Novel approaches for the management of biliary tract cancer: today and tomorrow

1. Introduction

In this interview, we ask Dr. Alessandro Rizzo, Guest Editor of this special issue on biliary tract cancers and member of the Steering Committee of the GICO (Italian Cholangiocarcinoma Group) to offer his perspective on the many intriguing key developments that appear to be propelling opportunities for drug clinical trials and future potential treatments. Immune checkpoint inhibitors, liquid biopsy, molecular profiling and precision medicine which represent the gateways to enhanced therapeutic approaches, come under the spotlight.

2. BTC is not a single disease, anatomically or molecularly, but do most physicians recognize this, or is there a tendency to group them together and treat them as one?

Thank you for your question. Yes, BTCs include intrahepatic cholangiocarcinomas (iCCAs), extrahepatic cholangiocarcinomas (eCCAs), and gallbladder cancers (GBCs), representing approximately the 3% of all gastrointestinal malignancies in adult patients. Unfortunately, grouping together iCCAs, eCCAs, and GBCs under the broad category of BTC represents a long-standing issue, ‘the capital sin’, affecting most of clinical trials in this setting. In fact, the advent of in-depth sequencing has shown that iCCA, eCCA, and GBC present unique molecular profiles, with these anatomical subgroups mirroring distinct epidemiology, biology, prognosis and treatment options.

3. Recent years have seen the increased utilization of next-generation sequencing in clinical care. What is the role of NGS in BTC management?

The advent of NGS has allowed for a greater understanding of the biology and the pathogenesis of BTC. In particular, the affordability of this technique has provided an unprecedented amount of data on each BTC subgroup, opening the doors of a new era. As supported by most of international experts, all BTC patients with metastatic disease should undergo comprehensive genomic testing, since the addition of routine genomic profiling has the potential to allow researchers and clinicians to gain more insight into BTC biology.

4. The identification of molecular drivers of BTC offer the possibility of changing the standard of care, particularly for iCCA. Would you consider iCCA to be a poster child for precision medicine?

Over the last decade, as previously stated, the molecular landscape of BTC has begun to emerge, leading to the development of novel molecularly targeted treatments, especially in iCCA patients. In particular, after decades of ‘stagnation’, treatment paradigms are rapidly changing in iCCA, where targeting fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase 1 (IDH-1) and IDH-2 mutations has become reality. However, these specific aberrations are detected only in a small proportion of all patients diagnosed with advanced BTC; in addition, the emergence of acquired resistance to targeted treatments represents an unmet clinical need in this setting, with strategies to overcome resistance mechanisms remaining to be elucidated. Thus, if on the one hand there is no doubt that iCCAs have recently entered into the era of precision oncology and the approval of novel treatments has represented a ‘breath of optimism’, the identification of additional drivers and more effective treatments remains a mandatory need in BTC.

5. What is the most notable agent being assessed in clinical trials and why?

I would say pemigatinib for now, following the results of the FIGHT-202 study [1]. Notably enough, pemigatinib received accelerated approval in April 2020 in the USA, representing the first historical approval of a targeted therapy in the landscape of cholangiocarcinoma. In the phase II FIGHT-202 trial, impressive results have been observed in the specific patient population of previously treated, advanced cholangiocarcinoma harboring FGFR2 fusion or other rearrangement. After a median follow-up of 17.8 months, the 35.5% of patients showed an objective response, with median progression-free survival (PFS) and overall survival (OS) of 6.9 months and 21.1 months, respectively. In particular, the latter represents an important result, especially taking into account the inclusion of heavily pretreated patients with advanced disease – whose median survival is less than a year from the moment of diagnosis. In addition, the IDH-1 inhibitor Ivosidenib has reported interesting results in the ClarIDHy phase III trial [2], and the recently published ROAR trial has provided first evidence supporting the use of dabrafenib plus trametinib in patients with BRAF^V600E-mutated BTC [3].

6. It appears that liquid biopsy could play a crucial role in the diagnosis, characterization, and treatment of these aggressive hepatobiliary malignancies. How may this tool modify the management of BTC?

Liquid biopsy has enormous potential in this setting. According to studies conducted over the last decade, up to 50% of BTCs are expected to be eligible for molecularly targeted treatments, something that supports the incorporation of genomic profiling in routine clinical practice. Since the lack of tissue for molecular analyses represent an important obstacle for implementing tailor-made therapies, the use of liquid biopsy could overcome this issue. In addition, liquid biopsy has potential applications in all stages of BTC management, including earlier diagnosis, monitoring of treatment response and detection of resistance mechanisms. Thus, this tool could profoundly change current clinical practice, by moving from tissue to blood as a source of information. Further studies are warranted in this direction.

7. Immunotherapy has revolutionized the therapeutic landscape of several hematological and solid tumors. What is the role of immune checkpoint inhibitors in BTC patients?

I think this is a very important question. Certainly, immune checkpoint inhibitors have provided unprecedented benefits in immunologically ‘hot’ tumors such as melanoma, urothelial carcinoma, non-small cell lung cancer, and renal cell carcinoma. Unfortunately, this is not the case of BTC so far, where immunotherapy is still trying ‘to find its way’. However, interesting results have been recently highlighted for dual checkpoint inhibition and for the combination of systemic chemotherapy plus immunotherapy. Moreover, combinations including an immune checkpoint inhibitor plus a molecularly targeted treatment are being assessed, and results of these trials are awaited.

8. How do you see the future for biliary tract cancer patients changing in the next 5 to 10 years? Is there any one key avenue of research that could make waves during this time period?

At this moment, more than 50 clinical trials in phases I to III are evaluating molecularly targeted treatments and immune checkpoint inhibitors, as monotherapy or in combination with other anticancer therapies, with the hope of adding more therapeutic options in BTC patients. Thus, we will probably witness the advent of further treatments; in addition, I think the near future will see a deeper understanding of resistance mechanisms and a wider use of liquid biopsy. I also hope that BTC patients will be diagnosed early, at a time when the malignancy can be treated and cured. More than ten years after the publication of the landmark ABC-02 phase III trial, there is no doubt that the BTC medical community is called to devote further efforts in this direction in the near future.

Disclaimer

The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Taylor & Francis.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.