Managing irAEs Across Frontline HCC Regimens Requires Clinical Judgment

The efficacy data from 3 frontline immunotherapy regimens for unresectable hepatocellular carcinoma (HCC) have reshaped survival expectations in a disease where the standard of care was unchanged for more than a decade. In many community practices, a challenge is the clinical fluency needed to manage the adverse events associated with these regimens. Grade 3 toxicities from checkpoint inhibitors in HCC do not always follow the same playbook as in lung cancer or melanoma, as the liver is already compromised, the etiology of a transaminase rise is rarely obvious, and an error in attribution can mean either undertreating a serious immune event or interrupting a regimen that is working.

During a virtual Case-Based Roundtable event, Amit Mahipal, MD, professor of medicine and leader of the gastrointestinal (GI) oncology program at Case Western Reserve University, walked participants through 3 clinical vignettes illustrating how immune-related adverse events (irAEs) differ in mechanism, grade interpretation, and management strategy. Mahipal emphasized that the CTCAE grade alone is an incomplete guide, as grade 3 events may require entirely different responses depending on the organ system involved and the drug responsible.

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

CASE SUMMARY

Patient is a 62-year-old man with uHCC.

• Two lesions in right lobe (4 to 5 cm); mild portal hypertension; splenomegaly; bilateral lung nodes (1 to 2 cm)​
• Type 2 diabetes well controlled with metformin and hyperlipidemia; ​no prior upper GI bleeding, coronary artery disease, or hypertension; ECOG performance status, 1; Child-Pugh score, A; Barcelona Clinic Liver Cancer stage, C​

SCENARIO 1

Frontline treatment approach:

• 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, and persistent dull pain in the right upper quadrant.​
• Symptoms were also noticed by his wife, who indicates he has been less active in the past 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 workup​:

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

Mahipal opened by asking the group how they assess a patient’s ability to tolerate grade 3 irAEs before treatment begins, a question he acknowledged has no clean answer. Ram Trehan, MD, a general hematologist-oncologist in suburban Maryland, put it plainly: “Treat and see how they do after the first…couple of treatments. Over the years, we’ve had no success in predicting patients who are going to have bad reactions.”

Uday Dandamudi, MD, a general hematologist-oncologist in Trinity, Florida, said he looks at prior autoimmune history and whether any existing condition is actively treated. Fayez Estephan, MD, a hospital-based hematologist-oncologist in Annapolis, MD, added pulmonary reserve to his pretreatment calculus: in patients with severe chronic obstructive pulmonary disease (COPD) or baseline interstitial changes, the prospect of immune-mediated pneumonitis changes his comfort level with a dual immunotherapy backbone.

The diagnostic challenge Mahipal described is specific to HCC and goes beyond what most CTCAE tables capture: elevated transaminases in a patient on immunotherapy can reflect disease progression into the liver, cirrhosis decompensation, or a true irAE, and each possibility must be actively excluded. A scan ruling out progression and a bilirubin that has not risen help narrow the differential, since worsening cirrhosis typically tracks with bilirubin elevation. With viral hepatitis serologies negative and imaging unrevealing, the diagnosis was grade 3 immune-mediated hepatitis.

CASE UPDATE

• Treatment was held temporarily.​
• Increased monitoring: Liver function tests (LFTs) were performed 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.

Venu Bathini, MD, a GI-focused medical oncologist at a Massachusetts General Brigham–affiliated practice in Framingham, MA, said he counsels patients upfront that CTLA-4–based combinations carry higher toxicity but that responders may achieve long-term survival, a framing drawn directly from melanoma data showing that even 1 or 2 doses of ipilimumab before discontinuation can confer durable benefit.¹

“Looking back at the melanoma data, patients who got even 2 doses of ipilimumab, or even 1 dose, and then discontinued, did far better than monotherapy,” Bathini said. “That’s the way I counsel them.”

Estephan questioned how many patients in CheckMate 9DW (NCT04039607) who experienced a significant irAE completed all 4 ipilimumab doses before converting to nivolumab maintenance. Mahipal acknowledged the completion rate was not immediately available but incomplete ipilimumab courses followed by nivolumab were well documented in the trial and associated with favorable outcomes, consistent with the finding that patients who discontinued due to toxicity had a median overall survival (OS) of 27.9 months compared with 23.7 months for the overall nivolumab plus ipilimumab arm.²

SCENARIO 2

In an alternate scenario, the patient was treated with a single dose of 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 lb without dietary change.​
• Routine laboratory results:
  • Thyrotropin level elevated: ​37.5 mlU/mL​
  • Free T4 level: 0.3 ng/dL​
  • Free T3 level: 2 pg/mL ​
• Further workup​:
  • No goiter, myxedema or bradycardia; mild periorbital puffiness​
  • Diagnosis: grade 3 immune-mediated hypothyroidism​

Mahipal used this case to make a point he returned to throughout the safety discussion: CTCAE grade is not a management protocol. Grade 3 hypothyroidism requires levothyroxine replacement and monitoring rather than a treatment hold or steroids. “Grade 3 hepatitis, I believe, is very different than grade 3 hypothyroidism,” Mahipal told the group. “We have to make a clinical judgment based on what kind of toxicity, what grade, and what symptoms the patient has.”

CASE UPDATE

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

By week 12 on treatment:​

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

The group discussed the HIMALAYA trial (NCT03298451) safety data in this context. Among patients receiving the STRIDE regimen, grade 3/4 treatment-related AEs occurred in 25.8%, immune-mediated grade 3/4 events in 12.6%, and treatment-related discontinuation in 8.2%, a more favorable profile than the nivolumab plus ipilimumab arm of CheckMate 9DW, where Mahipal noted that grade 3/4 treatment-related events reached 41%, immune-mediated grade 3/4 events 28%, and discontinuation 18%.^3,4 He attributed the difference largely to the single-dose tremelimumab design in STRIDE vs 4 cycles of ipilimumab at 3 mg/kg in CheckMate 9DW. Estephan noted that 3 mg/kg ipilimumab behaves as a meaningfully different drug from the 1 mg/kg dose used in non–small cell lung cancer combination regimens.

SCENARIO 3

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

• On week 8 of treatment​:
  • The patient reported increased fatigue, mild shortness of breath, and lower extremity swelling​.
  • He noticed frequent urination and foamy urine in the past week​.
• Evaluation and workup​:
  • 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​

Mahipal reviewed the workup and distinguished this from the irAEs in the prior 2 cases: bevacizumab-class toxicity is not steroid responsive and requires bevacizumab dose modification or hold rather than immunosuppression. IMbrave150 (NCT03434379) data showed proteinuria in approximately 29% of patients and hypertension in approximately 28%,⁵ with both becoming more clinically prominent as patients remain on treatment for longer periods than was typical in early real-world use. Several participants said they were now seeing more cumulative bevacizumab toxicity as responses deepened and treatment durations extended.

Mahipal closed with a cross-trial safety summary, noting that although grade 3/4 treatment-related AEs were broadly comparable between nivolumab plus ipilimumab (41%) and atezolizumab plus bevacizumab (43%),^3,5 the nature of those events differs in ways that matter to patient selection and monitoring: dual immunotherapy produces more immune-mediated hepatitis, hypothyroidism, and rash; atezolizumab plus bevacizumab adds proteinuria and hypertension that require a distinct management algorithm.

“The toxicities are real,” Mahipal said. “But patients who did discontinue because of treatment-related events actually tend to do better; they lived a long time, with long-term benefits from therapy.”

Trehan offered the closing observation that framed the group’s consensus: “I think that is the key; you learn how to manage them; you learn how to live with them. I would not avoid any treatment for fear of toxicity.”

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_{DISCLOSURES: Mahipal previously reported honoraria from Astellas, AstraZeneca, and BeiGene.}

REFERENCES:

1. Schadendorf D, Wolchok JD, Hodi FS, et al. Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol. 2017;35(34):3807-3814. doi:10.1200/JCO.2017.73.2289

2. Sangro B, Decaens T, Galle PR, et al. Overall evaluation of health-related quality of life (HRQoL) and efficacy assessment in patients (pts) who discontinued (d/c) due to treatment-related adverse events (TRAEs): Results from CheckMate 9DW. Ann Oncol. 2025;36(suppl 1):S62-S63. doi:10.1016/j.annonc.2025.05.161

3. 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

4. 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

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