI, 26.5%-45.4%) with 3 complete responses. Median PFS was 6.9 months (95% CI, 6.2-9.6), and median OS was 21.1 months (95% CI, 14.8-not reached).¹⁸

No responses were observed in patients with other or no FGF/FGFR gene alterations. The rate of hyperphosphatemia was 60% in this trial (all 18

The study demonstrated “very impressive results” for previously treated patients, Macarulla said. Abou-Alfa, who was involved in the phase II study, said the results provided the rationale for moving forward with the phase III FIGHT-302 study (NCT03656536) for patients with advanced, metastatic, or unresectable CCA and FGFR2 translocations.¹ The trial is comparing first-line therapy with pemigatinib versus gemcitabine plus cisplatin and permits patients in the chemotherapy arm to cross over if their disease progresses.^1,2

TAS-120

Zhu said he and several colleagues analyzed tumor tissue and circulating tumor DNA from 3 patients with FGFR2 fusion—positive iCCA who acquired resistance to infigratinib and discovered the emergence of “very meaningful mutations… in the FGFR kinase domain” that may have altered binding of infigratinib.¹⁹

Investigators subsequently conducted a phase I proof-of-concept study (NCT02052778) of another novel pan-FGFR inhibitor, TAS-120, in 4 patients with FGFR2-fusion-positive iCCA who acquired resistance to infigratinib or another FGFR2 inhibitor.¹⁹ TAS-120 produced a partial response in 2 patients and stable disease in the other 2 patients, which persisted for 5 to 17 months.

Click to Enlarge

Zhu said the study revealed the potential of next-generation FGFR inhibitors to overcome the emerging mutations. Abou-Alfa said that although it is premature to advocate for a second biopsy in patients with acquired resistance to infigratinib or pemigatinib, the work is important because it may reveal new actionable genetic alterations and open the door to new targeted therapies.

References

1. Bekaii-Saab TS, Valle JW, Borad MJ, et al. Trial design for a phase 3 study evaluating pemigatinib (INCB054828) versus gemcitabine plus cisplatin chemotherapy in first-line treatment of patients with cholangiocarcinoma with FGFR2 rearrangement. J Clin Oncol. 2019;37(suppl 4; abstr TPS462). doi: 10.1200/JCO.2019.37.4_suppl.TPS462.
2. Javle M, Kelley RK, Roychowdhury S, et al. A phase II study of infigratinib (BGJ398) in previously-treated advanced cholangiocarcinoma containing FGFR2 fusions. Hepatobiliary Surg Nutr. 2019;8(suppl 1; abstr AB051). doi: 10.21037/hbsn.2019.AB051.
3. Tibsovo [prescribing informtaion]. Cambridge, MA: Agios Pharmaceuticals, Inc; 2019. www.accessdata.fda.gov/drugsatfda_docs/label/2019/211192s001lbl.pdf. Accessed November 22, 2019.
4. Abou-Alfa GK, Macarulla Mercade T, Javle M, et al. ClarIDHy: a global, phase III, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. Ann Oncol. 2019;30(suppl 5; abstr LBA10_PR). doi: 10.1093/annonc/mdz394.027.
5. NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancers, version 3.2019. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Updated August 1, 2019. Accessed October 30, 2019.
6. Patel N, Benipal B. Incidence of cholangiocarcinoma in the USA from 2001 to 2015: a US cancer statistics analysis of 50 states. Cureus. 2019;11(1):e3962. doi: 10.7759/cureus.3962.
7. Bridgewater JA, Goodman KA, Kalyan A, Mulcahy MF. Biliary tract cancer: epidemiology, radiotherapy, and molecular profiling. Am Soc Clin Oncol Educ Book. 2016;35:e194-e203. doi: 10.1200/edbk_160831.
8. Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-year trends in cholangiocarcinoma incidence in the U.S.: intrahepatic disease on the rise. Oncologist. 2016;21(5):594-599. doi: 10.1634/theoncologist.2015-0446.
9. Khan SA, Tavolari S, Brandi G. Cholangiocarcinoma: epidemiology and risk factors. Liver Int. 2019;39(suppl 1):19-31. doi: 10.1111/liv.14095.
10. Stavraka C, Rush H, Ross P. Combined hepatocellular cholangiocarcinoma (cHCC-CC): an update of genetics, molecular biology, and therapeutic interventions. J Hepatocell Carcinoma. 2018;6:11-21. doi: 10.2147/JHC.S159805.
11. 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: 10.1158/1078-0432.CCR-18-0078.
12. Pellino A, Loupakis F, Cadamuro M, et al. Precision medicine in cholangiocarcinoma. Transl Gastroenterol Hepatol. 2018;3:40. doi: 10.21037/tgh.2018.07.02.
13. Valle JW, Lamarca A, Goyal L, Barriuso J, Zhu AX. New horizons for precision medicine in biliary tract cancers. Cancer Discov. 2017;7(9):943-962. doi: 10.1158/2159-8290.CD-17-0245.
14. Simile MM, Bagella P, Vidili G, et al. Targeted therapies in cholangiocarcinoma: emerging evidence from clinical trials. Medicina (Kaunas). 2019;55(2):pii:E42. doi: 10.3390/medicina55020042.
15. Lowery MA, Burris HA 3rd, Janku F, et al. Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study. Lancet Gastroenterol Hepatol. 2019;4(9):711-720. doi: 10.1016/S2468-1253(19)30189-X.
16. 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.
17. Javle MM, Borbath I, Clarke SJ, et al. Infigratinib versus gemcitabine plus cisplatin multicenter, open-label, randomized, phase 3 study in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: the PROOF trial. J Clin Oncol. 2019;37(suppl 15; abstr TPS4155). doi 10.1200/JCO.2019.37.15_suppl.TPS4155.
18. Vogel A, Sahai V, Hollebecque A, et al. FIGHT-202: a phase II study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA). Ann Oncol. 2019;30(suppl 5; abstr LBA40). doi: 10.1093/annonc/mdz394.031.
19. Goyal L, Shi L, Liu LY, et al. TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma. Cancer Discov. 2019;9(8): 1064-1079. doi: 10.1158/2159-8290.Cd-19-0182.