Hot Topics on Cholangiocarcinoma and Biliary Tract Cancer Presented at ASCO 2020

Several hot topics were presented at the recent ASCO 2020 annual meeting about cholangiocarcinoma (CCA), which I would briefly discuss here. First, it was very exciting to see 3 important studies regarding immunotherapy for CCA, which may represent a step forward in the development of CCA therapies.

The first study was presented by Do-Youn Oh, MD, PhD, Medical Oncology, Seoul National University Hospital, South Korea, and colleagues [Read More].

This phase 2 clinical trial is investigating the use of immunotherapy with durvalumab (Imfinzi) and the CTLA-4 inhibitor tremelimumab, in combination with gemcitabine and cisplatin chemotherapy. This interesting study has 3 components that include a biomarker cohort consisting of chemotherapy followed by chemoimmunotherapy, given sequentially. The study included patients with advanced biliary tract cancer and has 2 additional cohorts, a 3-drug cohort consisting of gemcitabine, cisplatin, and durvalumab, and a 4-drug combination arm consisting of gemcitabine, cisplatin, durvalumab, and tremelimumab.

The overall response rate (ORR) reported is very impressive, with approximately 70% in the 3-drug and the 4-drug combination arms, and for the first time showing a 50% response rate for the biomarker cohort. The duration of response was also good, between 9 months and 11 months, and the progression-free survival (PFS) was 11 months to 13 months, with a median overall survival (OS) of 18 months to 20 months.

These are certainly very promising results. The caveat here is that this was a biomarker- enrichment study, with a limited sample size. Most patients had intrahepatic CCA, a cohort that has a relatively good prognosis.

However, these results are certainly exciting. There was no significant difference between the 3-drug and 4-drug combination cohorts, but the study was not powered to detect these differences. The toxicities are reasonable. This combination will be further explored in a phase 3 clinical trial.

Let us juxtapose these results with 2 other immunotherapy studies. One study was led by Oliver Klein, FRACP, MD, Olivia Newton-John Cancer Research Institute, Heidelberg, Australia [Read More]. This was a study of ipilimumab (Yervoy) and nivolumab (Opdivo) for the treatment of rare tumors, and the investigators included a subset of 39 patients with biliary tract cancer.

In these 39 patients, the ORR was 24% and a clinical benefit response was seen in 45%. The PFS was low, and the duration of response varied from 2 month to 26 months, indicating that these data are still immature. Another interesting finding in this study was that 5 of the 13 patients with a response had gallbladder cancer—an orphan disease that needs further investigation.

The third immunotherapy study was by Vaibhar Sahai, MBBS, MS, Leader, Gastrointestinal Medical Oncology Section, University of Michigan, Ann Arbor, and his colleagues from University of Michigan [Read More]. This was a phase 2 clinical trial that randomized 71 patients to front-line immunotherapy with ipilimumab and nivolumab compared with gemcitabine and cisplatin chemotherapy plus nivolumab immunotherapy. The primary end point was 6-month PFS rate.

It was disappointing that the immunotherapy alone arm did rather poorly, with 4.1 months PFS. The chemotherapy plus immunotherapy arm did much better, with a PFS of 8.8 months. This is the PFS normally seen with chemotherapy alone. The investigators wisely remarked that it was unclear whether the addition of immunotherapy to chemotherapy resulted in a significant therapeutic advantage.

Overall, these 3 studies suggest a promising role for immunotherapy in the setting of these rare cancers. That role may be in the form of immunotherapy combinations that target PD-1 or PD-L1 plus CTLA-4, along with chemotherapy. Of note, this strategy shows good safety and tolerability. One caveat is that the Korean study was limited to Asian patients. It has previously been noted that Asian patients have better outcomes with immunotherapy than other populations.

Let us move to the next set of 3 studies related to targeting FGFR2 gene fusions in patients with CCA. Many of the FGFR-targeted drugs have been positioned for the second line setting after chemotherapy. No randomized study has previously shown benefit with FGFR inhibitors compared with second-line chemotherapy, such as the FOLFOX regimen.

Our group investigated the clinical outcomes of patients with CCA and FGFR2 genetic aberrations with standard second-line chemotherapy in a clinical trial in which most patients received the targeted therapy infigratinib (BGJ398), an FGFR inhibitor, in the third-line setting. In this study, which was presented at ASCO 2020 [Read More], we looked at the outcome with infigratinib and second-line chemotherapy.

We reported that the outcome with second-line chemotherapy with agents such as FOLFOX is not better in patients with FGFR fusions than in patients with FGFR wild-type cases. The PFS with second line chemotherapy was 4.6 months, and the response rate 5%, which is the same rate that was seen with FOLFOX in the ABC-06 clinical trial. This retrospective analysis indicates that the use of targeted FGFR inhibitors may have a better outcome than second-line standard-of-care chemotherapy.

Another study led by Lipika Goyal, MD, MPhil, Medical Oncologist, Tucker Gosnell Center for Gastrointestinal Cancers, Massachusetts General Hospital, Boston, and colleagues also discussed the natural history of FGFR-altered CCA [Read More].

In this study, Dr Goyal and her colleagues showed that CCA with FGFR alterations is a different disease, in which patients have intrinsic better biology. The study included 135 patients—the largest patient series so far reported for FGFR-altered CCA. The OS was 36 months, which is longer than what we expect for metastatic or advanced unresectable CCA. In this study, the OS with first-line gemcitabine plus cisplatin was similar or perhaps slightly inferior to what has been reported in previous studies with FGFR wild-type cases—approximately 6 months. The interesting findings in this new study is that most patients with FGFR fusions have normal CA 19-9 levels, and a high predilection for bony metastasis.

In the Clinical Science Symposium during the ASCO meeting, Dr Goyal also presented the results of the FOENIX-CCA2 phase 2, open-label clinical trial of futibatinib, an oral FGFR inhibitor, in patients with intrahepatic CCA and FGFR2 fusions or other genetic alterations [Read More]. This study showed that futibatinib is a very active agent in this patient population. Among the 67 patients discussed at the meeting, the ORR was 34%, with a 76% disease control rate.

The interesting thing was the fast time to response—an average of 1.6 months, indicating rapidity of the antitumor effect. The duration of response was about 6 months, which is what is seen with FGFR inhibitors. The toxicity profile was also typical to this drug class, including hyperphosphatemia, but there was a higher incidence of grade 1 and grade 2 diarrhea. We hope to see additional agents approved for patients with CCA and FGFR alterations.

Another second-line study was the TreeTopp study, a randomized phase 2 clinical trial comparing second-line varlitinib versus capecitabine (Xeloda) [Read More]. Varlitinib is a pan-HER inhibitor, including HER1, HER2, and HER3. In this phase 2 randomized second-line clinical trial, we combined varlitinib with capecitabine versus capecitabine plus placebo. The primary end point of the study was PFS, and the results were eagerly anticipated

But the final analysis of the study showed no statistical difference in the hazard ratio of PFS or OS. This study was not powered for subgroup interactions. There was an interesting signal noted in patients with gallbladder cancer, which showed a hazard ratio of 0.55. Another interesting finding was the differences seen between female and male patients, indicating that varlitinib may have a higher activity based on gender.

Another second-line study was led by Jin Won Kim, MD, PhD, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea. This phase 2 clinical trial enrolled 120 in Korea and compared the use of modified FOLFOX or modified FOLFIRI after first-line chemotherapy [Read More].

The 6-month OS was not statistically different between the 2 arms. This study provides additional information regarding the use of mFOLFIRI in the second-line setting, suggesting that for patients who cannot tolerate mFOLFOX, this may be a reasonable combination to consider.

Getting biopsies in patients with CCA continues to be difficult, because of the location of the tumor. Therefore, we need to consider liquid biopsies as a diagnostic option. The next 2 studies are related to liquid biopsy and detection of circulating tumor cell DNA (ctDNA). A study presented by Elia Aguado-Fraile, PhD, of Agios Pharmaceuticals, looked at IDH1 mutations in CCA, based on ctDNA, which were then correlated with response to therapy [Read More].

Of the 250 patients in this study, 193 had ctDNA, showing 92% concordance rate between the blood and the tumor, which is exciting. That suggests that this may be a valuable modality to detect mutations in this patient population. In this study, serial ctDNA was collected and showed that when the ctDNA cleared or could no longer be detected on serial liquid biopsies, that correlated with a better PFS than a persistence of ctDNA.

A study led by Jeffrey S. Ross, MD, Medical Director of Foundation Medicine, Cambridge, MA, looked at genetic aberrations in the primary tumor, in metastatic tumor, and in liquid biopsies [Read More]. These 3 modalities are different ways of looking at genetic aberrations within the tumor. It will be important to detect the genetic differences between the primary and the metastatic sites, and between solid or liquid biopsies, and indeed the investigators found some differences. For example, the incidence of KRAS was higher in liquid than in solid biopsies.

The team suggested that some of the intrahepatic CCA tumors were perhaps mislabeled. There was also a discussion about tumor heterogeneity, based on the assumption that liquid biopsies may detect areas of a tumor that are not detected with a needle biopsy. However, the study found a lower incidence rate of FGFR fusions in liquid biopsies.

Walid L. Shaib, MD, Medical Oncologist, Winship Cancer Institute of Emory University, Atlanta, GA, and his colleagues investigated the role adjuvant chemoradiotherapy [Read More] for biliary tract cancer. Based on the previous results of the BILCAP study, adjuvant capecitabine is currently the standard in the adjuvant setting, but what is the impact of radiation therapy in the adjuvant setting? The team from Emory University looked at data from the National Cancer Database of 240 patients with extrahepatic CCA who received adjuvant chemoradiotherapy versus chemotherapy.

This retrospective analysis showed an improvement in OS with chemoradiotherapy versus chemotherapy alone, with a hazard ratio of 0.64. One of caveats was that the study cohorts were unbalanced, with 147 patients receiving chemoradiation versus 89 receiving chemotherapy alone. It may be reasonable to assume that a patient’s physical condition might have played a role in the treatment selection. Regardless, these are very important data for future reference.