Hepatobiliary Cancer Coverage from Every Angle

Tremelimumab Plus Durvalumab

Posted: Wednesday, January 11, 2023

First Worldwide Approval

On October 21, 2022, the U.S. Food and Drug Administration (FDA) approved tremelimumab-actl (Imjudo) in combination with durvalumab (Imfinzi) for the treatment of adults with unresectable hepatocellular carcinoma (HCC).1 This represents the first worldwide approval for tremelimumab,2 a cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)-blocking antibody. In contrast, durvalumab,3 a PD-L1 inhibitor, is already approved for several indications, including in the treatment of non–small cell and small cell lung cancers as well as biliary tract cancers (durvalumab in combination with gemcitabine and cisplatin). Combining the two antibodies is an effort to harness CTLA-4 inhibition as part of a dual immunotherapy regimen with a PD-L1 inhibitor.

The approval of this combination regimen was based on the final results of the phase III HIMALAYA trial.4 The investigators of this trial reported a significant improvement in overall survival with tremelimumab/durvalumab compared with sorafenib. 

When asked about the setting of unresectable HCC, Robin Katie Kelley, MD, Professor of Clinical Medicine at the Hellen Diller Family Comprehensive Cancer Center at the University of California in San Francisco, shared her thoughts with JNCCN 360. Dr. Kelley was a researcher on the HIMALYA trial and is a coauthor on the publication of the study.4

Dr. Kelley commented: “The majority of patients who are either diagnosed with or progress to advanced stages of HCC are deemed to have unresectable disease because they have metastatic spread outside the liver; or there may be cancer involvement of the blood vessels within the liver, such that surgery to remove the tumor tissue is not possible. Sometimes, the liver may be so dysfunctional that surgery is not feasible; in some cases, with small sizes and number of tumors, liver transplantation may be an option, but for others, the extent of tumor burden also warrants starting systemic therapy.”

Another researcher and coauthor on the HIMALAYA study, A. Vincent Tam, MD, Associate Clinical Professor of Oncology and a medical oncologist at the Tom Baker Cancer Centre, University of Calgary, Canada, concurred that many HCCs are inoperable at diagnosis. “Nevertheless,” he pointed out, “routine ultrasound screening of high-risk patients with liver cirrhosis, and particularly those with hepatitis B, can lead to a diagnosis of HCC at an earlier stage. Solitary HCCs without invasion into the vasculature, with preserved liver function and no portal hypertension,” he added, “are usually resectable.” Having multiple HCCs that are large and more diffusely distributed in the liver, particularly if there is involvement of the cancer outside the liver (eg, vascular invasion, lymph node or distant metastases), “would make the patient’s situation unresectable and more likely appropriate for systemic treatment,” he told JNCCN 360. 

An Unmet Need

Before the new tremelimumab/durvalumab regimen was approved, recommended first-line systemic therapy options for certain patients with advanced or metastatic unresectable HCC included sorafenib, lenvatinib, atezolizumab plus bevacizumab, durvalumab, pembrolizumab, or nivolumab.5 According to Dr. Kelley, “sorafenib was the standard of care from 2007 to 2020.

In 2020, the IMbrave150 trial6 showed that the combination of atezolizumab plus bevacizumab was associated with significant improvement in overall survival, progression-free survival,and objective response rate—with acceptable safety and tolerability. These results led to global uptake of the atezolizumab-plus-bevacizumab regimen as the preferred systemic first-line treatment of patients with preserved underlying liver function, meaning Child-Pugh A and without contraindications to bevacizumab.” Dr. Kelley noted that those contraindications, which include severe portal hypertension with high-risk esophageal or gastric varices, confer bleeding risk and would render such patients ineligible for that bevacizumab-containing regimen.

Elaborating about the unmet need for systemic treatment of HCC, Dr. Tam observed that “although atezolizumab plus bevacizumab represents a significant improvement in efficacy and tolerability compared with sorafenib, patients with untreated esophageal varices, low platelets, increased bleeding risk, poorly controlled hypertension, and significant autoimmune disease may be ineligible for treatment with this regimen.”

Priming the Immune System

“Preclinical and translational studies suggest that tremelimumab elicits an initial population of activated, proliferative T cells in circulation, regional lymph nodes, and the microenvironment that would then prime a response to durvalumab.”

The HIMALAYA regimen was developed with the CTLA-4 agent—tremelimumab—given as a single dose only on day 1, “as a loading dose, with the intent to prime the immune system,” Dr. Kelley explained. “Preclinical and translational studies suggest that tremelimumab elicits an initial population of activated, proliferative T cells in circulation, regional lymph nodes, and the microenvironment that would then prime a response to durvalumab.”

The phase III HIMALAYA trial was a randomized, open-label, multicenter trial including patients with unresectable HCC who had Child-Pugh A liver function with no prior systemic therapy. Patients were randomly assigned to receive tremelimumab at 300 mg plus durvalumab at 1,500 mg (STRIDE), durvalumab monotherapy, or sorafenib.4 “Initially, the study included an arm with a lower dose of tremelimumab (75 mg), but this arm was discontinued after the phase II study7 showed that tremelimumab at 300 mg plus durvalumab at 1,500 mg was the superior combination in terms of efficacy,” Dr. Tam said.

HIMALAYA showed that the STRIDE regimen improved overall survival compared with sorafenib (median overall survival of 16.4 vs. 13.8 months, respectively; hazard ratio = 0.78, P = .0035). “STRIDE had a manageable safety profile, and the time to deterioration in quality of life favored STRIDE over sorafenib, which is in keeping with my clinical experience,” Dr. Tam told JNCCN 360.

Although this new first-line therapy is considered a “combination” regimen, “tremelimumab is given only once in cycle 1, on day 1, prior to the durvalumab,” Dr. Kelley told JNCCN 360. “There are no premedications necessary. Those would only be considered if a patient had experienced an infusion reaction to a prior dose,” she explained. “In our experience, infusion reactions have been quite rare with both tremelimumab and durvalumab. After the first cycle, durvalumab alone is continued every 4 weeks.”

Dr. Tam described durvalumab administration, explaining that “prior to each treatment, patients have their blood drawn and see their oncologist to discuss tolerability of the infusion and whether they have any new symptoms from the cancer or treatment. The infusion time totals approximately 120 minutes for cycle 1 when both drugs are given; then 60 minutes for subsequent infusions of durvalumab. No standard medications before or after treatment with durvalumab are required.”

Tolerability of Dual Immune Checkpoint Inhibition

“With dual immune checkpoint inhibitor therapy, a top concern is making sure we don’t miss any immune-related toxicity,” Dr. Kelley noted. “We monitor carefully for any laboratory abnormalities, particularly liver function test abnormalities. Additionally, we watch for symptomatic toxicities, ranging from respiratory symptoms (such as cough or shortness of breath), which can be a sign of early pneumonitis, to gastrointestinal toxicities (such as nausea, vomiting, pancreatitis symptoms, colitis, or enterocolitis-type symptoms like severe mucoid or bloody diarrhea, or dermatologic toxicities). During our trial, we noted that a common side effect of the combined regimen was pruritus. Fortunately, the itching was self-limited and tended to resolve within about the first 3 months.”

“With dual immune checkpoint inhibitor therapy, a top concern is making sure we don’t miss any immune-related toxicity.”

Dr. Tam reported that there were higher rates of grade 3 or 4 immune-related adverse events with the STRIDE regimen (12.6%) than with durvalumab monotherapy (6.2%) on the HIMALAYA trial.4 Nevertheless, “I have not observed any red flags when treating my patients with these regimens so far,” he noted.

Diarrhea, rash, and pruritus are the most common side effects, Dr. Tam continued, noting that patients should be monitored during treatment with regular blood work to assess for hepatitis, hypothyroidism, pancreatitis, and adrenal insufficiency. “In patients with HCC who also likely have underlying liver disease, it is important to monitor liver enzymes and bilirubin for signs of treatment-related autoimmune hepatitis impairing liver function. Treatment should be held if there is a concern regarding autoimmune hepatitis,” he cautioned.

Strategy After First-Line Therapy

Despite the efficacy of first-line treatments, most patients with any advanced or metastatic malignancy eventually experience disease progression. Both Drs. Kelley and Tam acknowledged there are currently no clinical trial data to support the use of any specific second-line regimens after either of the immunotherapy-based combinations.

“Most oncologists would favor the use of an oral tyrosine kinase inhibitor, such as lenvatinib or sorafenib, in the second-line setting,” Dr. Tam told JNCCN 360. “My preference is lenvatinib, which has shown superior response rates and progression-free survival compared with sorafenib in the first-line HCC setting (REFLECT trial).8 The median overall survival with first-line lenvatinib monotherapy from the recently presented LEAP-002 trial9 was also very impressive.”

More Treatment Choices, More Customized Decisions

“Now that we have multiple agents and regimens, including older drugs such as sorafenib and levantinib, as well as the combination regimens atezolizumab plus bevacizumab and tremelimumab plus durvalumab,” Dr. Kelley commented, “clinicians are in the favorable position of being able to select first-line treatment based on the patient’s individual clinical scenario. Although we do not have clinical indicators or biomarkers to predict which regimen will be most effective,” she added, “we can make assessments about which regimen will be safest based on the patient’s comorbidities and risk factor profile.”

“We can make assessments about which regimen will be safest based on the patient’s comorbidities and risk factor profile.”

The key differences between the two combination regimens (atezolizumab plus bevacizumab versus tremelimumab plus durvalumab) is that the bevacizumab-containing combination requires endoscopy and is also associated with a higher risk of thromboembolic events. According to Dr. Kelley, “this may not be the best choice of regimen for patients at high risk for blood clots/bleeding or other cardiovascular events. In contrast, the STRIDE regimen of tremelimumab plus durvalumab does not include an antiangiogenic component and may be a better choice for those patients with a high bleeding risk or cardiovascular risk.” Endoscopy is not required with the dual checkpoint inhibitor combination beyond the standard indications, and patients are not excluded based on endoscopic findings, unless active bleeding is present.

The population of patients with HCC is increasingly being driven by nonalcoholic fatty liver disease, Dr. Kelley observed, “a condition that often goes hand in hand with comorbidities, such as diabetes, hypertension, and cardiovascular disease. A regimen such as tremelimumab plus durvalumab may be a good option for patients who may be at higher risk for cardiovascular complications with bevacizumab.”

Dr. Tam shared a key take-away message for clinicians who are not familiar with the STRIDE regimen: The tremelimumab-plus-durvalumab combination is generally a well-tolerated regimen that has shown a significant survival benefit compared with earlier, first-line therapies for patients with unresectable HCC. “It could be considered a preferred first-line regimen in many patients with HCC and particularly in those with untreated esophageal varices, low platelets, increased bleeding risk, or poorly controlled hypertension,” he said.

“Tremelimumab plus durvalumab could be considered a preferred first-line regimen in many patients with HCC and particularly in those with untreated esophageal varices, low platelets, increased bleeding risk, or poorly controlled hypertension.”


Robin Katie Kelley, MD, has served as a consultant or advisor to Agios, AstraZeneca, Bristol Myers Squibb, Merck, and Exelixis/Ipsen with compensation to her institution. She has also served as consultant with personal compensation from Exact Sciences and Kinnate; has received institutional research funding from Lilly, Exelixis, Novartis, Bristol Myers Squibb, MedImmune, Merck Sharp & Dohme, Agios, AstraZeneca, Adaptimmune, Taiho Pharmaceutical, Bayer, QED, EMD Serono, Partner Therapeutics, Genentech/Roche, Surface Oncology, Relay Therapeutics, and Loxo/Lilly.

Vincent Tam, MD, has received honoraria from or participated in advisory boards for AstraZeneca, Eisai, Incyte, Ipsen, and Roche. In addition, he has received institutional research funding (to Tom Baker Cancer Centre) from AstraZeneca, Eisai, Ipsen, Roche, and clinical trials funding from AstraZeneca, Basilea, Exelixis, Merck, and Roche.


  1. S. Food and Drug Administration. FDA approves tremelimumab plus durvalumab for adult patients with unresectable hepatocellular carcinoma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tremelimumab-combination-durvalumab-unresectable-hepatocellular-carcinoma. Accessed December 15, 2022.
  2. Tremelimumab-actl (Imjudo). Prescribing information. AstraZeneca. October 2022. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761289Orig1s000Correctedlbl.pdf. Accessed December 15, 2022.
  3. Durvalumab (Imfinzi). Prescribing information. AstraZeneca. November 2022. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761069s033lbl.pdf. Accessed December 15, 2022.
  4. Abou-Alfa G, Lau G, Kuno M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid 2022;1(8).
  5. Benson AB, D’Angelica MI, Abbott DE, et al. NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers. Version 4.2022—December 9, 2022. To view the most recent version, visit NCCN.org.
  6. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020;382:1894–1905.
  7. Kelley RK, Sangro B, Harris W, et al. Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: randomized expansion of a phase I/II study. J Clin Oncol 2021;39:2991–3001.
  8. Kudos M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomized phase 3 non-inferiority trial. Lancet 2018;391:1163–1173.
  9. Finn RS, Kudo M, Merle P, et al. Primary results from the phase III LEAP-002 study: lenvatinib plus pembrolizumab versus lenvatinib as first-line therapy for advanced hepatocellular carcinoma. ESMO Congress 2022. Abstract LBA34.

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