Cholangiocarcinoma Awareness Day: Advances in Frontline and Later BTC Therapies

Nathan Bahary, MD, PhD

The biliary tract cancer (BTC) setting has seen expanding treatment options thanks to the approvals of therapies that offer new mechanisms for narrowly targeting the disease and extending survival for patients, including those with cholangiocarcinoma, an aggressive biliary tract epithelial malignancy.

“The field has changed in the sense that there's a realization that there are some novel chemotherapy combinations that can improve survival,” said Nathan Bahary, MD, PhD, in an interview with Targeted Oncology^TM. “As well, a further advent of targeted therapies has set the stage for multiple paradigm shifts in treating cholangiocarcinoma.”

In unresectable BTC, including cholangiocarcinoma, the phase 3 TOPAZ-1 trial (NCT03875235) was practice changing because it supported the addition of durvalumab (Imfinzi) to the prior preferred primary therapy of combination chemotherapy cisplatin plus gemcitabine.¹

Research is ongoing in determining the optimal approach to subsequent therapies. The efficacy of therapies designed to target molecular markers including FGFR, IDH, BRAF, and NTRK has made molecular testing a vital part of pathology. Immunotherapies, such as pembrolizumab (Keytruda), may be effective in patients with microsatellite instability–high (MSI-H) tumors, high tumor mutational burden (TMB), or high PD-L1 expression.

Bahary, division chief of medical oncology and director of clinical cancer research at the Allegheny Health Network (AHN) Cancer Institute, discussed adapting to these new therapy options and what the future holds for improving care for patients with cholangiocarcinoma.

Targeted Oncology^TM: How has the field of BTC treatment, particularly cholangiocarcinoma, changed over the past year?

BAHARY: Perhaps the most interesting one is the TOPAZ-1 trial. In this trial, durvalumab was added to gemcitabine and cisplatin and compared with cisplatin and gemcitabine alone. Durvalumab is an immune checkpoint inhibitor. Patients who had untreated locally advanced or metastatic intrahepatic or extrahepatic BTC were randomly assigned to the standard dosing of gemcitabine/cisplatin or gemcitabine/cisplatin plus durvalumab. Patients received chemotherapy for up to 8 cycles, followed by durvalumab or placebo until disease progression or toxicity.

What was fascinating was that the durvalumab-containing therapy significantly improved overall survival [OS], and the primary end point was reached. More interestingly than that was about twice as many individuals were still alive at 24 months, about 25% versus about 10% who didn't receive durvalumab.¹

Another interesting point was the higher objective response rate [ORR] with durvalumab, and it didn't appear to add significant toxicity. There is a nice tail on that Kaplan-Meier curve for the triplet therapy, suggesting that the immune checkpoint inhibitor alone might be a way of being able to give patients the benefit of survival and quality of life without giving them the toxicity of the systemic chemotherapy.

What other recent trials have impacted treating patients with cholangiocarcinoma?

The PRODIGE 38 AMEBICA trial [NCT02591030] randomly assigned about 190 patients with advanced BTC, most of whom had cholangiocarcinomas, to triplet chemotherapy with modified FOLFIRINOX [fluorouracil (5FU), irinotecan, and oxaliplatin] versus standard gemcitabine and cisplatin. What's fascinating is, we all thought that this would be at least equivalent or superior to gemcitabine/cisplatin because FOLFIRINOX has proven very effective and superior to standard chemotherapies in many instances [such as] in pancreatic cancer. However, that was not seen. There were no advantages in terms of OS, progression-free survival [PFS], or 6-month PFS rate.² We might be able to use pieces of FOLFIRINOX, but it seems upfront, it doesn't add anything over standard chemotherapy. Therefore, the standard triplet combination is now gemcitabine, cisplatin and durvalumab.

Previously, we had pemegatinib [Pemazyre] and infigratinib [Truseltiq] for FGFR-translocated tumors, and futibatinib [Lytgobi] was approved by the FDA late last year for FGFR2-mutated second-line patients.³ So it's going to be interesting to try to distinguish between these targeted therapies for FGFR translocated patients, but I'd much rather have a plethora of drugs than the absence of them.

[Looking at] the untargeted agents, there's clear efficacy for 5FU with oxaliplatin or capecitabine [Xeloda] and oxaliplatin. That's often our go-to if patients are doing well in terms of neuropathy and other adverse events [AEs]. More recently, however, the phase 2 NIFTY trial [NCT03524508] showed that liposomal irinotecan and 5FU showed significant OS benefit and ORR compared with the non-irinotecan comparator arm.⁴ The most common grade 3 or higher AEs were neutropenia, fatigue and nausea. But now we have an alternative therapy that doesn't have cross resistance to another [platinum-based agent] such as cisplatin. Patients who couldn't tolerate gemcitabine or were contraindicated to cisplatin can receive oxaliplatin in the first line, which can happen with gemcitabine/oxaliplatin or sometimes capecitabine/oxaliplatin if there are biliary issues.

What is the current state of targeted therapies in this setting?

The more interesting and exciting news is still within the molecularly targeted therapy group. There are several trials that have shown that targeting therapy for FGFR mutations with pemegatinib, infragatinib, or fugatinib in second-line therapy [can be done] if they have an FGFR mutation. There are other trials looking at non-selective targeted agents such as regorafenib [Stivarga]. There have been a couple of trials investigating the activity of regorafenib in the second-line setting. What was interesting with these is that there appears to be a 60% to 70% disease control rate.^5,6 But in the randomized double-blind phase 2 trial [REACHIN; NCT02162914], about 66 patients were randomized to regorafenib versus placebo, and the disease control rate was higher [than other trials].⁷ The primary end point of PFS was a little bit better with regorafenib but the median OS was unchanged. So, in terms of a non-targeted multikinase inhibitor, regorafenib might be best utilized in the third-line setting.

Patients whose tumors contain IDH mutations can now utilize the IDH1 targeted agent ivosidenib [Tibsovo], as it has been approved in this subset of tumors.8 People with TRK fusion cancers [may receive entrectinib (Rozlytrek) or] larotrectinib [Vitrakvi]. There are BRAF- and MEK-targeted combinations that are effective in BRAF-mutated [disease]. There are HER2-directed therapies for HER2-amplified cholangiocarcinomas, not uncommon in extrahepatic cholangiocarcinoma. For ROS1 fusion–positive intrahepatic cholangiocarcinoma, there are reports of patients responding to crizotinib [Xalkori].⁹

Another exciting development is the use of immune checkpoint inhibition in patients with MSI-H tumors, high TMB, or high PD-L1 expression. The data are clear for those people whose tumors are MSI-H tumors, that immune checkpoint inhibition has good efficacy.¹⁰ There are reports of similar efficacy with high TMB and high PD-L1 expression, and we have a number of patients who've done remarkably well in those latter 2 categories.¹¹

What is some advice you would give to community oncologists treating cholangiocarcinoma?

The advice I would offer in treating cholangiocarcinomas is the critical importance of specialty and multidisciplinary care in this disease. It may be paramount in incidentally discovered gallbladder cancer, or in potentially resectable tumors that might benefit from a combination of local and systemic therapy to make them resectable. Because [even] with all the progress we have made, cure still requires a surgical resection.

There are multiple local treatment options that are available: chemoembolization, Y90 spheres [Yttrium-90 radioembolization], hepatic artery infusion pump therapy, and we've even had patients who've done remarkably well with prolonged disease control of hepatic limited disease, who proceed on to hepatic transplant. These are very select cases, but it's critical to have these discussions as early as possible, in a multidisciplinary fashion.

In addition, the surgical skills that might be needed to obtain the best outcomes may not be present in the community. We [as specialists at AHN Cancer Institute] often receive [new patients via] our tumor boards where physicians will call in to discuss their patients by videoconferencing or when the patient comes for another opinion. The patients can then either have an in-person visit and then return for treatment in the community, or we can just guide their local oncologists through the tumor board mechanism. If specialty surgery or other local interventions are indicated, we can also offer that to them.

What trials in this setting are AHN participating in?

We have a couple of interesting trials. One of the ones that we've been working with is a trial of devimistat [CPI-613]. It's an anti-mitochondrial drug being developed by Cornerstone Pharmaceuticals. This is a trial [BilT-04; NCT04203160] out of the University of Michigan exploring the combination of gemcitabine/cisplatin with and without devimistat, and it is nearing [phase 2] enrollment. We're anticipating that it we will have efficacy data in the near future as well.

I would also like to highlight a very interesting ECOG study that is being undertaken. There have been a number of trials showing that in multiple cancers—breast cancers, rectal cancers, pancreatic cancers, upper GI cancers—there is a paradigm that neoadjuvant chemotherapy, and in some cases radiation therapy, has increasingly been found to be a benefit.

However, in cholangiocarcinoma, there's scant evidence or even investigation that the same principle will hold. There is now the EA2197/OPT-IN trial [NCT04559139]. It's a randomized phase 2/3 trial looking at patients with histologically confirmed stage T2 or T3 incidental gallbladder cancers. Its primary objective is to determine the difference in OS for offering neoadjuvant chemotherapy, then resection and adjuvant chemotherapy compared with patients receiving only adjuvant treatment.

Although this is a small number of incidentally found T2 or T3 gallbladder cancers, what I think it highlights is the possibility of unique designs in future cancer trials in cholangiocarcinoma, especially in what we like to call window-of-opportunity studies. If you're going to provide a treatment and you have an upfront biopsy—these patients should have upfront biopsies—we can begin to ask questions such as who responds to what? I think this trial is interesting as it is one of the first and only neoadjuvant trials. If we obtain some interesting data and prove it as a concept, it is a trial design that can be replicated outside of incidental gallbladder cancers. I think whatever the outcome, it facilitates our ability to undertake window-of-opportunity studies and investigate next-generation studies with multi-gene panels, blood testing, correlates, and sequencing to [advance] the field.

What else is crucial to be aware of in this setting?

I’ve highlighted all the growth and progress that we've made in this cancer, and yet, there's still so much to be done and so much to be learned. I want to push the fact that even if a patient has a potentially targetable mutation, it doesn't guarantee they are going to respond, despite the fact that we now have triplets such as gemcitabine, cisplatin, and durvalumab in the first-line setting.

Not everyone responds or has as good an outcome, so I believe whether targets are identified or not, clinical trial participation is the only way we'll improve care for these patients. I want to stress the importance of trying to open up clinical trials or identify clinical trials in your area. These cancers are not all that common and so sometimes will require referral to other centers.

Another point I'd like to stress is the need for palliative care and supportive care. These patients often have issues with their quality of life due to hepatic dysfunction, biliary issues, or sites of metastatic disease. There is an urgent need to support them and their family members in order to obtain the best outcomes as we help them navigate their disease journey. That entire palliative care multidisciplinary unit is important for taking care of these patients.

_References:

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_{8. FDA approves ivosidenib for advanced or metastatic cholangiocarcinoma. FDA. Published August 25, 2021. Accessed February 1, 2023. https://bit.ly/3B2MGSw}

_{9. Jakubowski CD, Mohan AA, Kamel IR, Yarchoan M. Response to crizotinib in ROS1 fusion-positive intrahepatic cholangiocarcinoma. JCO Precis Oncol. 2020;4:825-828. doi:10.1200/PO.20.00116}

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