The use of durvalumab and tremelimumab after atezolizumab and bevacizumab in patients with hepatocellular carcinoma: case report and literature review

ABSTRACT

Hepatocellular carcinoma (HCC) often presents at an advanced stage, limiting treatment options. Historically, systemic therapies like tyrosine kinase inhibitors and VEGF-targeted antibodies offered modest survival benefits. HCC’s immunosuppressive microenvironment, driven by regulatory T cells, myeloid-derived suppressor cells, and immune checkpoint signaling, hinders effective therapy. Immune checkpoint inhibitors (ICPIs) have revolutionized HCC management by targeting these pathways. Atezolizumab and bevacizumab (Atezo/Bev) is the standard first-line therapy for unresectable HCC, but post-progression options are limited. We explore the potential of switching to durvalumab and tremelimumab (Durva/Treme) as a second-line strategy. Recently approved, Durva/Treme shows promise, yet data on sequential ICPI use remain scarce. This editorial highlights the rationale for this approach, leveraging distinct immune targets to overcome resistance. Preliminary evidence suggests durable responses are achievable, but robust clinical trials are needed to validate efficacy, optimize sequencing, and identify biomarkers. Durva/Treme’s role as a second-line option could address the critical gap in HCC treatment, challenging the immunosuppressive tumor microenvironment. We advocate for bold innovation to improve outcomes in this complex disease, urging further research into ICPI rechallenge strategies to transform the therapeutic landscape for patients with unresectable HCC.

Plain Language Summary

Liver cancer (hepatocellular carcinoma or HCC) is often diagnosed at a late stage, making treatment difficult. A common first-line therapy is a combination of two drugs atezolizumab and bevacizumab but many patients eventually stop responding to this treatment. In this article, we present a case of a patient whose cancer progressed after receiving this stander therapy. The patient was then treated with a different combination of immunotherapy durvalumab and tremelimumab which led to stable disease and no major side effects. This case suggests that switching to a different immune-based treatment may still offer benefits, even after initial therapy stops working. More research is needed, but this approach could provide new options for patients with advanced liver cancer.

1. Introduction

Hepatocellular carcinoma (HCC) is a major global health challenge, accounting for 75–85% of all liver cancer cases, and is the third leading cause of canfoucer-related mortality [1]. HCC is primarily driven by cirrhosis caused by infections such as hepatitis B virus (HBV) or hepatitis C virus (HCV). Other contributing factors include alcohol consumption, dietary habits, drug use, autoimmune hepatitis, sedentary lifestyle, and nonalcoholic fatty liver disease, which caused a rise in the incidence of HCC despite the availability of treatment for hepatitis B and hepatitis C virus-related cirrhosis [2]. Diagnosis of HCC is mainly based on radiologic findings, which sometimes makes it challenging to diagnose particularly in the early disease stages due to mild or nearly absent symptoms. Early-stage manifestations, such as abdominal pain, weight loss, and fatigue, are often nonspecific, especially in patients with underlying liver disease like cirrhosis or hepatitis. As the disease progresses, more symptoms may appear, including jaundice, ascites, and fever, which are indicative of advanced liver damage. The overlap of those of chronic liver conditions further complicates early detection, and even advanced imaging may find it difficult to identify small lesions, delaying diagnosis and treatment [3]. Noninvasive imaging techniques, such as computed tomography [4] or magnetic resonance imaging (MRI), are frequently used to diagnosis HCC by radiographic characteristics, including arterial hyperenhancement, venous washout, and capsule enhancement. The Liver Imaging and Data System (LI-RADS) is a widely used scoring system for diagnosis HCC in patients with HBV infection or cirrhosis. It demonstrates a sensitivity of 76% and a specificity of 93% for identifying lesions larger than 1 cm in diameter. A biopsy remains essential for patients presenting with LR-4 or higher observation who lack risk factors for HCC or exhibit atypical imaging features. The use of biomarkers, including alpha-fetoprotein (AFP), prothrombin induced by vitamin K absence or des-gamma-carboxyprothrombin (DCP), and glypican-3, has demonstrated potential in enhancing the early detection of HCC [3].

1.1. Management approach of HCC

The presence of various first and subsequent-line systemic options for chemotherapy have widely changed the cornerstone of the treatment of HCC [5–10]. HCC predominantly arises as a result of cirrhosis which can highly affect the patient’s responses, eligibility, and tolerance to various treatment options. Thus, the management of patients with HCC needs an individualized treatment plan tailored to their unique characteristics.

The Barcelona Clinic Liver Cancer (BCLC) system is commonly used in clinical practice to guide treatment decisions and predict outcomes for HCC, based on the stage at diagnosis. Treatment options for HCC include liver transplantation, surgical resection, liver-directed therapies (such as locoregional treatments targeting the liver), systemic therapies (including immunotherapy), and combinations of these approaches [4]. Without treatment, HCC has a poor prognosis, with a median overall survival (OS) of 9 months and a 3-year survival rate of 12.7%. Liver transplantation, radiofrequency and microwave ablation, and surgical resection are the only curative treatments and are preferred for early-stage tumors due to their better outcomes. Resection is a primary treatment for HCC, but some patients may be deemed unresectable due to tumor location, extent, or advanced cirrhosis. For patients with intermediate-stage disease, liver-directed therapies such as transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) are suitable options. Systemic therapies are primarily reserved for those with advanced disease [4].

1.2. The immune microenvironment of HCC

The regulation of tumor progression and response to therapy, including resistance, are due to the tumor immune microenvironment, which plays a crucial part in regulating tumor actions. The immune microenvironment in HCC consists mainly of immunosuppressive cells and signals that aid in tumor evasion and metastasis to distant sites. The macrophages of the liver, known as Kupffer cells, reside in the liver sinusoids and primarily function to clear pathogens and cellular debris from the blood passing through the liver. These cells, along with M2-type tumor-associated macrophages, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) form the major immunosuppressive cells in HCC. Kupffer cells can induce tolerance by secreting factors that suppress T cells including interleukin (IL)-10, transforming growth factor (TGF)-B, and prostaglandin E2 [5]. Hepatic macrophages transition from the M1 phenotype to the cancer promoting M2 phenotype, resulting in the formation of tumor-associated macrophages, which in turn suppress the immune response, resulting in tumor growth, metastasis, and resistance to therapy. This promotes immune escape by various ways such as expression of PD-L1, downregulation of major histocompatibility complex class II (MHC-II), which plays a crucial role in the activation of CD4+ helper T cells by presenting tumor-associated antigens to the surface of these cells and in the whole anti-tumor immune response. Tregs, on the other hand, promote immune tolerance by targeting effector T cells or via antigen-presenting cells (APCs) modulation [5]. Tregs can target APCs by expressing cell surface receptors that have the ability to negatively regulate and suppress immune responses. Such receptors include cytotoxic T lymphocyte antigen 4 (CTLA-4), CD39, and CD73. It also can induce apoptosis in APCs by secreting perforin and granzyme B. Therefore, high levels of Tregs within the tumor microenvironment are often associated with poor prognosis among HCC patients [5].

1.3. HCC systemic and immunotherapy

Up until the year 2007, no standard systemic therapy was available for the treatment of HCC other than a few cytotoxic chemotherapies that were used and carried a high-risk profile with no or limited disease outcomes. In recent decades, the options for systemic treatment of unresectable HCC were mainly restricted to the anti-vascular endothelial growth factor receptor (VEGFR) and multi-target tyrosine kinase inhibitor (TKI) sorafenib [11]. The first clinical trial was the SHARP trial, which was carried out in the year 2007. The trial revealed an improvement in the survival outcomes among HCC patients who received sorafenib as part of their treatment regimen. Treatment with sorafenib has led to an increase in the median OS from 7.9 months to 10.7 months when compared to placebo (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.55–0.87; p < 0.001) [12]. In 2018, the Food and Drug Administration (FDA) approved lenvatinib, a multi-kinase TKI, as a first-line treatment for unresectable HCC, following the phase 3 randomized controlled trial (REFLECT: NCT01761266), which demonstrated that Lenvatinib median OS was not inferior to that of sorafenib (median OS 13.6 vs. 12.3 months, HR 0.92, 95% CI 0.79–1.06) [13]. A higher rate of treatment-related side effects was observed in the lenvatinib arm (43% vs. 30%).

Regarding later line settings, regorafenib was studied in the RESORCE study where HCC patients who were previously treated with sorafenib and encountered disease progression were allocated to either regorafenib or placebo. Regorafenib was found to improve median OS (10.6 months vs. 7.8 months, HR 0.63, p < 0.0001). Regarding safety outcomes, 46% of patients receiving regorafenib had grade 3 or 4 adverse events.

The CELESTIAL trial later studied the effect of cabozatinib, a multi-kinase TKI, in HCC patients who encountered disease progression after receiving 1 or 2 systemic treatments. Eligible patients were randomized to either receive cabozatinib or placebo. Patients treated with cabozatinib had an improved median OS of 10.2 months compared to 8 months in placebo (HR 0.76, 95% CI 0.63–0.92, p = 0.005) and median progression free survival (PFS) (5.2 vs. 1.9 months, HR 0.44, 95% CI 0.36–0.52, p < 0.001). Regarding safety profile, grade 3 or 4 treatment-related adverse events were encountered in 68% of patients in the cabozatinib arm. Cabozatinib was approved as a subsequent line in HCC patients who were previously treated with sorafenib in 2019.

Another agent was ramucirumab, a monoclonal antibody against VEGF receptor 2, which was studied in a randomized controlled trial in HCC patients with BCLC stage B or C who encountered disease progression on first-line sorafenib and who had a concentration of AFP of 400 ng/mL or greater. Ramucirumab resulted in an improved median OS among HCC patients (8.5 vs. 7.3 months in placebo, HR 0.71, 95% CI 0.53–0.95, p = 0.019) and median PFS (2.8 vs. 1.6 months, HR 0.45, 95% CI 0.34–0.60, p < 0.0001) [12].

Immune Checkpoint Inhibitors (ICPIs) have revolutionized the treatment and management of HCC after a study published in the year 2013 that demonstrated the safety profile and the efficacy of tremelimumab, a CTLA-4 inhibitor, against tumors in patients with HCC and HCV cirrhosis. ICPIs became widely used in clinical practice and it became a cornerstone in most HCC treatment regimens. However, not many patients responded to ICPIs as monotherapy, hence emphasizing the need for further research and trials of combined therapeutic options which may possibly yield superior response in HCC treatment [14].

The IMbrave-150 trial was a landmark trial in HCC treatment, which established the survival benefit of combining immunotherapy with targeted therapy [15,16]. This trial demonstrated that first-line treatment with atezolizumab and bevacizumab (Atezo/Bev) offered superior efficacy to sorafenib alone. Nevertheless, the majority of patients eventually progress on these therapies. In the IMbrave-150 trial, PFS for patients receiving Atezo/Bev was 6.9 months. In 2020, the FDA approved the combination of Atezo/Bev, which is now recognized as the standard of care for first-line systemic treatment of unresectable HCC [13].

Current treatment guidelines for patients who progress on Atezo/Bev recommend the use of monotherapy with TKIs or ramucirumab, with some case series suggesting benefits from the combination of nivolumab and ipilimumab as a second-line therapy post Atezo/Bev [17,18]. However, these treatments have limited efficacy and underscore the need for more effective second-line treatment options [19]. Furthermore, a subset of patients undergoes treatment discontinuation due to the toxicity from the combination of Atezo/Bev, with bleeding a significant morbidity and mortality risk. Even after excluding high-risk patients in the IMbrave-150 trial [15], about 10% of those treated experienced bleeding, and 6–10% suffered from grade 3 or higher hemorrhage [15,16].

More recently, the FDA approved the combination of durvalumab and tremelimumab (Durva/Treme) in 2022. The HIMALAYA trial further expanded the therapeutic landscape by showing an OS benefit for patients treated Durva/Treme compared to sorafenib as a first-line therapy [20]. However, given the paucity of effective second-line options, a query arises on the value of trying Durva/Treme as a second-line option. Advanced HCC patients have limited second-line treatment options after progressing on first-line therapies, highlighting the need for novel ICPI combinations like Durva/Treme to fill this critical treatment gap [21,22].

When ICPIs are stopped because of tumor progression, there are no established methods for addressing acquired resistance. Switching from one class of ICPIs to another might be an experimental approach to potentially restore the tumor’s responsiveness to immunotherapy [23]. This concept was initially established in the treatment of melanoma [24]. Due to the lack of data from prospective clinical trials, the role of subsequent ICPIs uses in patients with HCC who have previously received ICPIs treatment remains unclear [25].

In this paper, we present a unique case of a patient with unresectable HCC who received Durva/Treme following disease progression on first-line therapy of Atezo/Bevand subsequent rechallenge with Atezo/Bev therapy, who achieved a durable response throughout treatment. This case illustrates to demonstrate durable clinical benefit from sequential ICPIs strategies, including class-switching from -Atezo/Bev to Durva/Treme. We aim to highlight the potential of this combination as a second-line treatment in patients with unresectable HCC.

2. Case presentation

Our patient is a 59-year-old male who was diagnosed with HCC upon undergoing a PET/CT imaging which revealed a large mixed attenuation heterogeneously FDG-avid invasion of the right hepatic lobe with small intrahepatic metastases versus a multifocal primary tumor in the right hepatic lobe Figure 1. Upon referral to Houston Methodist, the patient received eight cycles of Atezo/Bev and was already on cabozantinib, which he continued to take and later underwent TARE to treat a hepatoma in the right lobe of his liver. Subsequent CT scans of the abdomen showed smaller hepatic lesions (≤1.3 cm) that indicated likely metastasis, so the patient underwent a rechallenge treatment with Atezo/Bev. Following three successful cycles, follow-up imaging revealed a stable dominant hepatic mass, with residual arterial enhancing focus in the left anterior measuring up to 2.8 X 2.6 cm. However, multiple new enhancing lesions was observed. A new lesion in hepatic segment 8/5. Additionally, there was an increase in size of a right hepatic lesion, and a new lesion was identified in segment consistent with progressive disease. This prompting a switch to an ICPI combination of Durva/Treme, adhering to STRIDE protocols. CT chest imaging acquired shortly following the new regimen showed interval growth of multiple metastatic pulmonary nodules, likely indicative of early metastasis. All AFP tumor marker levels were within range and demonstrated a relatively consistent decline over the course of treatment, even when PD was evident. At his most recent follow-up, the patient appeared to be stable. This case demonstrated disease stabilization rather than an objective radiological response. The initial interval growth of pulmonary nodules with later stability raises the possibility of a delayed immune-mediated effect, which is recognized in the context of ICPI therapy. Figure 2 illustrates the clinical responses and therapeutic interventions for the patient alongside the timeline of his treatment.

Figure 1.

MRI of the upper abdomen demonstrating multifocal hepatic lesions in the right lobe, consistent with hepatocellular carcinoma in a background of chronic liver disease. Lesions appear heterogeneously enhancing with irregular margins.

Figure 2.

Patient’s clinical history timeline. AtezoBev: Atezolizumab/bevacizumab, DurvaTreme: Durvalumab/tremelimumab, TACE: transarterial chemoembolization, TARE: transarterial radioembolization.

3. Discussion

Sorafenib was the first targeted therapy to demonstrate a survival benefit in patients with unresectable HCC, extending OS to approximately 10 months [26,27], leaving room for further improvement in HCC management and outcomes.

Recent studies and research in immunotherapy have revolutionized the landscape of HCC treatment, with single-agent immunotherapies showing good efficacy in HCC treatment. However, response rates remain low. Liver tumors generally have many immunosuppressive factors necessitating combination therapies that target multiple immune pathways to enhance treatment efficacy. Hence emerged the utilization of combined ICPIs in the treatment of HCC to provide dual blockage of more than one pathway of immune suppression which was expected to yield a superior response than blocking a single immunosuppressive factor [5].

The combination of atezolizumab, a PD-L1 inhibitor, along with bevacizumab, a VEGF inhibitor, was evaluated in the IMbrave150 and reported the median OS in Atezo/Bev arm as 19.2 months (95% CI 17.0–23.7) and the median PFS was 6.9 months (95% CI 5.7–8.6). HIMALAYA trial assessed the combination therapy of durvalumab PDL-1 inhibitor, with tremelimumab (CTLA-4 inhibitor). The median OS (16.43 months) was found in patients who received Durva/Treme combination therapy [14].

These trials established Atezo/Bev and Durva/Treme as first-line treatment options for unresectable or advanced HCC. However, choosing the appropriate first-line treatment for patients with HCC remains challenging as there is no direct comparison between these two regimens [28]. The American Association for the Study of Liver Diseases (AASLD) guidelines recommend Atezo/Bev for treating advanced- or intermediate-stage HCC, except for liver transplant and autoimmune disease cases [29]. In contrast, Durva/Treme is specifically indicated for cases with a high risk of gastrointestinal bleeding. On the other hand, the landscape for second-line therapy post-progression on first-line ICPI-based therapies remains inadequately defined due to the absence of well-designed randomized controlled trials and no prospective studies on ICPI rechallenge have been released.

Current treatment guidelines, such as those from the National Comprehensive Cancer Network (NCCN), recommend TKIs like cabozantinib or lenvatinib as second-line therapies. According to the American Society of Clinical Oncology (ASCO) 2024 guideline update, after progression on first-line Atezo/Bev, eligible patients may receive one of the following on the second line: TKIs (e.g., cabozantinib) ramucirumam (for AFP ≥400 ng/mL), Durva/Treme, or Nivo/Ipi [18]. The CELESTIAL trial demonstrated that cabozantinib offers a median OS of 10.2 months compared to 8.0 months with placebo, and a median PFS of 5.2 months versus 1.9 months with placebo. Additionally, the efficacy of Lenvatinib in patients who had progressed on ICPI therapy was reported by Aoki et al. with a median OS of 15.8 months, median PFS of 10 months, and an ORR of 55.6%, demonstrating lenvatinib as a viable second-line option.

There is anecdotal evidence supporting the use of combination immunotherapy as a rechallenge after Atezo/Bev. Roessler et al. analyzed patients receiving nivolumab plus ipilimumab after prior ICPI-based treatment failure and reported median OS and median PFS of 7.4 months and 2.9 months, respectively, with overall response rate of 30% [11]. Wong et al. also reported on patients receiving ipilimumab with either nivolumab or pembrolizumab, noting a median OS of 10.9 months, median PFS of 3.0 months, and an ORR of 16%.

Currently available retrospective reports on ICPI rechallenge include a study by Sho et al. which analyzed 45 patients treated with Durva/Treme. Of these patients, 55.6% (25/45) underwent ICPI rechallenge. The ORR for these patients was 14.3% (3/21), while the DCR was 47.6% (10/21), while all patients who had the best response to PD with initial Atezo/Bev also experienced PD during the ICPI rechallenge. Comparable to the rates observed in those initially treated with Durva/Treme. The study concluded that the safety and efficacy profiles of Durva/Treme as ICPI rechallenge are satisfactory [30]. Recent evidence supports the feasibility of ICPIs rechallenge strategies in advanced HCC. In 2024 study published by Lai et al., evaluated patients who had progressed in anti-PD-1 agents and were subsequently treated with durvalumab. The study demonstrated that a subset of patients experienced clinical benefit, including disease stabilization and manageable toxicity profiles. This finding suggest that switching from one ICPI class to another specifically from ant-PD-1 to anti-PD-L1 therapy may help overcome primary or acquired resistance mechanisms in certain individuals [31].

In contrast to this retrospective study by Ryoichi et al., 16 patients with unresectable HCC were treated with Atezo/Bev as first-line therapy, followed by Durva/Treme second-line therapy. The study focused on ICPIs by directly switching between ICPI regimens. The ORR for Atezo/Bev was 56.3%, with a DCR of 87.5%, whereas the ORR for Durva/Treme was 0%, with a DCR of 62.5%. Notably, the ORR for second-line ICPI therapy was significantly lower than that of first-line treatment [32].

Our study focused on immunotherapy rechallenge but with a regimen that has proven efficacy in a randomized controlled trial setting in patients with unresectable HCC. The regimen demonstrated reasonable efficacy in our patient resulting in SD 6 months after starting Durva/Treme. Although stable disease does not constitute an objective response, it may still indicate disease control in a patient who had previously demonstrated progression. This outcome, particularly in the setting of limited therapeutic alternatives, supports the consideration of ICPI rechallenge in select clinical scenarios.

Although the use of Durva/Treme following Atezo/Bev is associated with a higher incidence of immune-related adverse events (irAEs) due to the intensified immune response and disruption of immune system balance the clinical benefits of this combination often outweigh the risks. The rate of grade 3 or 4 irAEs is around 14% with anti-PD-1 monotherapy, 23% with anti-CTLA-4 monotherapy, and 53% with combination therapy [33]. Sho et al., reported the incidence of adverse events was similar between the groups receiving Durva/Treme as ICPI rechallenge and those receiving it initially. Furthermore, 75% of patients who had irAEs with Atezo/Bev encountered similar irAEs during ICPI rechallenge [30]. Conversely, Ryoichi et al.‘s retrospective study reported no Grade 3 irAEs occurred during Atezo/Bev treatment, 37.5% of patients experienced Grade 3 irAEs during Dur/Treme therapy. Colitis was the most common irAE in both regimens; of the five patients who developed colitis with Atezo/Bev, 3 (60%) also had colitis with Dur/Treme, with 2 (40%) experiencing exacerbations [32].

Our patient did not show any significant side effects associated with the use of Durva/Treme in this setting. This study was based on one case, which underscores the need for more data. To assess the reproducibility of the findings, we believe it is essential to gather additional cases in the future. Kawamura et al. reported a case series involving two patients treated with Durva/Treme after progression on Atezo/Bev, adding to the anecdotal evidence but underscoring the need for larger studies to validate these observations. In their study both participants demonstrated excellent disease control without any irAEs.

A similar concept of immunotherapy beyond the progression of first-line immunotherapy has been explored in various cancers, including non-small cell lung cancer, renal cell carcinoma, and colon cancer. Wang et al. reported a numerical but not significant OS benefit for patients receiving immunotherapy rechallenge after first-line immunotherapy [34]. Another study by Xu et al. studied the efficacy of ICPI rechallenge after progression on immunotherapy plus chemotherapy in patients with NSCLC. Interestingly, their results showed a higher PFS with the immune rechallenge compared to first-line therapy [35]. These studies provide enough proof of concept that warrants further investigation with randomized controlled trials.

It is important to acknowledge that the patients who received both cabozantinib and TARE prior to Durva/Treme. Both treatments have been shown to modulate the tumor microenvironment and immune response, which may have influenced the clinical outcome. Cabozantinib a TKIs, has demonstrated immunomodulatory properties in HCC by reducing immunosuppressive cell populations such as MDSCs and regulatory T cells, while enhancing infiltration and activity of cytotoxic CD8+ T cells, therapy promoting antitumor immunity. Similarly, TARE induces localized tumor cells death and release tumor antigens, which can prime and activate the immune system, promoting tumor-infiltrating lymphocytes and enhancing responsiveness to ICPIs. These immunomodulatory effects may have contributed ti the disease stability observed with Durva/Treme [36,37].

Furthermore, the differences in the mechanism of action of Durva/Treme compared to Atezo/Bev, can help overcome resistance that tumor cells develop to Atezo/Bev. Mechanisms of resistance to Atezo/Bev include increased hypoxia-inducible factor and an immunosuppressive microenvironment [38]. Adding a second ICPI, such as a CTLA-4 inhibitor, may overcome this resistance by targeting different immune evasion strategies. It is noteworthy that durvalumab monotherapy did not significantly improve efficacy compared to sorafenib in the HIMALAYA trial, and it was the addition of tremelimumab, a CTLA-4 inhibitor, that enhanced its effectiveness. This observation raises a question on whether the full potential of atezolizumab is not being realized when combined only with a VEGF inhibitor and not adding a CTLA-4 inhibitor. Additionally, the development of anti-drug antibodies against atezolizumab, another mechanism of resistance that tumor cells use, can reduce its efficacy, a problem that can be potentially mitigated by switching to Durva/Treme [39].

Future research efforts should focus on the establishment of comprehensive registries of biomarker driven studies to refine patient selection for ICPIs rechallenge. Biomarkers such AFP have demonstrated predictive value in HCC treated with ICPIs. Additionally, tumor PD-L1 expression serves as an established immunologic biomarker associated with treatment response. Moreover, characterization of the T-cell receptor repertoire may provide insight into dynamics of anti-tumor immunity and identify patients most likely to benefit from rechallenge strategies [40,41].

Looking forward, this case supports the hypothesis that sequential use of distinct ICPIs classes may offer therapeutic opportunities beyond current guidelines-recommended lines of therapy. As more patients receive first-line Atezo/Bev, the clinical must consider whether reactivation of the immune response is possible through alternate checkpoint combinations. Future trails particularly those stratifying patients based on tumor immunogenomic profiling, immune-release biomarker, or prior immunotherapy exposure may help identify which patients are most likely to benefit from this strategy.

4. Conclusion

This case report highlights the potential of using durva/Treme after progression on Atezo/Bev in patients with unresectable HCC. While preliminary evidence suggests potential benefits of using Durva/Treme after Atezo/Bev, robust clinical trials and continued clinical research investigations in novel combinational therapies are imperative to establish definitive second-line treatment guidelines. Future research should aim to fill this critical gap, providing clearer pathways for sequential therapy in patients with unresectable HCC.

Funding Statement

This paper was not funded.

Article highlights

• HCC is often present at an advanced stage, requiring individualized systemic treatment strategies.

• Atezo/Bev is the current first-line standard therapy for unresectable HCC.

• There are limited data and no formal guidelines on second-line ICPIs combinations after progression on Atezo/Bev.

• This case report presents a patient with unresectable HCC treated successfully with Durva/Treme following progression on Atezo/Bev.

• The sequential use of distinct ICPCs may help overcome acquired resistance.

• Durva/Treme was well tolerated, and no immune-related adverse events were observed in this case.

• This case highlights the feasibility of ICPIs class-switching as a second-line strategy and urging for more research to improve outcomes in unresectable HCC.

Author contributions

For the development of this case study titled “The Use of Durvalumab and Tremelimumab After Atezolizumab/Bevacizumab in Patients with Hepatocellular Carcinoma,” the contributions were as follows: Maen Abdelrahim and Abdullah Esmail conceptualized and designed this case study, with Abdullah Esmail also providing administrative support. Maen Abdelrahim and Abdullah Esmail were responsible for providing study materials and patient-related data. The collection and assembly of data were handled by Abdullah Esmail, while Maen Abdelrahim led the case analysis and interpretation efforts. Both authors – Maen Abdelrahim and Abdullah Esmail – actively participated in writing the manuscript for this case study and gave their final approval to the completed document.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Ethical declaration

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Review Board of Houston Methodist Hospital (No. PRO00035386). Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Data availability statement

The data from this case study that support our results are available upon request from the corresponding author, Maen Abdelrahim (mabdelrahim@houstonmethodist.org).