Roundtable Discussion: Treatment Goals for HCC and Tolerability of Frontline Regimens

Richard S. Finn, MD (Moderator)

Professor, Department of Medicine

Division of Hematology/Oncology

David Geffen School of Medicine at UCLA

Santa Monica, CA

CASE SUMMARY

A 77-year-old White woman presented to her primary care physician complaining of abdominal pain and fatigue. She had cirrhosis due to heavy alcohol use; Crohn disease, controlled with infliximab (Remicade); and a history of variceal bleeding, with banding 2 months ago. Her ECOG performance status was 1.

A CT scan of the chest, abdomen, and pelvis with triphasic liver evaluation showed a 4.5-cm Liver Imaging Reporting and Data System category 5 (LR-5) hepatic mass in the right lobe and metastatic disease in the lung. She was Child-Pugh class A, with an α-fetoprotein (AFP) level of 380 ng/mL.

DISCUSSION QUESTIONS

• Would you recommend a biopsy in this patient? Would your use of biopsy be different if the patient did not have cirrhosis? Would it differ if the lesion were LR-4?
• Assuming a biopsy was obtained and confirmed hepatocellular carcinoma (HCC), would you suggest any further genetic analyses of the biopsy tissue?
• Would you recommend any further imaging?

DEKKER: I would do a biopsy because it could be liver disease, but people could have all kinds of other cancers. So yes, it looks suspicious. But if she had a previous lesion in the liver, or had a suspicious lesion, or had a bad baseline, we would know that something was there, [and] I probably would be more comfortable to go without biopsy. Otherwise, I would go for biopsy in this situation.

FINN: Not unreasonable. Biopsies can be done safely. They do give more information, and LR-5 is not 100% [diagnostic of HCC]. It’s well over 90%.

DEKKER: It’s still possible that she had one lesion, but if she did not have a recent colonoscopy, if there is any questionable lesions seen on the imaging, it would be even more reason to biopsy.

FINN: Sure, [I see] no issue there.

CHAUDHARY: What about the value of AFP being 380 ng/mL?

FINN: AFP is not part of the noninvasive diagnostic criteria for liver cancer. Certainly, patients can have an elevated AFP just with hepatitis, but it certainly builds the case suggesting liver cancer in this person. I would agree with that.

What if it wasn’t LR-5? Would someone [who said no to] biopsy [now say] yes to biopsy, or not necessarily?

FU: If one has any doubt, they need to confirm the diagnosis and make sure it’s not a cholangiocarcinoma or another type of cancer because the treatments would be very different. In terms of further analysis, I think the biopsy mainly is just to confirm the diagnosis. I usually do not order the [genetic] testing because driver mutations are rare in liver cancer. I don’t know, maybe you can hit the jackpot [sometimes].

FINN: I would recommend further imaging. The other thing you can do if it’s an LR-4 lesion is you could use another imaging modality: a CT scan for LR-4 and MRI if it’s LR-5. It can confirm the finding. That used to be one of the recommendations for noninvasive diagnosis, but imaging has gotten better.

CASE UPDATE

A biopsy was obtained, and it confirmed HCC. Using the American Joint Committee on Cancer (AJCC) staging system, it is stage IV disease and Child-Pugh A cirrhosis.

FINN: The patient in our case is someone who is a candidate for systemic treatment, and atezolizumab [Tecentriq] plus bevacizumab [Avastin], as we know, is now probably the most active regimen we have in advanced liver cancer. It is a combination of a PD-L1 inhibitor with VEGF inhibition, which seems to be synergistic in this disease. Now keep in mind that before this regimen, sorafenib [Nexavar] was the standard of care for a long time, and then lenvatinib [Lenvima] was approved based on noninferiority to sorafenib a few years back.¹

Durvalumab [Imfinzi] as a single agent is not approved in liver cancer. There is a recently published paper from the HIMALAYA study [NCT03298451] that looked at durvalumab with tremelimumab [Imjudo], the CTLA-4 inhibitor, and that combination was superior to sorafenib in terms of survival and objective response, but it did not improve PFS [progression-free survival].² The HIMALAYA study also included an arm of single-agent durvalumab vs sorafenib, and it met its noninferiority end point. But neither of these regimens are FDA approved at this time for liver cancer. [Editor’s note: This event took place before the FDA granted approval to durvalumab/tremelimumab for HCC.³]

Pembrolizumab [Keytruda] got accelerated approval in the second-line setting.⁴ But again, keep in mind, every drug studied in the second-line setting has only been studied after prior sorafenib. So all the things we have approved in the second line including regorafenib [Stivarga], cabozantinib [Cabometyx], ramucirumab [Cyramza], pembrolizumab, or even ipilimumab [Yervoy] plus nivolumab [Opdivo] have only been approved after prior sorafenib in prospective studies.

The challenges of using atezolizumab plus bevacizumab in this patient are [that] she had a GI [gastrointestinal] bleed 2 months ago, a variceal bleed, which must give us pause. It doesn’t mean it can’t be used, but I think we need to make sure that those varices are under good control. Often patients get scoped a few weeks after an initial bleed. The other thing is, she has Crohn disease. Again, I think that must give us pause. It is not always an absolute contraindication, but this patient is on infliximab, which is an immune suppressant. This case is leaning away from atezolizumab plus bevacizumab for these 2 reasons. In that regard, sorafenib or lenvatinib would probably be the more conservative choice.

DISCUSSION QUESTION

• How would you consider age, etiology of cirrhosis, toxicity, comorbidities, performance status, and other factors in selecting frontline systemic therapy for this patient?

HAJJAR: I think this patient was in her 70s. She has Crohn disease, has a GI bleed, and good performance status, but these 2 are significant comorbidities. I’d be concerned about bevacizumab for this patient. I would discuss it with her. I would tell her that there’s a chance that the Crohn disease might get worse and she might have detrimental GI bleeding. Taking into consideration the not-so-large benefit from this combination compared with a well-tolerated TKI [tyrosine kinase inhibitor], I would be leaning more toward recommending the TKI. If she were younger [without these] comorbidities, I would go with bevacizumab plus atezolizumab. But in this patient, I felt that managing the quality of life is more important.

DEKKER: I agree with his comments. Plus, one of the problems with combination regimens, especially in older, sicker patients, is that one never knows 100% what is causing the problem.

FINN: Can you tell me what factors are making you give TKIs? Can someone tell me what characteristics you’re considering for that?

CHANDURI: I think the age and the disease, secondary to alcohol. This patient must have gone to the hospital a couple of times with portal hypertension and GI bleed. These are the patients who may not tolerate other kinds of treatment, so it will give us some time to see if they can tolerate TKIs. Even TKIs are very difficult for these patients to tolerate. I don’t have much experience, but the couple of patients I treated in the past could not tolerate them.

FINN: That’s interesting. You’re saying from your experience the patients who have these other comorbidities are the ones who have had challenges with a doublet.

CHANDURI: Especially if the cirrhosis is due to alcohol consumption. Younger patients with cirrhosis due to hepatitis or some other things behave differently.

FINN: From the trials, we have not seen that per se, but obviously there’s real world and there are trials. The populations are different, but I won’t dispute your personal experience.

DEKKER: Yes, we talk about primarily Child-Pugh A patients, but in many cases, patients come to us with Child-Pugh A disease, get chemoembolization, then get to Y90 [yttrium 90 radioembolization]. By the time they have had 2 to 3 embolization sessions, even though on the surface they are still Child-Pugh A, as soon as you give them something a little bit more strenuous, they start rapidly decompensating. I think this is one of the challenges of when to stop interventional procedures.

FINN: Yes, that’s a very important thing especially now that we have so many options, and it’s not fair to just do treatment beyond progression for patients. When I say treatment, I mean TACE [transarterial chemoembolization] beyond progression.

DEKKER: I think that is one of the issues. If somebody truly has Child-Pugh A disease, they should be able to tolerate a combination regimen. But, in many cases, we do stretch a little bit and many of the patients have Child-Pugh B disease, and that’s where all that hesitation comes from. I cannot speak for everybody, but I suspect this is one of the reasons that people see so much toxicity and so many issues.

FINN: How about oral vs IV [intravenous]? Does anyone have a preference there?

HSU: Logistically, IV is so much easier for me and my case manager. Oral [agents] have a lot of co-pays and all these things.

FINN: Yes, I’ve heard that before.

CASE UPDATE

• Lenvatinib 12 mg daily was initiated. The patient experienced modest weight loss and reported loss of appetite, leading to a dose reduction to 8 mg daily, and she was referred for nutritional therapy. Imaging at 16 weeks showed a partial response. Eight months after initiation of therapy, treatment was discontinued due to disease progression.

FINN: Remember, lenvatinib is dosed by weight, greater or less than 60 kg, 12 mg vs 8 mg for those [weighing] less than 60 kg.⁵ Both these doses are less than what’s used in kidney cancer or thyroid cancer.

DISCUSSION QUESTION

• What is your approach to adverse event prevention, monitoring, and management with lenvatinib?

FINN: What’s your preferred management of hypertension, because it is not that infrequent?

DEKKER: [I would] refer to…either a primary care physician or cardiologist.

CHO: I usually give amlodipine [Norvasc].

FINN: I like that, too. It’s very easy to manage.

CHAND: I usually send the patient with a prescription for amlodipine because the blood pressure can start going up very quickly after starting lenvatinib. According to the drug representatives, in the starter kits for lenvatinib, they usually have a blood pressure monitor. The pharmacies are supposed to send those to the patients when they first start lenvatinib for any indication. I don’t know if pharmacies are sending it to the patient, but it’s offered free from the drug company. I start off with amlodipine, and then if the blood pressure is still uncontrolled, which can be even after 10 mg of amlodipine, I usually send the patient to cardiology for additional antihypertensives.

_REFERENCES

_{1. FDA approves lenvatinib for unresectable hepatocellular carcinoma. FDA. Updated August 16, 2018. Accessed November 16, 2022. https://bit. ly/3EDatMp}

_{2. Abou-Alfa GK, Chan SL, Kudo M, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. J Clin Oncol. 2022;40(suppl 4):379. doi:10.1200/ JCO.2022.40.4_suppl.379}

_{3. FDA approves tremelimumab in combination with durvalumab for unresectable hepatocellular carcinoma. FDA. Updated October 24, 2022. Accessed November 16, 2022. https://bit.ly/3tBGaPW}

_{4. FDA grants accelerated approval to pembrolizumab for hepatocellular carcinoma. FDA. Updated November 14, 2018. Accessed November 16, 2022. https://bit.ly/3X26QH7}

_{5. Lenvima. Prescribing information. Eisai Inc; 2018. Accessed October 26, 2022. https://bit.ly/3TIErUj}