Publication

Article

Evidence-Based Oncology
April 2022
Volume 28
Issue 3
Pages: SP114-SP115

Conference Coverage: Cholangiocarcinoma Foundation 2022

Author(s):

Coverage from the 2022 annual meeting of the Cholangiocarcinoma Foundation, which met February 23-25 in Salt Lake City, Utah.

Clinical, Scientific Updates at CCF 2022 Highlight Advances in Cholangiocarcinoma

As recently as 2006, cholangiocarcinoma (or biliary duct cancer) did not have a standard of care, much less advanced treatments. However, the rise of precision medicine and research to create models of how this rare disease works have improved options for the 8000 patients diagnosed each year in the United States,1 according to the cochairs for the 9th Annual Cholangiocarcinoma Foundation (CCF) Conference, held February 23-25, 2022, in Salt Lake City, Utah, and online.

Lipika Goyal, MD, MPhil, assistant professor of medicine at Harvard Medical School and a faculty member in gastrointestinal medical oncology at Massachusetts General Hospital in Boston, offered an overview of the clinical developments in cholangiocarcinoma (CCA). In addition, Jesper B. Andersen, PhD, associate professor and group leader at the Biotech Research and Innovation Centre at the University of Copenhagen in Denmark, reviewed progress in basic science, especially the development of biomarkers, that is advancing treatment in the disease.

Andersen likened his early years of researching CCA at the National Institutes of Health (NIH) to Sisyphus pushing a boulder up the hill. Fifteen years ago, he said, the landscape was bereft not only of treatments but also cell lines for research. “There was nothing,” he said. Fast forward to 2022, and there have been great strides. Goyal highlighted a tripling in the number of clinical trials, and Andersen pointed to the soaring number of papers published in the field—including 2000 this past year—as signs of progress.

Goyal is best known for her work on how FGFR resistance develops and how patients can benefit for longer stretches from FGFR inhibitors, a new class of targeted therapy (the first, pemigatinib [Pemazyre], was approved for previously treated patients in 2020).2

Her talk reviewed recent progress in chemotherapy, targeted therapy, and immunotherapy. She said one reason for progress is that the field has moved beyond characterizing CCA purely by where it is in the body, and instead, looking at each tumor’s mutations. “Now we’re learning to segregate this disease into different molecular buckets,” Goyal said, with the hope that partnering with scientists can yield the same progress seen in melanoma, lung, or colon cancer.

Acquisition of tissue through biopsies and donations has allowed investigators to build models of the disease, which Goyal said are now used to develop “more rational clinical trials that have a better chance of helping patients.”

Chemotherapy. Goyal said the chemotherapy standard of gemcitabine and cisplatin would now be joined by the immunotherapy, durvalumab, based on recent results from the TOPAZ-1 trial (NCT03875235). These data were presented at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI).3 She also highlighted other new data presented at ASCO GI, which found that adjuvant treatment with S-1, an oral fluoropyrimidine derivative, improved overall survival when given after surgery.4

Additionally, Goyal reviewed a study led by the CCF that seeks to pinpoint which patients need adjuvant therapy after resection. One method being pursued is to collect patients’ blood after surgery for a liquid biopsy, as an analysis for circulating tumor DNA may reveal whether cancer is likely to recur.

Targeted therapy. Reviewing patients’ tissue after biopsy can reveal whether patients have a mutation driving the cancer—and in CCA, there is no shortage of targets, Goyal said. The 2020 breakthrough of achieving FDA approval for therapies that targeted FGFR2 alterations is just a start, she said.2 It’s what has caused experts in the field to think about CCA differently.
“Over time, we think of the different anatomic subtypes by mutation, as well,” Goyal said. A campaign to reach patients and urge them to ask about biomarker testing is just part of the solution. “The onus is on us, as oncologists, to offer [testing] to all patients, especially because now there are FDA-approved therapies.”

Basket trials, which study mutations across multiple tumor types, have been a boon for CCA research, as it’s still a rare disease despite rising numbers. In some cases, there wouldn’t be enough patients to merit an entire study, but the disease could be studied in an arm or even a few patients in a larger study. Today, patients with CCA can be included in clinical trials involving well-known therapies that have been used to treat other cancers so more is known about adverse events. Goyal offered the example of research with pertuzumab and trastuzumab, HER2 inhibitors that have been used for years in breast cancer, which have now demonstrated tumor shrinkage in CCA.

A first-in-human trial, involving an agent called RLY-4008, produced incredible results in a 35-year-old patient whose tumor was unresectable. He received the FGFR2-specific inhibitor, which caused his tumor to shrink 83%, to the point where he could have surgery.5 Studies like this are less risky than in the past, Goyal said. “A lot of oncologists don’t do phase 1 trials. Sometimes they [think], ‘Oh, the response rate is 5%.’ But we now have these models—we now have this way of interrogating tumors to figure out what the mutation [is],” she said. “Clinical trials in phase 1 are having much more efficacy than they used to.”

Immunotherapy. Goyal offered additional details on TOPAZ-1, noting that the patients who received durvalumab along with the standard chemotherapy combination had much better survival at 24 months—25% vs 10%. She highlighted the tail on the curve in the results, saying, “There’s a population of patients who are getting significant benefit at 2 years, even though the difference in median survival was not too different.”

Biomarker advances. In his talk, Andersen described how investigators in CCA have emerged from “the Dark Ages” and are catching up in precision oncology, including next-generation sequencing (NGS). Ten years ago, Andersen’s work at NIH led to the first genomic classification prognostic classifier in CCA, which is still used. At that time, Andersen identified that patients with poor prognosis had inflammation and higher levels of EGFR or HER2 expression and KRAS mutations. Those who lived longer had changes in genes involving immune responses, according to Anderson. In time, the work led to the identification of IDH1, KRAS, TP53, and other cancer drivers. The identification of the IDH1 mutation led to the 2021 approval of ivosidenib (Tibsovo).

A separate study classified existing drugs by the pathway of their response, with the hope of using off-the-shelf treatments (drugs already used to treat other cancers) to help specific groups of patients with CCA. The number of patients in the study being treated this way grew from 500 to 1500 in just a few years.

A half dozen important studies in the past 18 months have focused on single-cell genomics, which examines the individuality of cells, which is made possible by NGS. Andersen said this work helps answer important questions. “For example, with immunotherapy, we can start to understand why some will respond and some will not respond, because it gives an intensified view of the stromal and immune cell niche,” he said. This work also gets into the role of proteins and how cells interact with one another, Andersen added.
Biomarkers matter, he said, “because if we really are to make a difference in [CCA], we [must] diagnose the disease much earlier than today.”

Andersen explained how there are many types of biomarkers, including prognostic biomarkers, that can monitor both the development of the disease and the response to therapy. This can answer whether it makes sense to continue therapy.

Notably, bile duct cancers are being studied alongside more common cancers in major biomarker studies, such as the DELFI study (NCT04825834) at Johns Hopkins School of Medicine that is examining circulating tumor DNA, Anderson explained. Biomarker research may allow for greater matching of patients to drugs and even prompt investigators to take a second look at therapies that fared poorly in clinical trials. “If we now find the right patients, maybe we can also reuse some of those drugs that are already out there,” he said. 

References
1. Key statistics for bile duct cancer. American Cancer Society. Updated January 12, 2021. Accessed February 27, 2022. https://www.cancer.org/cancer/bile-duct-cancer/about/key-statistics
2. Jeremias S. FDA approves orphan drug pemigatinib for rare bile duct cancer cholangiocarcinoma. American Journal of Managed Care®. Published April 20, 2020. Accessed February 27, 2022. https://www.ajmc.com/view/-fda-approves-orphan-drug-pemigatinib-for-rare-bile-duct-cancer-cholangiocarcinoma
3. Oh DY, He AR, Qin S, et al. A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. Presented at: 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, January 20-22, 2022; San Francisco, CA. Accessed February 27, 2022.
4. Ikeda M, Nakachi K, Konishi M, et al. Adjuvant S-1 versus observation in curatively resected biliary tract cancer: a phase III trial (JCOG1202: ASCOT). J Clin Oncol. 2022;40(suppl 4):382. doi:10.1200/JCO.2022.40.4_suppl.382
5. Schram AM, Kamath SD, El-Khoueiry AB, et al. First-in-human study of highly selective FGFR2 inhibitor, RLY-4008, in patients with intrahepatic cholangiocarcinoma and other advanced solid tumors. J Clin Oncol. 2021;39(suppl 15):TPS4165. doi:10.1200/JCO.2021.39.15_suppl.TPS4165

Shroff: Multiple Targets in Cholangiocarcinoma Make Biomarker Testing Essential

The abundance of treatment targets in cholangiocarcinoma (CCA) means biomarker testing at diagnosis is “essential” and that next-generation sequencing is needed to clarify a treatment strategy, according to a speaker at the Cholangiocarcinoma Foundation (CCF) 2022 Annual Conference in Salt Lake City, Utah.

Rachna Shroff, MD, MS, associate dean of clinical and translational research and associate professor of medicine at the University of Arizona, offered a review of early-stage research in her February 24 talk, “The Hottest Targeted Therapies on the Horizon for Cholangiocarcinoma.”

Targeting IDH1 and IDH2. Shroff discussed a phase 1 dosing trial for Loxo Oncology’s LY3410738, a first-in-class covalent inhibitor of mutant IDH1, found in 20% to 30% of intrahepatic CCA diagnoses. It was described in a May 2021 abstract at the American Society of Clinical Oncology (ASCO) Annual Meeting as offering a “unique covalent binding mode,” increased potency, and a binding site that may work in “second-site” IDH1 mutations. Shroff said the investigational therapy appears to work in a pathway that would allow it to target IDH2 mutations as well.1 “That’s important here because thus far we do not have something in the clinic available for IDH2 mutations,” Shroff said.

Results seen in HER2. Shroff spent time discussing the MyPathway study (NCT02091141), which is examining currently approved therapies in non-indicated tumors. Results published in September 2021 showed that this approach has yielded results in HER2+ advanced biliary tract cancer when the well-known therapies pertuzumab and trastuzumab were used to treat 39 patients. After a median follow-up of 8.1 months, 9 patients achieved a partial response of 23%.2 “Clearly, HER2 is targetable,” Shroff said, noting that some patients stayed on therapy for much longer than the median follow-up.

Such a finding “sparks interest and makes us think that there are potentially ways to target this important pathway in biliary cancers.” Zanidatamab, a bispecific antibody targeting HER2, has also shown promise in a phase 1 study, she said. Results for 20 patients with CCA or gallbladder cancer, published at the 2021 ASCO Gastrointestinal Cancers Symposium, showed an overall response rate of 47% for the 17 evaluable patients.3 Based on these results, the HERIZON-GEA-01 study is proceeding, which will include about 100 patients with HER2-amplified biliary tract cancer, she said.4

NRG1 fusions. While rare, Shroff said, neuregulin-1 fusions are “incredibly important to find” because of their behavior. “NRG1 is the predominant ligand in HER3 and, to a lesser extent, HER4,” she said. “This pathway is involved with downstream activation of the HER pathways when you think through tumor proliferation and cellular dysregulation.”

She explained how seribantumab, an anti-HER3 monoclonal antibody, inhibits the downstream pathway by inactivating NRG1 and limiting HER2 and HER3 dimerization; these actions in turn impact P13K/AKT and MAP kinase pathways. In addition to the dual activity of the drug, Shroff said, so far seribantumab seems to be well tolerated. It will be further evaluated in a pivotal cohort of the CRESTONE trial (NCT04383210), studying patients without prior Pan-ERBB, HER2, or HER3 targeted therapy. CRESTONE also has 2 exploratory cohorts for patients with prior targeted therapy and those with specific types of NRG1 fusions.5

Finally, there is zenocutuzumab, which is being studied in multiple tumor types, including cholangiocarcinoma, through an NRG1 development program. A CCA patient showed a 32% reduction in target lesions, which was considered a partial response, Shroff said.6

DDR pathway.
DNA damage repair (DDR) studies could be particularly beneficial the 25% to 35% of Asian people who have alterations driving biliary tract cancer, which include the well-known BRCA1/2 genes. “There’s a large component of our patients who may have some potential sensitivity to PARP inhibitors,” Shroff said, explaining that olaparib (Lynparza) is being studied in the ACCRU 1702 study (NCT04042831).7

MDM2 and p53. Shroff concluded by mentioning a study with an experimental treatment that will target the MDM2 oncoprotein, which plays a role in p53 activity. The dual agent BI 907828 is being evaluated in in a first-in-human study (NCT03449381) of multiple advanced tumor types.8 “It seems to exert its impact in 2 different ways, through direct targeting of the MDM2-p53 as well as through some immunomodulation of the tumor microenvironment,” she said.
“There are many potential targets in biliary tract cancers,” Shroff said. “Upfront biomarker testing—I’m sure we’ve heard this 100 times already today—is essential. These rare alterations are crucial to find because now we have trials for these patients. And we may soon have drugs available for these patients. Comprehensive testing, looking for fusions, looking for alterations, mutations, amplifications is going to be very important here.”

References
1. Pauff JM, Papadopoulos KP, Janku F, et al. A phase I study of LY3410738, a first-in-class covalent inhibitor of mutant IDH1 in cholangiocarcinoma and other advanced solid tumors. J Clin Oncol. 2021;39(suppl 3):abstract TPS350. doi:10.1200/JCO.2021.39.3_suppl.TPS350
2. Javle M, Borad MJ, Azad NS, et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2021;22(9):1290-1300. doi:10.1016/S1470-2045(21)00336-3
3. Meric-Bernstam F, Hanna DL, El-Khoueiry AB. Zanidatamab (ZW25) in HER2-positive biliary tract cancers (BTCs): results from a phase I study. J Clin Oncol. 2021;39(suppl 3):abstract 299. doi:10.1200/JCO.2021.39.3_suppl.299
4. Buntz B. Zymeworks and its partner Beigene expand zanidatamab pivotal trial in Asia. Drug Discovery. December 9, 2021. Accessed February 28, 2022. https://www.drugdiscoverytrends.com/zymeworks-and-its-partner-beigene-expand-zanidatamab-pivotal-trial-in-asia/
5. Elevation Oncology. CRESTONE website. Accessed March 1, 2022. https://nrg1fusion.com/
6. Schram AM, O’Reilly EM, O’Kane GM, et al. Efficacy and safety of zenocutuzumab in advanced pancreas cancer and other solid tumors harboring NRG1 fusions. J Clin Oncol. 2021;39(suppl 15):3003. doi:10.1200/JCO.2021.39.15_suppl.3003
7. Olaparib in treating patients with metastatic biliary tract cancer with aberrant DNA repair gene mutations. ClinicalTrials.gov. Updated January 6, 2022. Accessed March 1, 2022. https://clinicaltrials.gov/ct2/show/NCT04042831
8. This study aims to find the best dose of BI 907828 in patients with different types of advanced cancer (solid tumors). ClinicalTrials.gov. Updated February 8, 2022. Accessed March 1, 2022. https://clinicaltrials.gov/ct2/show/NCT03449381

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