Joan Culpepper-Morgan, MD

Though the field of hepatocellular carcinoma (HCC) is complex, there is hope with committed experts who constantly work to develop new advancements and treatments for patients. With early detection methods, the future is becoming brighter for patients with liver cancer.

October is Liver Cancer Awareness Month, and strides continue to be made in the realm of liver cancer diagnosis and treatment. Two experts, Joan Culpepper-Morgan, MD, and Susanne G. Warner, MD, shed light on some of the treatment options available in the space.

"What's on the menu depends entirely on the staging of the patients when they present," said Warner, associate professor of surgery at the Mayo Clinic, in an interview with Targeted Oncology^TM.

For those diagnosed with HCC, an aggressive form of liver cancer, a diverse array of therapies has emerged that are tailored and personalized to the specific needs of each patient.

Treatment Landscape

Tyrosine Kinase Inhibitors

First-line treatment options for advanced HCC currently include lenvatinib (Lenvima) and sorafenib (Nexavar). Sorafenib was approved in 2008 by the FDA based on findings from the SHARP study (NCT00105443).¹ The double-blind, placebo-controlled trial enrolled 602 patients with advanced HCC. Patients were randomly assigned to receive 400 mg of sorafenib twice daily or placebo.²

Susanne G. Warner, MD

After a planned interim analysis of the trial demonstrated a statistically significant advantage in overall survival (OS) for patients who had received sorafenib, the trial was stopped and it was concluded that median survival and time to radiologic progression were close to 3 months longer among those who received sorafenib vs those who received placebo.

Later, lenvatinib gained FDA approval based on efficacy findings from the REFLECT study (NCT01761266), which assessed the primary end point of OS and secondary efficacy end points, as well as other safety end points. Among patients treated with lenvatinib, the OS was 13.6 months (95% CI, 12.1-14.9) vs 12.3 months among those given sorafenib (95% CI, 10.4-13.9). These data showed noninferiority of lenvatinib to sorafenib (HR, 0.92; 95% CI, 0.79-1.06).

Overall, targeted therapies alone or in combination have demonstrated improved rates of OS in a variety of clinical trials in this patient population.

“[These data] have been pretty impressive and encouraging. We have been able to actually have some hope for some long-term survival,” said Morgan, chief of gastroenterology at Harlem Hospital in New York City.

Immune Checkpoint Inhibitors

In the IMbrave150 study (NCT03434379) investigators evaluated the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) compared with sorafenib. A total of 501 patients with unresectable HCC who had not previously received systemic therapy were enrolled in the study and randomly assigned in a 2:1 fashion to either the treatment arm (n = 336) or the control arm (n = 165).³

The OS rate at 12 months was 67.2% (95% CI, 61.3%-73.1%) among those in the treatment arm vs 54.6% (95% CI, 45.2%-64.0%) in the control arm. The PFS was 6.8 months (95% CI, 5.7-8.3) with the atezolizumab/bevacizumab combination and 4.3 months (95% CI, 4.0-5.6), with sorafenib, respectively (HR, 0.59; 95% CI, 0.47-0.76; P <.001).

These data led to the FDA approval of atezolizumab in combination with bevacizumab for patients with unresectable or metastatic HCC in the first-line setting.

Then, the phase 3 HIMALAYA study (NCT03298451) investigated the efficacy and safety of durvalumab (Imfinzi) plus tremelimumab (Imjudo) compared with sorafenib in patients with no prior systemic therapy for unresectable HCC.⁴ There were 1171 patients randomly assigned in the study to receive durvalumab plus tremelimumab (n = 393), durvalumab alone (n = 389), or sorafenib alone (n = 389).

Findings showed that the combination led to a significant improvement in OS vs sorafenib (HR, 0.78; 96% CI, 0.65-0.92; P = .0035). Patients treated with durvalumab alone demonstrated a noninferior OS vs sorafenib (HR, 0.86; 96% CI, 0.73-1.03). The median OS was 16.4 months (95% CI, 14.2-19.6) in the durvalumab/tremelimumab arm vs 16.6 months (95% CI, 14.1-19.1) in the durvalumab alone arm, and 13.8 months (95% CI, 12.3-16.1) in the sorafenib arm. Further, median follow-ups were 16.1, 16.5, and 13.3 months in the durvalumab/tremelimumab, durvalumab, and sorafenib arms, respectively.

Liver Cancer : © Rasi - stock.adobe.com

Curative Intent

Curative intent therapies that are available for patients are directed at the visible tumor. There are interventions designed to delay the progression, and systemic therapies available that can be utilized in versatile ways.

“In terms of curative liver-directed therapy, the age-old standard ever since the Milan criteria came out has been transplantation for patients with HCC because that gives us the most durable long-term survival from the cancer,” said Warner.

In recent years, medical professionals like Morgan and Warner have been at the forefront and following the groundbreaking new therapies coming into play for the treatment of HCC.

As Warner explains, the available options are diverse, tailored to the specific needs of each patient.

"We have curative intent therapies that are directed just at the tumor that we can see. We have therapies that are designed to kick the can down the road, and then we have systemic therapies that can be used in a variety of different ways. We're evolving in our understanding of how we can use them."

Newfound Hope

In addition to these advancements, patients have access to a variety of treatments, including liver-directed therapy, resection, ablation, and surgical intervention.

Warner notes that significant strides have been made in minimally invasive surgery, with laparoscopic and robotic liver surgeries offering promising outcomes, a realm that previously was not explored due to technological limitations. With this, there has been a surge in the adoption of these innovative techniques, creating hope for patients with HCC.

"We're witnessing a surge in laparoscopic and robotic liver surgeries. Although the skill required is immense, the adoption of minimally invasive liver surgery is growing, aligning us with our global counterparts," Warner said.

Traditionally, HCC has been treated anatomically. This has included procedures like chemoembolization and radiofrequency ablation. According to Morgan, there is a heavy importance that rests on early diagnosis for this disease. She emphasizes the need for at-risk patients to participate in regular screening programs.

"Our goal is to get these tumors as quickly as possible," Morgan said.

Another area showing promise is immunotherapy, since they enhance vulnerability to chemotherapies and provide hope for long-term survival. Immunotherapy has shown transformative potential in treatment for patients with cancer.

“We have a bit more by way of immunotherapy for these cancers. These antibodies set the cancer up to be killed by other chemotherapies, allowing previously unresectable cancers to have hope for long-term survival," said Morgan.

The dedication by professionals to push the boundaries in the liver cancer space has offered new hope for patients with this disease, and experts continue to shape the treatment landscape to provide even more options.

REFERENCES:

1. Llovet JM, Ricci S, Mazzaferro V, et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390. doi:10.1056/NEJMoa0708857

2. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi:10.1016/S0140-6736(18)30207-1

3. Finn RS, Qin S, Ikeda M, et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745

4. Abou-Alfa GK, Lau G, Kudo M, et al; HIMALAYA Investigators. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8):1-12. doi:10.1056/EVIDoa2100070