One of the most important issues emerging is improving the bar of survival, which is 19.2 months for atezolizumab in the front line. More patients are exposed to systemic therapies, not only to 1 line but to 2 or 3 lines of therapies. Recent trials reported that around 50% of patients in the second line are receiving effective systemic therapies that impact the outcome. Atezolizumab is the frontline therapy, and a portion of patients will receive sorafenib or lenvatinib, depending on the criteria of the physician. But what happens with progression on atezolizumab? I’ve been checking the guidelines, and I’m involved in the AASLD [American Association for the Study of Liver Disease] guidelines.

Other guidelines, like the EASL [European Association for the Study of the Liver] guidelines or reviews, have suggested that we should respect the hierarchy. We reported in the AASLD trial design and end points paper last year and the hierarchy was established, let’s say sorafenib and lenvatinib first, and then regorafenib, cabozantinib, and ramucirumab afterward which should be respected. The ASCO [American Society of Clinical Oncology Annual Meeting] guidelines stated, “all treatments that are effective should be considered, but we should give priority to sorafenib or lenvatinib.” ESMO [European Society for Medical Oncology Congress] is more open. It stated, “Choose whatever treatment has been reported as positive, as superior compared with placebo, because we don’t have trials where patients progressed with atezolizumab.”

In cases of progression with atezolizumab, how do you enforce or suggest treating your patients with the established hierarchy, using lenvatinib or sorafenib? Or are you considering using other types of therapies that were approved in second-line progression to sorafenib?

We don’t have data from the phase 3 trial of the combination therapy. The problem is the local possibility of each state. In Italy it’s not possible to prescribe lenvatinib after atezolizumab-bevacizumab. You can only prescribe sorafenib. After progression of sorafenib, we prescribe cabozantinib. The USDA [United States Department of Agriculture] guidelines state that we should use the best option for the first and second lines. In the first line, sorafenib and lenvatinib are good because we have more options for our patients.

I just published a paper on Palermo [Italy] colleagues that evaluated the different overall survival between sorafenib and lenvatinib. In the second line, after this emerges…the colleagues see that lenvatinib is superior after sorafenib in 2 months. These data are known only in clinical practice, but we’re considering performing a study after progression from a first-line phase 2 or 3 trial. It’s difficult to conduct a study in the second line after atezolizumab. In the future I predict a study with regorafenib and pembrolizumab, and we will see the continuous forms of immunotherapy in the first, second, and third lines. As we change the TKI [tyrosine kinase inhibitor] associated with immunotherapy, we prescribe sorafenib, with lenvatinib as another option.

Dr Chan, what’s your opinion about second-line progressing atezolizumab?

I tend to be more restrictive. The simple reason is because the TKI sequence is already established by the phase 3 trials. The cabozantinib and regorafenib are second-line agents after sorafenib because of the additional targets, like RAF or EGFR inhibitions. If we allow using whatever TKI as a second-line therapy after atezolizumab-bevacizumab, then a lot of patients will require third- or fourth-line treatment. If you use cabozantinib, then what’s next? We have evidence to use lenvatinib or sorafenib afterward. I follow the established sequence: sorafenib and lenvatinib first, and then we follow the traditional sequence.

I concur. I’ve been supporting this option in AASLD and in ESMO guidelines because of the evidence. We don’t have evidence in progressors to atezolizumab-bevacizumab, but we have evidence that regorafenib works as a progressor to sorafenib, or cabozantinib as a progressor to sorafenib. We need to build on previous knowledge. Otherwise, every time there’s a new treatment, all the evidence we’ve built for 15 years doesn’t work.

Videos

Andrea Casadei Gardini, MD, leads the discussion on the optimal sequencing of systemic therapy for advanced HCC. 

Sequencing Systemic Therapy for Advanced HCC

 If you chose TKI [tyrosine kinase inhibitor] for whatever contraindications to a desert map in this patient, considering the aggressiveness of the disease—meaning segmental portal vein invasion—an infiltrative tumor is an indirect sign of aggressiveness and AFP [alpha-fetoprotein] of 9000 ng/mL. What’s your decision in terms of frontline single TKI?

I’d choose lenvatinib for this patient. Normally I prescribe a combination. I chose it because lenvatinib and sorafenib are 2 very different drugs. Lenvatinib is a response to the disease—our patient has a high alpha-fetoprotein invasion, and it filters to the liver lesion. Our response to this patient is to prolong the overall survival. The difference between the 2 TKIs is the response and the adverse events. My patients have demonstrated a tolerability to lenvatinib. There are fewer skin reactions, and we have more hypertension. I usually prescribe 5 mg of Norvasc [amlodipine] if there’s hypertension during treatment. Another problem with lenvatinib is anoxia, but we don’t have cases in our hospital [San Raffaele Research Hospital]. It has a better response and better tolerability, so in this case, I choose lenvatinib for our patient.

This week, there was a press release for the HIMALAYA trial. The final analysis compares durvalumab-tremelimumab with sorafenib head-to-head. After several months, the analysis in the press release showed positive results for the primary end point, which is OS [overall survival] superiority. This is the first I/O [immuno-oncology]–I/O combination in HCC [hepatocellular carcinoma] that may change the landscape of management. In the decision-making process, we need the OS, progression-free survival, objective response, adverse events, and patient-reported outcomes. How does this impact frontline management?

This study will be very important, possibly a landmark study. The HIMALAYA trial is a phase 3 trial with a robust sample size—it’s close to 1200 patients—with 3 arms. The control arm is sorafenib. One experimental arm is single-agent durvalumab, and the other experimental arm is 1 dose of tremelimumab and durvalumab. The primary objective of this study was to compare tremelimumab-durvalumab vs sorafenib. I was impressed not only with the positivity of the clinical trial and the end point but also the clinically meaningful difference.

In the press release we mentioned statistical significance and clinical meaningfulness. My interpretation of 

 means an improvement of OS, at least 1 to 2 months. It also suggested that they successfully demonstrated the noninferiority between the durvalumab and the sorafenib. CheckMate 459 has not demonstrated that. The key message of this study is that we have a safer and more effective I/O–I/O combination. It also suggests that single-agent I/O durvalumab may be an alternative option for sorafenib. We must read the full data, which will probably be at ESMO [European Society for Medical Oncology Congress] next year.

Experts in gastroenterology share their approaches to first-line single-agent and combination TKI therapies for the treatment of advanced HCC.

Optimizing the Selection of Frontline TKIs for Advanced HCC

 Let’s move to model 2, which is about the first-line systemic therapy for advanced HCC [hepatocellular carcinoma], and I would like to hear about the case from Dr Casadei.

 I will present a case of a 63-year-old male with chronic hepatitis B, who recently started antiviral therapy. He presented with nausea and abdominal pain, and a blood examination highlighted a count of 63,000 platelets, 9000 [ng/mL] alpha-fetoprotein, 1.2 [mg/dL] bilirubin, 3.9 [g/dL] albumin, transaminases of 76 [U/L], and alanine aminotransferase of 122 [U/L]. The DNA hepatitis B is lower, it is 12. The patient’s CT scan showed evidence of multifocal infiltrate liver lesion and segmental portal vein invasion in the right lobe. The patient was diagnosed with advanced hepatocellular carcinoma with good liver function, Child-Pugh A score, ECOG performance status of 1.

 We have a classic case of advanced HCC with vascular invasion and ECOG performance status of 1, but still with all the characteristics of liver function and performance status in those who receive any type of systemic therapy. We need to discuss a few things, first, what is the first option for this patient? According to our guidelines, that would be atezolizumab plus bevacizumab. We must understand the status of esophageal varices or gastric varices at endoscopy, which are not mentioned. We can assume that most Child-Pugh A patients do not have at risk varices. So by default, the question is would your first treatment option be atezolizumab, bevacizumab? Imagine that it’s atezolizumab, bevacizumab, you need to justify why. Then in what cases do you think there are contraindications for atezolizumab, bevacizumab, where you will use a single-agent TKI [tyrosine kinase inhibitors] like sorafenib or lenvatinib?

 For this patient with BCLC [Barcelona Clinic Liver Cancer] stage C disease, still with preserved hepatic function, I will follow the guideline and the phase 3 data now, the IMbrave150 data. The standard still is atezolizumab and bevacizumab. We need to have an endoscopy for this patient because the…is a bit low, this patient may have chronic portal hypertension and also untreated varices. Yes, atezolizumab and bevacizumab, but in some cases I may consider the TKI, especially lenvatinib. For example, if the patient had history of a transplant, but not applicable to this patient, or patients with poorly controlled or severe autoimmune disease. These pose contraindication to the anti–PD-1 or ICI [immune checkpoint inhibitor] treatment. Another point is sometimes I see patients who are less fit and with aggressive disease from their history. It takes time to arrange the endoscopy, so if I want to start treatment today or tomorrow, I may start with lenvatinib. We still see a number of patients with response among this group of patients, so this is my first-line choice.

 When you’re checking the story of this patient, the platelet count is 63,000. Generally this reflects portal hypertension, so an endoscopy would be required prior to starting the therapy. We were discussing contraindications. We have high-risk varices, particularly associated with the risk of bleeding with bevacizumab, so this would be a contraindication if they are untreated. Another contraindication would be patients who have been treated with a liver transplantation for the primary tumor, due to potential graft rejection. Another contraindication is autoimmune disease, and these situations all lead to choosing lenvatinib or sorafenib, in the front line.

Andrea Casadei Gardini, MD, presents the case of a 63-year-old man diagnosed with advanced HCC, and the panel reviews available first-line treatment options for patients with advanced HCC.

Updates to First-line Treatment Options for Advanced HCC

Let’s imagine a scenario where we’re not talking about a single tumor, but this tumor is 7 cm with an additional node—either metastasis or a synchronic tumor because it’s difficult to tell if you don’t run molecular studies—in another segment of 2 cm. We have 2 nodules, 7 cm and 2 cm, surgery is not the ideal strategy, and we are in the intermediate setting. TACE [transarterial chemoembolization] has been a standard of care for the last 15 years, and there are trials testing drug combinations with no positive results. I’m remembering the study by [Masatoshi] Kudo, [MD,] presented with lenvatinib or others in intermediate HCC [hepatocellular carcinoma]. Dr Chan, in which circumstances might you consider these combinations? Or do you treat the patient with the conventional standard of care, and then depending on the progression of the disease, you make a decision?

We know the BCLC [Barcelona Clinic Liver Cancer] B stage of HCC is a heterogeneous disease. Some patients who a relatively small disease burden, they will benefit from the TACE alone. Patients with larger tumors, like as mentioned larger than 7 cm, or with a tumor number of more than 5, or sometimes we call it up-to-7 criteria, will have a higher chance of developing refractoriness to TACE, even though we can technically treat them with it. In the APPLE [Asia-Pacific Primary Liver Cancer Expert] consensus statement, we call these TACE unsuitable tumors. We don’t have high-level evidence for how to treat this type of patient with a larger disease burden. One proposal, as mentioned by Dr Llovet, is that we can add a TKI [tyrosine kinase inhibitor] to the treatment of these tumors. When you read the data and look at the clinical trials, we have some study on axitinib, and while the response rate is higher, the PFS [progression-free survival] slightly improved, the overall survival [OS] has not dramatically changed. So I don’t think this will be routine.

Now, industries and investigators are testing the addition of PD-1 or PD-1 combinations, like the EMERALD-1 study, and we need to wait for the data from this phase 3 clinical trial. In the study by Kudo, which I’m a part of, we asked if a single systemic therapy can benefit this type of high-burden BCLC stage B disease, like beyond the up-to-7 criteria. We showed that single-agent lenvatinib in this type of TACE unsuitable patients, large disease burden, have a better overall survival and PFS in a matched prospective cohort study. This is not a randomized study, it’s a matched cohort study. Also, those patients treated with lenvatinib had preservation of hepatic function during the course of treatment, while patients treated with TACE have a higher chance of developing deterioration of function in terms of ALBI [albumin-bilirubin] score and Child-Pugh score. This is still an open area, and we need more studies in the future to guide us.

 I would say that overall, for intermediate HCC, this means liver-only disease without metastasis and good performance status, the standard of care is locoregional therapies, TACE, and even in the United States, Y-90 [yttrium-90 radioembolization] is accepted as an alternative option. Adding systemic therapies is not indicated by guidelines. There are preliminary data that are appealing. There are several ongoing trials, the EMERALD-1 , the LEAP-012, and the CheckMate 74W. These trials are combining locoregional and systemic therapies, but at this point we cannot indicate these treatments in the management of intermediate HCC.

Gastroenterology experts discuss whether there a is a role for systemic therapy for the management of intermediate HCC.

Is There a Role for Systemic Therapy for Patients With Intermediate HCC?

 We assume that the primary treatment for this patient is resection, but some centers might consider transarterial radioembolization Y-90 or even TACE [transarterial chemoembolization]. What’s your opinion about these treatments at this early stage?

 This patient has a very high risk of relapse after surgery, and neoadjuvant treatment is a good option for our patient. Between days on radioembolization, I prefer radioembolization because the lesion of our patient is often 7 cm and their response is 2 days, and this isn’t better. It’s important to offer neoadjuvant treatment. We select patients with response and the probability of a better genetic profile. It’s important to perform neoadjuvant therapy for this patient before surgery. We don’t have phase 3 trial data, but we’re moving on with neoadjuvant therapy and locoregional therapy before surgery.

Andrea Casadei Gardini, MD, and Stephen L. Chan, MD, examine the use of TACE and TARE-Y90 for the treatment of HCC.  

Role of TACE and TARE in the Treatment of HCC

® titled “Emerging Treatment Considerations in Hepatocellular Carcinoma: An Expert Case-Based Discussion.” I’m Josep Llovet, and I’m the director of the liver cancer program and a professor of medicine at the Icahn School of Medicine at Mount Sinai in New York. I’m joined by 2 experts in the field of liver cancer. I’d like to welcome my esteemed fellow panelists. Dr Andrea Casadei, please introduce yourself.

 Thank you. My name is Andrea Casadei Gardini, and I’m an oncologist at San Raffaele Research Hospital in Milan, Italy. I’m the head of the liver unit in the oncology department.

 Thank you. I’m Steven Chan. I’m a professor in the department of clinical oncology at the Chinese University of Hong Kong, and I’m a medical oncologist.

 Thank you for joining me in this discussion about the emerging treatment in HCC [hepatocellular carcinoma]. We’re going to discuss several updates in HCC, including abstracts at ASCO [American Society of Clinical Oncology Annual Meeting] and ESMO [European Society for Medical Oncology Congress] 2021. We’ll also discuss the data of other updates in the treatment landscape and their impact on clinical practice. Let go to the first topic. Is there a role for adjuvant or neoadjuvant therapy in patients with HCC undergoing resection, or ambulatory treatment?

 I’m going to present a patient’s history briefly. We have a 72-year-old woman with a mild alcoholic cirrhosis. An abdominal ultrasound was performed because of an increased gamma GT. Subsequent CT demonstrated liver cancer with a single tumor of 7 cm. There are no vascular invasions or extrahepatic spread. The liver function is Child-Pugh class A, and the ECOG performance status was 0. The liver function, albumin, and the bilirubin were normal, and the alpha-fetoprotein was 20 ng/mL. This patient underwent surgery. The pathologies showed complete recession and confirmed it to be FCC [follicular cell carcinoma].

 This is framing a classic case in which resection is performed. R0 is achieved by the pathology assessment. The natural history of these patients would be 50% to 70%, with recurrent rate at 5 years. Do we have a choice in terms of primary adjuvant therapy? What do you think about the current data on therapies for this patient?

 This is an important area because in the West, and more likely in the East, our surgeons like to operate on patients with liver tumors, but the criteria for operation may be different. Western surgeons are more selective in terms of selecting the patient for surgery. In the East, our surgeons tend to operate on patients with advanced tumors, bigger tumors, multiferroics…this explains why the recurrence rate and the survival may vary between the East and West and even between different centers. Can we give atrophic treatment for these patients so that we can reduce the recurrences? In the old days, in our center, we participated in a study, adjuvant iodine-131, which showed no improvement in overall survival. In the era of sorafenib, there was the STORM phase 3 study. Unfortunately, the use of sorafenib was unable to prolong disease-free survival, and we found adjuvant use of TTI [time to treatment initiation] was not tolerable. A lot of patients opted for poor compliance. We’re moving toward the adjuvant use of anti–PD-1. Now we have a number of phase 3 trials by different industries, some testing on single use of anti PD-1, some on combinations.… We need data. The regimen works in the metastatic setting or advanced setting, but that doesn’t mean it must work in the adjuvant setting, when there’s no gross tumor. We don’t have a standard, but we eagerly await those phase 3 clinical trials.

 I concur. After running more than 20 phase 3 trials in this arena, all these trials were negative, except 1 with adoptive immunotherapy. This has not been adopted by guidelines. Unfortunately for this patient, at this point, the decision could be to follow the patient with a regular screening to check for potential recurrence and tag them early. There’s no recommended systemic therapy or operational therapy in the adjuvant setting. There are few studies already reported in the neoadjuvant. These studies are assessing checkpoint inhibitors in a small group of 20 patients. So far, the results are promising, with a readout of pathological response. We need a thorough phase 3 investigation so I could say that the neoadjuvant arena is appealing. It’s scientifically sound, and the preliminary data are promising, but we need additional studies.

Stephen L. Chan, MD, reviews the case of a 72-year-old woman with mild alcoholic cirrhosis and provides insight on the potential role of adjuvant and neoadjuvant therapy for the treatment of HCC.

Stephen L. Chan, MD, The Chinese University of Hong Kong

Articles

Sequencing Systemic Therapy for Advanced HCC

Optimizing the Selection of Frontline TKIs for Advanced HCC

Updates to First-line Treatment Options for Advanced HCC

Is There a Role for Systemic Therapy for Patients With Intermediate HCC?

Role of TACE and TARE in the Treatment of HCC

Updates to Adjuvant and Neoadjuvant Therapy in Early HCC