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TARE In Advanced HCC: When Is It Optimal And Why?
Jin Woo Choi, MD, PhDSeoul National University Hospital Seoul National UniversitySeoul, Republic of Koreajwchoi.Med@snu.Ac.KrDisclosures: None.
Transarterial radioembolization (TARE) can be considered for patients with unilobar hepatocellular carcinoma (HCC) and ipsilateral portal vein tumor thrombosis (Vp1-3), provided there is no hepatic vein invasion, no extrahepatic spread, Child-Pugh A status, and an ECOG (Eastern Cooperative Oncology Group) performance status of 0 to 1. Although this represents an advanced stage of HCC, locoregional treatments may still be viable, and an effective locoregional treatment can potentially increase the likelihood of curative outcomes.
Despite the rapid development of immune checkpoint inhibitors, which are now the frontline treatment for advanced HCC, there is a significant lack of detailed data for this specific patient population posttreatment with immune checkpoint inhibitors. Historically, Asian countries have considered lobectomy as a viable option for these patients, particularly in cases of Vp1 and Vp2. This aggressive approach can result in a cancer-free status if there are no occult tumors in the remaining liver; however, it can be catastrophic if any small tumor seeds are present. Indeed, overall survival (OS) and recurrence-free survival rates substantially decrease during the first 18 months, stabilizing in the following years.1,2 Nevertheless, this approach could be justified in the past, even in the era of tyrosine kinase inhibitors, due to the limited survival outcomes after systemic treatments. However, with immune checkpoint inhibitor–based systemic treatments now offering longer OS, the opportunity cost of this risky approach increases.
In this context, TARE can be an ideal frontline treatment for this specific patient population. For Vp1 and Vp2, ablative TARE can effectively downstage the tumor, providing a test of time and inducing hypertrophy of the future liver remnant, or it can serve as a definitive treatment. For Vp3, TARE may lead to curative conversion, although the chances are lower than in Vp1 and Vp2 cases, or it can assist subsequent systemic treatments by safely reducing tumor burden. However, high-level evidence for TARE in locally advanced HCC is lacking, and ongoing trials, including the RESOLVE trial (NCT06166576), will help establish the role of TARE in this potentially curative yet advanced HCC population.
Riad Salem, MD, MBAVice Chair, Image-Guided TherapyChief, Vascular and Interventional RadiologyDepartment of RadiologyProfessor of Radiology, Medicine, and TransplantationNorthwestern MedicineFeinberg School of MedicineChicago, Illinoisrsalem1@nm.OrgDisclosures: Consultant to Boston Scientific Corporation, Cook, Siemens, Sirtex, Terumo, AstraZeneca, Genentech, Eisai, Autem, Roche, and TriSalus.
Currently, treatment for HCC is guided by the BCLC (Barcelona Clinic Liver Cancer) algorithm, and patients with vascular invasion fit into the category of advanced HCC and can be effectively treated with systemic therapy. However, many physicians believe that patients with liver-only disease and vascular invasion (so-called locally advanced HCC) should be treated with TARE. Why is that? First, TARE is an arterial therapy that allows you to give high-dose radiotherapy in vascular tumors such as HCC with vascular invasion and portal vein thrombosis. Second, there is evidence of a strong antitumoral effect on the portal vein thrombus with TARE in that we have treated patients where the thrombus has retracted or completely dissolved, and patients have subsequently undergone resection and even transplant. This is an area where we can potentially find a patient population where we can break the guideline rules and individualize treatment.
In my opinion, patients with locally advanced HCC should be treated with TARE first, and most should be treated relatively quickly (within a few weeks) and augmented with systemic therapy (ie, 4-6 weeks); we are noticing that patients respond very well to TARE and do not have additional side effects when you add systemic therapy.
We also now have very strong data from the DOSISPHERE-01 study, which randomized patients with large tumors and vascular invasion to normal-dose or high-dose TARE. With use of high-dose TARE in portal vein thrombosis, survival increased by > 150%, and patients were 10-fold more likely to receive curative resection in large tumors.1 With this, we now have randomized data showing the role of TARE in patients with portal vein thrombosis, who we are now resecting and transplanting, as well as data showing the safety of standard-of-care systemic therapies following TARE. For me, there still is a role of TARE in that locally advanced patient population.
Conversely, scenarios where radioembolization might not be beneficial include patients with vascular invasion but extrahepatic disease or if the vascular invasion is associated with significant lung shunting where you cannot administer a good dose. In addition, if the Tc-99m MAA (macroaggregated albumin) scan shows that the spheres will not accumulate in the portal vein thrombus or if the thrombus is bilobar, I think that's too much thrombus to really be beneficial. One other scenario where TARE would not be considered is in the presence of liver dysfunction (ie, poor liver function tests, very low albumin, elevated bilirubin) or liver failure.
An area of disagreement for use of TARE is in patients with main portal vein thrombosis. My contention is the data are just as good with radioembolization in main portal vein thrombosis as they are with systemic therapy, so I would still try TARE and then augment with systemic therapy.
Combination Locoregional and Immunotherapy in Practice
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Hepatic (Liver) Adenoma Formation And Treatment
Hepatic adenoma is an uncommon type of non-cancerous tumor that forms in the liver, usually occurring in younger women with a history of oral birth control use. People often find out they have one when they get imaging tests like ultrasounds, magnetic resonance imaging scans (MRIs), or computed tomography (CT) scans for other health reasons.
About 50% of the time, these tumors don't cause any symptoms, so many people don't even realize they have one until it shows up on a scan. Even though hepatic adenomas are benign, they can still cause problems, like bursting or becoming cancerous.
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Symptoms Hepatic adenomas often do not cause symptoms, so they can go unnoticed for long periods. However, if they grow large enough or if complications arise, some individuals may experience: Mild to severe abdominal pain in the upper right quadrant of the abdomen Bloating In rare cases, adenomas can rupture, causing symptoms like: Severe abdominal pain Vomiting, often with blood Blood in stool Lightheadedness Hepatic Adenoma and Birth Control: What's the Link? Research has shown a strong association between the development of hepatic adenomas and the use of hormonal contraceptives, particularly those containing higher doses of estrogen. In addition, stopping the oral contraceptive often leads to tumor regression. Tumor Formation Research has shown that using estrogen over a long period can increase the risk of developing liver tumors, including hepatic adenomas. There are three molecular pathways involved in the development of hepatocellular adenoma: HNF1α Inactivation: HNF1α is like a "control switch" for liver cells. When this switch is turned off (inactivated), the liver cells can grow too much and become abnormal, forming a tumor. β-Catenin activation: In this pathway, a protein called β-catenin becomes overactive. This can happen due to mutations in the gene that codes for β-catenin. When β-catenin is overly active, it promotes cell growth and division, contributing to tumor formation. Inflammatory activation: This pathway is associated with inflammation in the liver, often linked to conditions like obesity and excessive alcohol consumption. Inflammation can lead to changes in liver cell behavior, increasing the risk of tumor development. Women who take oral contraceptives have a similar risk for all three types of hepatic adenomas. While there have been rare cases where a hepatic adenoma turned into a more severe cancer called hepatocellular carcinoma (HCC), studies have not found strong evidence linking the use of oral contraceptives to an increased risk of HCC. Other Risk Factors Aside from hormonal influences, several other factors may be associated with developing hepatic adenomas, including: Consuming too much alcohol Obesity Metabolic syndrome Using anabolic steroids Awareness of these risk factors can help individuals and healthcare providers identify those who may benefit from regular monitoring. Testing and Radiology Findings When hepatic adenomas are suspected, imaging studies are crucial for diagnosis and evaluation. Here are the primary modalities used in the assessment of hepatic lesions: Ultrasound: Often the first imaging technique used, ultrasound can help visualize liver lesions, including hepatic adenomas. These tumors typically appear as well-defined, homogeneous masses. Magnetic resonance imaging (MRI): Magnetic resonance imaging (MRI) provides detailed images of liver lesions and helps differentiate hepatic adenomas from other types of tumors or lesions. Adenomas often show characteristic patterns, such as a hyperintense signal on T1 or T2-weighted images. Computed tomography (CT) scan: CT scans can provide additional information on the size and vascularity of the adenoma. Contrast-enhanced CT scans help evaluate the tumor's characteristics and assess for potential complications, such as hemorrhage. If a hepatic adenoma is diagnosed, additional imaging may be required to monitor its size and behavior over time. Regular imaging follow-ups can ensure that any changes are detected early. Treatment The management of hepatic adenomas largely depends on their size, symptoms, and the individual's overall health. For hepatic adenomas that are smaller than 5 centimeters (cm) and linked to oral contraceptive use, healthcare providers usually take a careful approach. They may suggest stopping the birth control pills and regularly checking the tumor using imaging tests like ultrasounds or MRIs. Many times, this can help the tumor shrink over time. During pregnancy, most small adenomas don't change much, and women with these tumors are generally not discouraged from getting pregnant. When Providers Consider Removal Surgical intervention may be warranted under certain conditions, such as: Size: In women, the adenoma may be removed if the adenoma is larger than 5 cm. At this size, it may cause more serious problems. Suspicion of malignancy: If imaging raises concerns about the potential for cancer, surgical removal is often recommended to ensure accurate diagnosis and treatment. Surgery to remove the adenoma is typically recommended for all men, no matter how big the tumor is. This is because men are more likely to have adenomas that can cause cancer. The surgery for removing the tumor is considered a safe and effective treatment. However, it will only be done if necessary since all surgery carries some risk. The main surgical options for treating hepatic adenomas are: Laparoscopic resection: This minimally invasive technique involves removing the adenoma through small incisions. It typically results in quicker recovery and less postoperative pain. Open surgery: In cases where the adenoma is particularly large or complicated, open surgery may be necessary to ensure complete removal. Transarterial embolization (TAE) is a medical procedure for treating hepatic adenomas when bleeding occurs inside the tumor. This procedure blocks blood flow to the tumor, which helps stop the bleeding. TAEs are usually performed within two to three days of the bleeding occurring, and it may be followed by surgery to remove the tumor if necessary. Surgery Recovery Recovery from surgery for hepatic adenoma can vary based on the individual's overall health, the surgical technique used, and the size of the tumor. Here are some general recovery considerations: Hospital stay: Laparoscopic procedures typically require a shorter hospital stay (1–2 days) than open surgery (3–6 days). Activity limitations: Patients may need to limit physical activity for several weeks post-surgery to allow the liver to heal properly. Statistics on Recurrence The outlook for people with hepatocellular adenoma (HCA) is not well understood. Stopping oral contraceptives can sometimes shrink or heal the tumor. Surgical resection may significantly reduce the likelihood of recurrence. In a study of 118 people who had surgery to remove hepatic adenomas, 8% had the tumor come back or get bigger. For the 10 patients whose tumors became cancerous, there were no signs of cancer returning after an average follow-up period of 78 months. Summary Hepatic adenomas are benign liver tumors primarily influenced by hormonal factors, particularly estrogen. While often asymptomatic, they can lead to significant complications, making awareness and monitoring critical. Early detection through imaging techniques such as ultrasound, MRI, and CT scans can facilitate timely intervention. Treatment options, including surgical removal, may be necessary based on the size of the adenoma and the symptoms experienced. If you or a loved one has been diagnosed with a hepatic adenoma, discussing your specific situation and treatment options with your healthcare provider is essential to ensure the best possible outcome.18 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.Wang X, Zhang X. Hepatocellular adenoma: where are we now? WJG. 2022;28(14):1384-1393. Doi:10.3748/wjg.V28.I14.1384
Baker FA, Zeina AR, Mouch SA, Mari A. Benign hepatic tumors: from incidental imaging finding to clinical management. Korean J Fam Med. 2021;42(1):2-8. Doi:10.4082/kjfm.18.0188
British Liver Trust. Hepatocellular adenoma.
American Liver Foundation. Benign liver tumors.
Haring MPD, Gouw ASH, de Haas RJ, Cuperus FJC, de Jong KP, de Meijer VE. The effect of oral contraceptive pill cessation on hepatocellular adenoma diameter: a retrospective cohort study. Liver Int. 2019;39(5):905-913. Doi:10.1111/liv.14074.
Villa E. Role of estrogen in liver cancer. Womens Health. 2008;4(1):41-50. Doi:10.2217/17455057.4.1.41
Liver Fellow Network. What is THAT on your liver?
American Cancer Society. Tests for liver cancer.
Jacob DK. Hepatic adenoma. Radiopaedia.
Wong VK, Fung AW, Elsayes KM. Magnetic resonance imaging of hepatic adenoma subtypes. Clinical Liver Disease. 2021;17(3):113-118. Doi:10.1002/cld.996
Noels JE, van Aalten SM, van der Windt DJ, et al. Management of hepatocellular adenoma during pregnancy. J Hepatol. 2011;54(3):553-558. Doi:10.1016/j.Jhep.2010.07.022
Thomeer MG, Broker M, Verheij J, et al. Hepatocellular adenoma: when and how to treat? Update of current evidence. Therapeutic Advances in Gastroenterology. 2016;9(6):898.
de'Angelis N, Memeo R, Calderaro J, et al. Open and laparoscopic resection of hepatocellular adenoma: trends over 23 years at a specialist hepatobiliary unit. HPB (Oxford). 2014;16(9):783-788. Doi:10.1111/hpb.12257
Viganò L, Elamin A, Costa G. Hepatic adenoma: indications for minimally invasive resection. Laparoscopic Surgery. 2019;3.
van Rosmalen BV, Klompenhouwer AJ, de Graeff JJ, et al. Safety and efficacy of transarterial embolization of hepatocellular adenomas. Br J Surg. 2019;106(10):1362-1371. Doi:10.1002/bjs.11213
Savikko J, Vikatmaa L, Hiltunen AM, et al. Enhanced recovery protocol in laparoscopic liver surgery. Surg Endosc. 2021;35(3):1058-1066. Doi:10.1007/s00464-020-07470-2
Chopinet S, Cauchy F, Hobeika C, et al. Long-term outcomes following resection of hepatocellular adenomas with small foci of malignant transformation or malignant adenomas. JHEP Rep. 2021;3(4):100326. Doi:10.1016/j.Jhepr.2021.100326
Dokmak S, Paradis V, Vilgrain V, et al. A single-center surgical experience of 122 patients with single and multiple hepatocellular adenomas. Gastroenterology. 2009;137(5):1698-1705.
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Other Helpful Report an ErrorTherapeutic Advances In Gastrointestinal Cancers: Immuno-oncology And Beyond
Colorectal Cancer: Novel Combination TherapiesLonardi discussed recent advancements in immunotherapy for CRC, focusing on the impact of MSI-H status on treatment response. Historically, CRC was not considered responsive to immunotherapy until the identification of MSI-H, a marker of DNA mismatch repair associated with high mutation rates and neoantigen exposure.1-3 These insights have transformed the treatment landscape for MSI-H tumours, enabling the development of immune checkpoint inhibitors. Despite these advancements, MSI-H CRCs continue to exhibit complex immune evasion mechanisms, including overexpression of immune checkpoints such as programmed death-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), underscoring the ongoing need to explore combination therapies.4
Development and Results of Combination RegimensThe CheckMate 142 trial, a Phase II multi-cohort study, evaluated the combination of nivolumab (NIVO) and low-dose ipilimumab (IPI) in patients with MSI-H metastatic (m) CRC who had progressed after prior treatments. In a cohort of 119 patients treated with NIVO + IPI, the combination demonstrated a median progression-free survival (PFS) that had not yet been reached, with 52% of patients remaining progression-free at 5 years. Grade 3 or 4 treatment-related adverse events (TRAE) occurred in 32% of patients.5
Pembrolizumab was subsequently investigated in the 1L setting through the KEYNOTE-177 trial, comparing it with standard chemotherapy in patients with MSI-H/mismatch repair deficient (dMMR) mCRC. The trial enrolled 307 patients, with 153 receiving pembrolizumab and 154 receiving chemotherapy. The median PFS was 16.5 months (95% CI: 5.4–32.4) in the pembrolizumab group and 8.2 months (95% CI: 6.2–10.2) in the chemotherapy group (hazard ratio [HR]: 0.60; 95% CI: 0.45–0.79). Grade 3 or higher TRAEs were reported in 21.6% of patients in the pembrolizumab group compared to 66% in the chemotherapy group.6
Ongoing Trials and Future DirectionsThe randomised Phase III trial 8HW is currently comparing nivolumab monotherapy, nivolumab + ipilimumab, and standard chemotherapy in the 1L setting for MSI-H patients. This study features dual primary endpoints: PFS between NIVO + IPI and chemotherapy and a direct comparison between nivolumab monotherapy and nivolumab + ipilimumab. In the NIVO + IPI arm, which included 171 patients, the median PFS was not reached, with a CI of 38.4 months to not evaluable. This compared to a median PFS of 5.9 months (95% CI: 4.4–7.8) in the chemotherapy group of 84 patients (HR: 0.21; 97.91% CI: 0.13–0.35; p<0.0001). The study demonstrated that 79% of patients in the NIVO + IPI arm were progression-free at 12 months, and 72% remained progression-free at 24 months, compared to 21% and 14% in the chemotherapy group, respectively. The PFS benefit with NIVO + IPI was consistent across various analyses, including PFS by blinded independent central review. Data comparing nivolumab monotherapy versus nivolumab + ipilimumab are still awaited, and ongoing analysis aims to provide further insights. Additionally, NIVO + IPI had a different safety profile compared with chemotherapy, with fewer Grade 3/4 TRAEs, while improving health-related quality of life and reduced symptoms versus chemotherapy. Figure 1 demonstrates the data from CheckMate 8HW.7-9
Lonardi discussed the potential for further improving outcomes in MSI-H CRC through various dual immuno-oncology (IO) combinations. While multiple IO-based combinations are under investigation, she emphasised that using IO earlier in locally advanced resectable disease for MSI-H patients could deliver the most substantial improvement in outcomes.
Lonardi highlighted the NICHE-2 trial, which investigated neoadjuvant immunotherapy in patients with previously untreated, resectable clinical Stage II/III dMMR colon adenocarcinoma. In this trial, patients were treated with NIVO and low-dose IPI for one dose, followed 2 weeks later by a single dose of nivolumab monotherapy before surgery. A pathological complete response (pCR), defined as no residual viable tumour, was achieved in 67% of patients. Additionally, 95% of patients achieved a major pathological response, which includes both pCR and patients with ≤10% residual tumour. The trial also demonstrated promising long-term outcomes. With a median follow-up of 26.2 months, no disease recurrences were observed. The safety profile of this neoadjuvant IO approach was notable, with only 4% of patients experiencing Grade 3 or 4 immune-related AEs.10,11 Data presented at ESMO 2024 of 3-year disease-free survival from NICHE-2 showed unprecedented 3-year DFS of 100% in patients with high-risk, locally advanced dMMR colon cancer with only two cycles of neoadjuvant immunotherapy. All patients were circular tumour (ct)DNA negative at minimal residual disease time point, in line with 0% recurrences. Association of (early) clearance with pCR: ctDNA may aid in organ preservation.12
KRAS Mutations and Other Colorectal Cancer SubtypesLonardi closed the session by noting that only about 5% of CRC patients are MSI-H,13 highlighting the need to develop new strategies for the remaining 95% of patients with CRC. One promising approach is targeting Kirsten rat sarcoma virus (KRAS) mutations, specifically KRASG12C, which is present in approximately 3% of patients with CRC.14 Preclinical data suggest that activation of epidermal growth factor receptor signalling can overcome KRASG12C inhibition in CRC.15,16
The CodeBreaK 300 trial evaluated sotorasib + panitumumab versus standard of care (SOC) in pre-treated KRASG12C-mutant mCRC. The median PFS was 5.62 months in the higher-dose group (sotorasib 960 mg + panitumumab) and 3.91 months in the lower-dose group, compared to 2.20 months with SOC. The objective response rate (ORR) was 30% in the higher-dose group, 8% in the lower-dose group, and 2% with SOC. Grade 3 or higher TRAEs occurred in 36% of the higher-dose group, 30% of the lower-dose group, and 43% of the SOC group.17
The KRYSTAL-1 trial evaluated the efficacy of adagrasib combined with cetuximab in pre-treated KRASG12C-mutant mCRC. In this trial involving 94 patients, the median PFS was 6.9 months (95% CI: 5.7–7.4), and the median OS was 15.9 months (95% CI: 11.8–18.8). The ORR was 34%, with a median duration of response of 5.8 months. Grade 3 or 4 TRAEs were reported in 28% of patients. These findings highlight the potential of targeted therapies like adagrasib combined with cetuximab in managing KRASG12C-mutant mCRC.18
Lonardi concluded that MSI is the more robust biomarker in CRC and recommended testing all patients from the outset. Pembrolizumab and NIVO + IPI are the SOC in the 1L setting for MSI-H patients,10 and NIVO + IPI in the neoadjuvant setting has shown high efficacy in resectable MSI-H colon cancer, with a 68% pCR rate. Data presented at ESMO 2024 of 3-year disease-free survival from NICHE-2 showed unprecedented 3-year DFS of 100% in patients with high-risk, locally advanced dMMR colon cancer with only two cycles of neoadjuvant immunotherapy.11,12 Lastly, targeting KRASG12C and epidermal growth factor receptor is an effective therapeutic approach for advanced, pre-treated mCRC with a KRASG12C mutation. The continued exploration of these strategies will be essential in refining treatment options and optimising outcomes for patients with CRC.15,16
Gastro-oesophageal Cancers: The Role of Immunotherapy Tania Fleitas Kanonnikoff Overview of Gastro-oesophageal CancersKanonnikoff provided an overview of oesophageal and gastric cancers, which rank as the 7th and 5th most common causes of cancer-related death worldwide.19 The main types of oesophagal cancer are oesophageal squamous cell carcinoma (ESCC) and oesophageal adenocarcinoma (EAC). Gastro-oesophageal adenocarcinoma (gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma) is treated in a similar way. Gastric cancer is known to exhibit significant heterogeneity. Biomarkers such as human epidermal growth factor receptor 2 (HER2), MSI-H, programmed death ligand-1 combined positive score (PD-L1 CPS), and recently Claudine 18.2 are essential in guiding treatment.
ESMO Guidelines for 1L Treatment in Oesophageal Squamous Cell CarcinomaThe ESMO guidelines recommend platinum plus fluoropyrimidine chemotherapy in the 1L treatment for PD-L1-negative patients. For PD-L1-positive patients with a tumour proportion score (TPS) of ≥1%, NIVO + chemo or NIVO + IPI is advised. For patients with a CPS score of ≥10, pembrolizumab plus chemotherapy is recommended.20 As of July 2024, the Committee for Medicinal Products for Human Use (CHMP) recommended the approval of toripalimab + chemotherapy for the 1L treatment of advanced ESCC.21
CheckMate 648: NIVO + Chemotherapy Versus Chemotherapy in Oesophageal Squamous Cell CarcinomaCheckMate 648 is a pivotal trial that evaluated NIVO + chemotherapy versus chemotherapy alone as a 1L treatment in ESCC. The trial included patients with varying levels of PD-L1 expression. The median OS for the entire population was 13.2 months (95% CI: 11.1–15.7) in the NIVO + chemotherapy group, compared to 10.7 months (95% CI: 9.4–12.1) in the chemotherapy-only group (HR: 0.77; 95% CI: 0.65–0.92). In patients with PD-L1 tumour cell expression ≥1%, also known as PD-L1 TPS, the median OS was 15.0 months (95% CI: 11.9–18.7) for the NIVO + chemotherapy arm versus 9.1 months (95% CI: 7.7–10.0) for chemotherapy alone (HR: 0.60; 95% CI: 0.47–0.77). In the subgroup of patients with tumour cell PD-L1 expression <1%, the HR for OS was 0.97, indicating that enriched benefit was observed in patients with higher PD-L1 expression.22
The long-term follow-up provided valuable insights into the survival benefit of immunotherapy combined with chemotherapy. Grade 3 or 4 TRAEs were reported in 49% of patients receiving NIVO + chemotherapy and 37% in the chemotherapy-only group.22
CheckMate 648: NIVO + IPI Versus Chemotherapy in Oesophageal Squamous Cell CarcinomaAn additional arm of CheckMate 648 assessed NIVO + IPI versus chemotherapy alone as a 1L treatment for ESCC. The trial reported a median OS of 12.7 months (95% CI: 11.3–15.5) for the NIVO + IPI group compared to 10.7 months (95% CI: 9.4–12.1) for the chemotherapy-only group (HR: 0.78; 95% CI: 0.65–0.92). In patients with tumour cell PD-L1 expression ≥1%, the median OS was 13.1 months (95% CI: 11.2–17.4) for NIVO + IPI versus 9.1 months (95% CI: 7.7–10.0) for chemotherapy (HR: 0.63; 95% CI: 0.49–0.81). For patients with tumour cell PD-L1 expression <1%, the HR for OS was 0.94, indicating that the benefit of NIVO + IPI was more pronounced in patients with higher PD-L1 expression. Grade 3 or 4 TRAEs were reported in 33% of the NIVO + IPI group and 37% in the chemotherapy-only group.22
KEYNOTE-590: PEMBRO + Chemotherapy Versus Chemotherapy in Oesophageal Squamous Cell CarcinomaThe KEYNOTE-590 trial evaluated PEMBRO + chemotherapy versus chemotherapy alone in ESCC. In the overall ESCC population, the median OS was 12.6 months (95% CI: 10.2–14.2) for PEMBRO + chemotherapy versus 9.8 months (95% CI: 8.6–11.1) for chemotherapy alone (HR: 0.71; 95% CI: 0.60–0.85).23
For ESCC patients with PD-L1 CPS ≥10, the median OS was 13.9 months (95% CI: 11.1–16.0) in the PEMBRO + chemotherapy group compared to 8.8 months (95% CI: 7.8–10.5) in the chemotherapy group (HR: 0.59; 95% CI: 0.45–0.76). The 5-year OS rate was 13.8% for PEMBRO + chemotherapy and 3.7% for chemotherapy alone, highlighting the long-term benefit of immunotherapy in this subgroup.24
Additionally, in patients with PD-L1 CPS <10, the OS HR was 0.84, indicating a less pronounced benefit in this lower expression group.24 Grade 3 or higher TRAEs were reported in 71.9% of patients receiving PEMBRO + chemotherapy and 67.6% in the chemotherapy-only group.
Fleitas discussed the duration of 1L therapies in her clinical practice. Current guidelines recommend chemotherapy combined with either PEMBRO or NIVO.19 In her practice, she typically discontinues oxaliplatin after eight cycles and continues with immunotherapy and fluoropyrimidine if there is a clinical benefit for the patient.
KEYNOTE-811 in HER2- Positive Gastric/Gastro-oesophageal Junction CancerFor HER2-positive advanced gastric, gastro-oesophageal junction cancer, and EAC, the addition of PEMBRO to trastuzumab (TRAS) and chemotherapy is now a recommended treatment option for PD-L1 CPS ≥1, supported by results from the KEYNOTE-811 trial.24,25 The trial demonstrated significant improvements in PFS and OS when PEMBRO was added to the standard TRAS + chemotherapy regimen for the PD-L1 positive population.26,27
For patients with PD-L1 CPS ≥1, the median PFS was 10.9 months (95% CI: 8.5–12.5) in the PEMBRO group compared to 7.3 months (95% CI: 6.8–8.5) in the placebo group (HR: 0.71; 95% CI: 0.59–0.86). The median OS was 20.5 months in the PEMBRO group versus 15.6 months in the placebo group (HR: 0.79; 95% CI: 0.64–0.98). The ORR was 73.2% in patients with PD-L1 CPS ≥1 receiving PEMBRO + TRAS + chemotherapy, compared to 58.4% in the placebo group.26,27
Grade 3 or 4 TRAEs occurred in 58% of patients receiving PEMBRO and 50% of patients in the placebo group, reflecting the manageable safety profile of the combination therapy. This combination has become an established standard of care for HER2-positive patients with PD-L1 expression. Fleitas mentioned that in her practice she continues both pembrolizumab and trastuzumab until the disease progresses as a maintenance strategy.26,27
CheckMate 649 and KEYNOTE-859 in HER2-Negative Gastric/Gastro-oesophageal Junction Cancer/Oesophageal AdenocarcinomaThe CheckMate 649 and KEYNOTE-859 trials investigated the addition of immunotherapy to chemotherapy in advanced gastric, gastro-oesophageal junction cancer, and EAC, demonstrating that the addition of IO to chemotherapy showed superior benefit to chemotherapy alone. It also demonstrated that higher PD-L1 expression levels are associated with better treatment outcomes. EAC patients were only enrolled in CheckMate 649 study.
CheckMate 649 trial in HER2-negative gastric/gastro-oesophageal junction cancer/oesophageal adenocarcinoma28
Both trials highlight the critical role of PD-L1 expression as a predictive biomarker, with higher expression correlating with improved survival outcomes when immunotherapy is added to chemotherapy.
Fleitas emphasised the critical role of biomarker testing in the management of gastro-oesophageal cancers. Ongoing research and future trials will continue to refine these treatment strategies, with a focus on expanding therapeutic options and improving outcomes across different patient subgroups.
Hepatocellular Carcinoma: 1L Treatment Options in the Metastatic Setting Thomas Decaens Rationale for Immunotherapy in Hepatocellular CarcinomaDecaens discussed immunotherapy's role in HCC. HCC often arises from chronic inflammatory liver conditions such as non-alcoholic steatohepatitis, alcohol-related liver disease, and viral aetiologies, like hepatitis B and C infection.31-33 These chronic conditions create an immunosuppressive environment characterised by a low tumour mutation burden and fewer tumour-associated antigens, contributing to the resistance of HCC to immune-modulating therapies.34-36 The inherent immunotolerance of the liver further complicates effective immune engagement.37 In most cases in the West, cirrhosis is present, leading to modifications in liver endothelial cells that hinder tumour-associated antigen presentation.38 Additionally, the fibrotic liver alters cell trafficking, affecting the entry of immune cells from the blood.39
Mechanisms of Combination TherapyDue to these challenges, combination therapy has become necessary in HCC treatment, as trials investigating single agents have often failed. In the current landscape, anti-PD-L1 agents, which enhance pre-existing T cell responses and cytokine production, are combined either with anti-vascular endothelial growth factor therapies to normalise tumour vasculature and reduce immunosuppression or anti-CTLA-4 therapies to increase T cell priming.40-42 This combination shifts a cold tumour to a hot tumour. Anti-CTLA-4 therapies, in addition to increasing T cell priming in the lymph node, enhance tumour antigen presentation and activate T cells, providing a broader immune response against the tumour.43,44
Clinical Trials and Efficacy of 1L TreatmentsDecaens highlighted pivotal Phase III clinical trials comparing immunotherapy combinations to standard tyrosine kinase inhibitors (TKI), sorafenib (SOR), or lenvatinib in the 1L setting:
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