How to Respond to Toxicities of Each Combination HCC Regimen

Several combination regimens including immunotherapy have been approved to treat advanced hepatocellular carcinoma (HCC) over the past years. The underlying liver conditions such as cirrhosis associated with HCC may make certain adverse events (AEs) associated with these agents particularly challenging in this disease setting. In a virtual Case-Based Roundtable event moderated by Mark Yarchoan, MD, associate professor and medical oncologist at Johns Hopkins Hospital in Baltimore, Maryland, participants were presented with 3 alternate scenarios for a patient depending on which frontline regimen was selected and which serious AE presented, and they discussed how to monitor and manage these toxicities most effectively.

This article is part 2 of a 2-part series from a Case-Based Roundtable event.

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CASE SUMMARY

• 62-year-old man with unresectable HCC (uHCC)
• 2 lesions in right lobe (4-5 cm); mild portal hypertension; splenomegaly; bilateral lung nodes (1-2 cm)​
• Type 2 diabetes well controlled with metformin) & hyperlipidemia; ​no prior upper gastrointestinal bleeding, coronary artery disease, or hypertension; ECOG performance status 1; Child-Pugh A; Barcelona Clinic Liver Cancer C​
• The selected front-line treatment approach was nivolumab (Opvido) plus 4 cycles of ipilimumab (Yervoy).​
• The patient had a favorable response to therapy.

On week 6 of treatment​

• The patient reported mild nausea, reduced appetite, increasing fatigue, & persistent dull pain in right upper quadrant.​
• Symptoms were also noticed by his wife, who indicates he has been less active in the last week​.

Routine laboratory results:

• Alanine aminotransferase (ALT): 380 U/L​
• Aspartate aminotransferase (AST): 410 U/L​
• Total bilirubin within normal limits: 0.9 mg/dL​
• Alkaline phosphatase: 160 U/L​

Further work-up​

• Abdominal ultrasound: no biliary dilation, no thrombosis​
• Antinuclear antibody low positive; IgG levels mildly elevated​
• No sign of viral or autoimmune hepatitis​
• Diagnosis: grade 3 immune-mediated hepatitis​

Mark Yarchoan, MD: You've seen elevated liver enzymes from checkpoint inhibitors in HCC and beyond HCC. How would you all approach this?

Bety Ciobanu, MD: We’ll hold the treatment and start prednisone at 1.0 or 1.5 mg/kg, follow liver enzymes weekly, and if it gets down to grade 1, start tapering slowly over 1 month.

Yarchoan: I’ve found that hepatitis can linger more than other irAEs [immune-related adverse events]. I don't know if that's been your experience. I am a part of Johns Hopkins Hospital’s immune-related toxicity team, so I see all these [uncommon] cases. If steroids are not sufficient to control this, what's your go-to for a second agent?

Zhineng Jayson Yang, MD: I've used mycophenolate mofetil with improvement.

Yarchoan: Do you avoid tumor necrosis factor inhibitors because these patients have cirrhosis?

Yang: If the LFT [liver function test] goes up into the 1000s [U/L] and they’re on high-dose steroids and mycophenolate mofetil and are not doing well, I think we'll reach for that.

Yarchoan: Doesanybody use tacrolimus or Janus kinase inhibitors for refractory cases? That's been my go-to.

Murtuza Rampurwala, MD, MPH: I usually have them see hepatology by that point.

Stanley Nabrinsky, MD: Yes, I wouldn't be comfortable going beyond steroids by myself. If something persists, they go straight to gastroenterology or hepatology.

Yarchoan: It sounds like people are just starting to use this in HCC, but do you have clinical experiences with it in other settings? Is this something you're pretty comfortable with?

Husam Tarawneh, MD: I am comfortable with this regimen, but we have to look for the AEs. At times, the AEs might not come until you finish the 4 cycles [of ipilimumab]. Sometimes you might get gastrointestinal AEs like duodenitis and pancreatitis and also peripheral neuropathies and dysphagia.

Yarchoan: Nivolumab/ipilimumab is a regimen that's active and can cause irAEs. There was a 4% rate of grade 5 AEs.¹ I have not seen this in my own practice, but maybe I've been lucky. We do need to be vigilant and warn patients this is a real possibility. These irAEs can affect any organ system, and the different organ systems are incredibly varied. There wasn't one irAE that was particularly common in these patients. There may have been more hepatitis in this cohort than other cohorts of ipilimumab/nivolumab, which is not surprising, because the organ that's involved in the underlying cirrhosis probably increases the risk of hepatitis.

Different irAEs have different chronicities, and in particular, the rash often happens early. Endocrinopathies like type 1 diabetes and adrenal insufficiency are often a very late event for reasons that I don't understand. It's the adrenal insufficiency that always gets me caught up. These patients are doing great, and then a year later, when you think that they're in the clear, is when I see the endocrinopathies. They tend to happen very late, whereas the rash is usually a very early event and doesn't tend to happen later.²

CASE UPDATE

Treatment was held temporarily.​

• Increased monitoring: LFTs were to be checked every 2 to 3 days​.
• The patient was initiated on supportive care and high-dose corticosteroids were initiated per guidelines​.

By week 10 of treatment:​

• ALT/AST improved to baseline​.
• Treatment with nivolumab plus ipilimumab was resumed, and LFTs were to be monitored weekly over the next month.

Yarchoan: This patient got steroids alone, and AST/ALT improved, and then nivolumab/ipilimumab was resumed, which I think is a little bit daring. We know there's about a 25% rate of recrudescence of irAEs if you rechallenge with the same regimen. Maybe in my practice, I would have done nivolumab alone here, but this patient was able to continue the doublet.

ALTERNATE SCENARIO

In an alternate scenario, the patient was treated with single dose tremelimumab (Imjudo) plus durvalumab (Imfinzi) every 4 weeks (STRIDE; single tremelimumab regular interval durvalumab)​.

• On week 8 of treatment​:
• The patient reported increasing fatigue, decreased activity levels, and cold intolerance​. He gained 3 lbs without dietary change​.
• Routine laboratory results:
  • Thyroid-stimulating hormone (TSH) elevated: ​37.5 mlU/mL​
  • Free T4: 0.3 ng/dL​
  • Free T3: 2 pg/mL ​
• Further work-up​:
  • No goiter​, no myxedema or bradycardia​, mild periorbital puffiness​
• Diagnosis: grade 3 immune-mediated hypothyroidism​

Yarchoan: We don't have a head-to-head with STRIDE vs ipilimumab/nivolumab, but overall, I think the selling point of STRIDE is that it's very well tolerated, and the rate of irAEs might be a little bit lower. The grade 3/4 irAE rate was 12.6%, which is numerically lower than we saw with ipilimumab/nivolumab.³ Numerically, the response rate was also lower. It’s hard to draw definitive conclusions, because they haven't been compared head-to-head.

Similar to other checkpoint inhibitor regimens, we worry about irAEs. As with other studies, the time that you worry the most is about 2 months after starting therapy, and then the rate of AEs goes down dramatically, except for endocrinopathies that can happen later.

CASE UPDATE

• Levothyroxine was initiated (75 µg/day initial dose)​
• TSH and free T4 testing planned in 4 weeks​
• Symptoms were monitored closely over next few weeks​.

By week 12 on treatment:​

• Energy levels were improved, with resolution of cold intolerance.​
• TSH was trending down and free T4 improved.
• Durvalumab was continued with no interruption. ​
• TSH and free T4 monitoring scheduled every 4 to 6 weeks for further adjustment.

Yarchoan: When you give these dual checkpoint inhibitor regimens in HCC or otherwise, are you monitoring TSH routinely?

Tarawneh: I usually monitor every other cycle; if I’m seeing them every 6 weeks, I do it every 6 weeks.

Yarchoan: Do you monitor anything else, like troponin, adrenocorticotropic hormone, or anything like that?

Krishnan Rao, MD: I monitor cortisol, and on the comprehensive metabolic panel, there would be glucose. For a baseline before the start of therapy, I'll get hemoglobin A1c.

Tarawneh: From time to time, I get NT-proBNP; I might get it as a baseline. At times I might have creatine phosphokinase, depending on the complaints. I have gotten troponin from time to time, depending on what the patient tells me that day.

ALTERNATE SCENARIO

In an alternate scenario, the patient receives atezolizumab (Tecentriq) plus bevacizumab (Avastin) for their uHCC.

• On week 8 of treatment​:
  • The patient reports increased fatigue, mild shortness of breath, and lower extremity swelling​.
  • He noticed frequent urination and foamy urine in the last week​.
• Evaluation & work-up​:
  • Urinalysis: 3+ protein, negative hematuria​
  • Urine protein creatinine ratio [UPCR]: 5.2 g/g​
  • Albumin 2.4 g/dL​
• Serum creatinine: 1.3 mg/dL​
• Diagnosis​: Nephropathy with significant proteinuria​
  • No hypertension​
  • Grade 3 proteinuria​

Ciobanu: This is because of the bevacizumab, and we should routinely monitor the UPCR and ideally stop before the patients reaches severe proteinuria, when we usually just hold the treatment and wait for this to resolve and maybe rechallenge, or if it's not resolving, then the patient needs to stop the bevacizumab.

Yarchoan: I haven't seen this, where they go from normal to 3+ protein with a nephrotic range proteinuria. Normally it's a gradual process and you can stop the bevacizumab before this happens. That's been my experience.

Ciobanu: I agree. If you monitor the UPCR periodically, usually you catch this before the patients become symptomatic.

Tarawneh: Usually, it's very gradual. I look at the patients for any lower extremity edema and what's happening with the blood pressure. I have given bevacizumab even with up to 2 g per day of protein. But I do get UPCR with every patient I am seeing on every visit on bevacizumab.

Yarchoan: Patients can get AEs related to bevacizumab [or] related to atezolizumab. I think if there's one AE that makes me nervous, it's the bleeding with the bevacizumab. We used to be insistent 100% of the time about getting an endoscopy before starting this. Now I don't always get an endoscopy right away. Sometimes I just start therapy when I need to. I'm giving more patients carvedilol to try to prevent bleeding. Is everyone else getting an EGD [esophagogastroduodenoscopy] 100% of the time?

Tarawneh: I get EGD almost 100% of the time.

Yarchoan: Bevacizumab was developed as a single agent for HCC a long time ago, and the development was stopped because of unacceptable rates of bleeding. When the drug company [investigated] atezolizumab/bevacizumab, they made sure that patients were not going to bleed on the trial. They got endoscopies and they excluded patients who had a particular propensity to bleed. In spite of that, there was numerically more bleeding with the atezolizumab and bevacizumab than sorafenib [Nexavar], but this has been manageable in most of our clinics.

The patients who are most at risk of bleeding with the atezolizumab/bevacizumab are patients who have VP4 disease, the patients with portal vein invasion. Every single patient who had a major bleeding event on this trial had portal vein thrombosis. Interestingly, they were included on the study; they weren't even included on the immunotherapy doublet studies, but it's also the group where I worry the most about the bevacizumab. [Looking at] the most common treatment-related AEs, the bleeding is not at the top of the list, it's just the one that we worry the most about.⁵

DISCUSSION QUESTION

• Are there specific AEs that might be more challenging to manage in your practice?

Tarawneh: I would imagine the hepatitis [is challenging]. In general, when you read about the AEs in immunotherapy, it's always higher when CTLA-4 is included in the regimen.

Nabrinsky: The more we use immunotherapy, the more we get surprised by unusual AEs, and for me, it’s any neurological AEs. As soon as they call neurology consult, they will attribute any global issues like central nervous system symptoms to AEs of immunotherapy, and maybe that's the case, but you have to stop it permanently. That's the class of events I'm the most worried about.

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DISCLOSURES: Yarchoan reported institutional grant/research support from Bristol-Myers Squibb, Exelixis, Incyte and Genentech; honoraria from Exelixis, AstraZeneca, Replimune, Hepion, Lantheus, Genentech and Incyte; is the co-inventor of a patent related to neoantigen vaccines; and is a co-founder with equity of Adventris Pharmaceuticals. Rampurwala reported advisory board fees from AstraZeneca. There were no other known relevant disclosures.

REFERENCES:

1. Galle PR, Decaens T, Kudo M, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): First results from CheckMate 9DW. J Clin Oncol. 2024;42(suppl 17):LBA4008. doi:10.1200/JCO.2024.42.17_suppl.LBA4008

2. Decaens T, Yau T, Kudo M, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line (1L) treatment for unresectable hepatocellular carcinoma (uHCC): Expanded analyses from CheckMate 9DW. Ann Oncol. 2024;35(suppl 2):S657. doi:10.1016/j.annonc.2024.08.1025

3. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8):EVIDoa2100070. doi:10.1056/EVIDoa2100070

4. Lau G, Sangro B, Crysler OV, et al. Temporal patterns of immune-mediated adverse events (imAEs) with tremelimumab (T) plus durvalumab (D) in the phase 3 HIMALAYA study in unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2023;41(suppl 16):4073. doi:10.1200/JCO.2023.41.16_suppl.4073

5. Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76(4):862-873. doi:10.1016/j.jhep.2021.11.030