Li Assesses Evolving Therapies in Biliary Tract Cancers

Daneng Li, MD (MODERATOR)

Codirector, Neuroendocrine Tumor Program

Associate Professor, Department of Medical Oncology and Therapeutics Research

City of Hope Comprehensive Cancer Center

Duarte, CA

CASE SUMMARY

A man aged 72 years presented to a local hospital with a 4-month history of jaundice, dark urine, itchy skin, and an unintentional weight loss of 8 lb. He was referred to a gastrointestinal (GI) specialist 2 months ago by his primary care physician but has had no resolution of symptoms. Physical examination shows an obese, tired-appearing man, but his medical history is unremarkable aside from a 20–pack-year history of smoking and relatively heavy alcohol consumption at approximately 15 drinks per week.

His most recent laboratory results show:

• Total bilirubin: 22.9 mg/dL
• Direct bilirubin: 19.2 mg/dL
• Alkaline phosphatase: 89 U/L
• Alanine aminotransferase: 89 U/L
• Aspartate aminotransferase: 99 U/L
• λ-Glutamyl transpeptidase: 222 U/L
• Cancer antigen 19-9: 14 U/mL
• Carcinoembryonic antigen: 10 ng/mL
• α-Fetoprotein: 20 ng/mL
• Hepatitis B virus screening and autoimmune profile were negative.

His diagnosis was extrahepatic cholangiocarcinoma. Endoscopic retrograde cholangiopancreatography was performed, and the bilirubin level was within normal limits 3 weeks later. A CT scan demonstrated multiple liver lesions plus extrahepatic perihilar regional lymph nodes and lesions in the left lung and left femur.

LI: Have you seen more cases of biliary tract cancer [BTC] in your practice over time? Let’s say, in the past 5 years?

DEKKER: I am practicing in the northern cape of Los Angeles, California, in Valencia and Mission Hills…. It’s difficult to say, because those patients typically come in spurts. You don’t have many patients and then suddenly you have 3 or 4, so probably yes [I have].

LI: One of the comments I’ve heard is that [previously, some of these cases] might not have been called…cholangiocarcinoma; we might have classified them as adenocarcinomas of unknown primary tumor. Have any of you seen more of these [cases] being called cholangiocarcinoma?

DEKKER: I would say, [today], pathology is pretty good about identifying the disease. I don’t recall [seeing a diagnosis of] unknown primary recently unless it was squamous cell. For squamous cell, yes. For adenocarcinoma, probably in the past couple years there was [a better diagnosis to use].

HENDIFAR: I agree with you. Advanced endoscopy has made the diagnosis a lot easier. Interventional endoscopists are much better now at diagnosing these lesions, especially differentiating extrahepatic and pancreas tumors. So, yes…we’re getting better at this.

LI: Yes…it’s a good thing. Patients are probably getting the right treatments.

DISCUSSION QUESTION

• How similar are the symptoms of BTCs to those of other GI malignancies?

LI: Many of these patients [receive diagnoses of] more advanced disease, and that’s because, initially, a lot of the symptoms might not be specific in terms of pain and weight loss. Ultimately, they might present with obstructive jaundice. In terms of work-up, often we will get routine labs, including tumor markers, to assess the jaundice along with imaging [and] pathology. Sometimes this is a diagnosis of exclusion, meaning that you have a liver mass that you see on imaging without a primary [tumor] but that, based on pathologic diagnosis, is consistent with a BTC.

Do you see much of a difference between the symptoms [of BTC] compared with those of other malignancies?

DEKKER: Many patients’ [diagnoses] are relatively accidental findings. For example, patients [have] symptoms of acute cholecystitis, and cancer is found. Or they come in with jaundice. Or their primary care physician does liver function tests because of a change in the dose of lipid-lowering agents and [abnormal results are] found, and then the patient gets an ultrasound or a CT scan…and the cancer is found.

LI: I do agree. Often, these can be found incidentally, either on imaging or at the time of event, for example, with cholecystitis [or] incidental resection of the gallbladder.

LI: For the minority who would choose “other,” I’m curious about…the other regimen that they would choose.

DEKKER: I have moved on from gemcitabine and cisplatin. I would use GEMOX [gemcitabine plus oxaliplatin (Eloxatin)] instead.

LI: Is there any…reason that you’re interested in GEMOX?

DEKKER: In my experience, and [based on] what I have read, oxaliplatin by itself is more efficacious in upper GI tract cancers, including cholangiocarcinoma. The toxicity profile is also better. It’s also [given] every 2 weeks, [and is therefore] better to manage from the patient’s…and from the clinic’s standpoint. Gemcitabine and cisplatin was only selected as a backbone, like in the TOPAZ-1 study [NCT03875235], primarily because it is still the dominant regimen outside the United States.

FU: I think gemcitabine and cisplatin still has the most data [to support use] with this type of cancer. You’re right that oxaliplatin is probably best for the GI tract, but I’m not sure [about using it] for this type of cancer. In my experience, the gemcitabine and cisplatin is [given as] a split dose and the split dose is well tolerated. Patients don’t have much diarrhea or neuropathy, although they can have some neuropathy but it is not as bad as with the oxaliplatin. And [these drugs] do work; I haven’t seen any patient not responding to the gemcitabine-and-cisplatin regimen.

LI: Since the approval,¹ have all of you…chosen gemcitabine, cisplatin, and durvalumab [Imfinzi]? Are there any patients for whom you’re holding back and not giving gemcitabine, cisplatin, and durvalumab?

MIEL: I’ve given it. I did have a problem with a patient developing renal insufficiency with cisplatin, so I had no choice but to hold it, but I continued the gemcitabine and durvalumab. [I’m waiting] to see if the kidney function worsens, but so far it hasn’t. I just had to stop the cisplatin.

YEH: Just to be a devil’s advocate, [let me say that] the TOPAZ-1 trial stopped at 8 [cycles].² Typically, when you treat cholangiocarcinoma, you can keep going. You don’t stop at 8. Who’s to say that, if you kept going with gemcitabine/cisplatin and durvalumab—and gemcitabine/cisplatin and durvalumab is a well-tolerated drug—that the curves wouldn’t separate?

LI: Absolutely. That point has been brought up a lot, and that’s certainly up for debate. Going along with that question: In practice, when you’re using the gemcitabine/cisplatin and durvalumab combination, are you continuing it beyond 8 cycles?

YEH: The question is: Do you need the durvalumab? I hear physicians talk about that [and the possibility of ] continuing the gemcitabine/ cisplatin and durvalumab, because the control arm stops at 8 cycles.²

LI: In real-world practice right now, in your clinic, when you give gemcitabine/cisplatin and durvalumab after 8 cycles you will stop the gemcitabine/cisplatin, right? I’ve heard that others have continued the gemcitabine/ cisplatin plus durvalumab even beyond 8 cycles.

YEH: I guess you can, but…once you get an excellent response, you could always come back to gemcitabine/cisplatin if they relapse later. If they have a PFS [progression-free survival] event, you can come back and give them a nice break. The question is: What’s the value of the immunotherapy, and there was no maintenance in the control arm. If you look at the separation of [the results,] they separate after 6 months.²

LI: I’ve also heard that some physicians start with gemcitabine/cisplatin and then they add the durvalumab after 1 to 3 cycles if they see that the tumor is not shrinking. Have any of you done it that way? It seems to me that most of you are doing it [differently from] the trial [From the Data²].

FU: I keep it going unless the patient has intolerable [adverse] effects or progressive disease. It’s a discussion between the patient and the physician, where you tell them, “We could keep going, or we could stop here and give you a break.” Most of them opt to continue, but some, especially those with [adverse] effects, do want to have a break.

CHAUDHARY: But the cytopenias become dose limiting. I have not been able to continue, just because of the bone marrow suppression.

LI: Yes, that’s a great point; I have certainly heard that. Physicians will say that the patients are pretty beaten up after 8 cycles, so it’s a good time to give them a break and keep them on maintenance durvalumab. These are all good points. Since the approval, I think everyone is trying to [adjust] the regimen for their respective patients.

SHIN: Can you use gemcitabine plus carboplatin when you’re worried about cisplatin?

LI: It depends on what your worry is. Usually, the cisplatin dose for BTC is relatively low, and it’s given as a split dose. I haven’t run into too many issues such that we have to make a switch from cisplatin to carboplatin. Often, if the patient does develop some toxicity, it might happen later and be caused by renal insufficiency, and it might be time to just drop the platinum agent, because you might have to use platinum [agents] as a second-line treatment down the road. I don’t think I would have to force the platinum [therapy] in the first cycle, depending on how things go.

DISCUSSION QUESTION

• What has been your experience in practice with durvalumab in patients with BTCs?

YEH: What do you do, Dr Li? Do you follow the TOPAZ-1 regimen,² or do you do something different?

LI: I vary the treatment depending on the patient. If a patient really doesn’t like chemotherapy, then once we get good disease control after 8 cycles, if they tolerate 8 cycles, then we’ll just go to durvalumab maintenance. If it’s a patient where I see that we’re getting a good response, I might go beyond 8 cycles of the gemcitabine/cisplatin, because I think the combination does have good activity.

I was one of the individuals [who] questioned whether [the way] gemcitabine/cisplatin [was administered] is the actual standard of care in the United States. It might be the standard of care in the world, in terms of 8 cycles, but maybe in the United States we would continue [beyond that]. For a fit patient who is tolerating it, I might continue beyond 8 cycles with the durvalumab and everything; otherwise, I think the TOPAZ-1 data have shown that durvalumab is fairly well tolerated.² So, I don’t have trouble [using] the combination as a triplet combination up front.

What about your experience specifically with the durvalumab portion? Have you had any issues with durvalumab that have been hard on patients?

YEH: The hard thing is when a patient is progressing, you don’t know [whether the] hepatotoxicity is from [the] immunotherapy or [ from] cancer. Sometimes it’s hard to tease those out. When the patient’s liver function [test result levels] start to go up and there may be a little ascites here and there, you don’t know what’s going on—whether it’s the immunotherapy, toxicity, or cancer progression. So, sometimes I struggle with that. Sometimes the images are not very clear, and if the bilirubin is not going up, it’s kind of hard.

FU: That can apply to the actual hepatic biliary. Sometimes you have just got the cytology [report], and you do not have good imaging to make an assessment. Sometimes you have [a little bit] of the tumor. Sometimes I use that to test, or I use the patient’s general history: If they have been on this regimen for a while, maybe this is true progression.

HENDIFAR: For the concern of progression vs autoimmune hepatitis, the picture of the liver dysfunction is a little different [between those scenarios]. If you look at it carefully, maybe you can tell the difference. Liver disease progression or even bile duct blockage will be more cholestatic and have more of an alkaline phosphatase elevation. But, with autoimmune hepatitis, you usually get just liver enzyme elevation, which…is a problem, but…one way to tell the difference is to take a careful look.

FU: In terms of the durvalumab, my patient handled it well, unlike [the situation for patients with] triple-negative breast cancer: The pembrolizumab [Keytruda] plus chemotherapy is horrible. I don’t know why. The patients with breast cancer experience [many] more immune-related severe adverse events, [but] I don’t have any patients who have issues with durvalumab.

LI: Yes…that’s what we’re hearing a lot. That’s why…a lot of practitioners, as these data have come out and they’ve gained more experience, are saying that it’s OK to add the third agent, because they haven’t seen much more toxicity with the addition.

DISCUSSION QUESTION

• After so many years without an approval in BTC, what does the approval of the gemcitabine/cisplatin/durvalumab combination¹ mean for the landscape and future trials?

LI: Are there any future trials that you’re looking forward to?

CHAND: Even with this approval, I think that for BTCs in general, the prognosis is still poor for most patients, given the late diagnosis. With the addition of durvalumab, there is a small group of patients, maybe 10% or 15%, who have durable responses. But the rest of them still don’t do very well. We don’t know, unfortunately, how to [identify] these patients up front…. There is a lot of room for improvement. With next-generation sequencing, we are able to [identify] some patients who have targetable mutations. For example, I have a patient with an IDH1 mutation, and she is doing well on ivosidenib [Tibsovo], but [patients like] this are few and far between. I haven’t been able to get too many patients with these targetable mutations, for some reason, and most of them don’t make it to third-line treatment. It’s a tough disease.

_REFERENCES

_{1. FDA approves durvalumab for locally advanced or metastatic biliary tract cancer. FDA. September 2, 2022. Accessed April 3, 2023. https://bit.ly/41x0AJk}

_{2. 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. J Clin Oncol. 2022;40(suppl 4):378. doi:10.1200/JCO.2022.40.4_suppl.378}