Neoadjuvant Immunotherapy Improves Outcomes in Treatment of High-risk Liver Cancer

Patients diagnosed with liver cancer (hepatocellular carcinoma; HCC) who received immune checkpoint inhibitors (ICIs) before surgery—including those who would not have been eligible for surgery by conventional criteria—had similar outcomes to patients who received surgery upfront.

This conclusion is based on results from a retrospective study, supported by the National Institutes of Health (NIH), the Lou and Nancy Grasmick Fellowship, the Linda Rubin Pancreatic Cancer Fellowship, and the James and Frances McGlothlin Fellows to Faculty Award. The outcome of the study were published in Cancer Research Communications, a journal of the American Association for Cancer Research (AACR).[1]

Today, surgical resection for localized liver cancer is generally reserved for patients with solitary tumors without vascular invasion as defined by the criteria established by the Barcelona Clinic Liver Cancer (BCLC) Staging System, an algorithm most widely used to manage patients with hepatocellular carcinoma.

However, neoadjuvant immunotherapy may even benefit high-risk patients to undergo successful margin-negative resection and achieve comparable long-term clinical outcomes compared with upfront resection.[1]

According to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program , an estimated estimates 41,630 new cases of liver and intrahepatic bile duct cancer will be diagnosed in the United States in 2024. Un addition, some 29,840 people are expected to die of these diseases. The relative 5-year survival rate is 21.6 percent.[2]

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Current Treatment
First approved in 2005 by the U.S. Food and Drug Administration (FDA), sorafenib (Nexavar®; Bayer Pharmaceuticals), an oral multikinase inhibitor that works by blocking signals that tell cancer cells to grow and by preventing them from forming new blood vessel, has for a long time been the standard of first-line treatment for advanced liver cancer.

However, with the introduction of immunotherapy and immune checkpoint inhibitors, a class of immunotherapeutic agents first approved in 2011, scientists started to investigate the possible treatment of liver cancer with these different modalities.

While immunotherapy has become a mainstay for the treatment of advanced or metastatic liver cancer, the primary curative treatment modality for patients with early-stage disease is surgery alone.

“Only around 30% of patients are eligible for surgical resection due to factors such as tumor size, proximity to critical structures, the presence of multiple tumor foci, and safety concerns,” explained noted Mari Nakazawa, MD, first author of the study and a clinical research fellow at the Johns Hopkins Kimmel Cancer Center, who conducted the study togethether with Mark Yarchoan,* MD, senior author of the study and an associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

Nakazawa added that even patients who receive curative intent surgery often experience a recurrence.

“There’s a strong unmet need to expand the number of patients who may be eligible for surgery and, further, to transform more patients with early-stage liver cancer into long-term survivors of this disease,” she added.

Neoadjuvant treatment
Studies from other cancers demonstrated that neoadjuvant immunotherapy may mitigate some high-risk features and help unresectable tumors meet the eligibility criteria for surgery. It may also help the immune system destroy micrometastases, thereby preventing distant recurrences later.

For example, in an unrelated a phase 3 studies by researchers from Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins investigating the feasibility and efficacy of neoadjuvant cabozantinib (Cabometyx®; Excelixis) in combination with nivolumab (Opdivo®; Bristol-Myers Squibb), followed by definitive resection for patients with locally advanced liver cancer in patients with unresectable disease, demonstrated that the neoadjuvant approach successfully facilitated resection in 12 patients and induced major pathologic response (>90% necrosis) in an additional 5 patients (NCT03299946).

Results from another study, a phase 2 clinical study using neoadjuvant cemiplimab (Libtayo®; Regeneron Pharmaceuticals) for the treatment of patients with upfront resectable disease, showed that approximately 20% of participating patients demonstrated significant tumor necrosis (>70% necrosis of resected tumor), while another 15% showed a partial response (50–70% necrosis (NCT03916627).

Another study included nivolumab alone or in combination with lymphocyte activation gene-3 (LAG3) inhibitor relatlimab (Opdualag™; nivolumab and relatlimab; Bristol Meyers Squibb)(NCT04658147) was especially designed to investigate the feasibility and efficacy of perioperative nivolumab with or without relatlimab for patients with potentially resectable liver cancer.

Based on these and other study results, the authors hypothesized that neoadjuvant immunotherapy may help make surgery safer and more effective in patients with high-risk, localized liver cancer.

Study design
Nakazawa, Yarchoan, and colleagues retrospectively examined outcomes from 92 patients who underwent resection for hepatocellular carcinoma at Johns Hopkins from 2017 to 2023. This included 36 patients who received neoadjuvant ICI therapy, many of whom were treated under clinical trial protocols assessing the feasibility and efficacy of immunotherapy prior to surgery.

Prior to receipt of immunotherapy, 61.1% of these patients would not have been candidates for curative surgery based on traditional surgical resection criteria.

Outcomes
Compared with patients who received surgery upfront, patients who received neoadjuvant immunotherapy more commonly exhibited high-risk disease features, including high serum alpha fetoprotein, tumors larger than 5 cm, portal vein invasion, and multiple tumor foci. These high-risk features have previously been associated with worse outcomes. [3]

However, in their retrospective study , patients who received neoadjuvant immunotherapy—who may have been expected to have worse outcomes due to high-risk features—had comparable outcomes to patients who received upfront surgery. Among those who received neoadjuvant immunotherapy, 94.4% underwent successful margin-negative surgical resection, and the median recurrence-free survival was 44.8 months, compared to 49.3 months among those treated with upfront surgery. The median overall survival was not reached in either cohort.

Commenting on the outcomes of the study, Yarchoan said: “This study shows that the criteria by which we classify patients as being candidates for curative therapy is probably too narrow for this disease.”

The authors further emphasized that these findings are retrospective and intended to be hypothesis generating, but they believe these data set a promising stage for future research.

“Prospective trials that are thoughtfully designed in the right populations can help us understand which patients can benefit most from this approach,” Nakazawa said.

“Our findings demonstrate that systemic therapy may not only be useful for patients with advanced disease but can potentially be paradigm changing in patients with early-stage disease,” Yarchoan added.

“There is a group of patients with high-risk liver cancer who, in a contemporary era, may have long-term survival through aggressive treatment with systemic therapy followed by surgery.” Yarchoan concluded.

Study Limitations
Limitations of this study include its retrospective, single-institution nature with a relatively small sample size. Further, as the study cohort was compiled from patients treated in several different clinical trials, as well as those who underwent upfront surgery as the standard of care, factors such as baseline disease characteristics, the duration of neoadjuvant immunotherapy (if received), use of locoregional therapies, and receipt of adjuvant immunotherapy differed between patients.

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Note: * Mark Yarchoan, MD, is a co-founder with equity of Adventris Pharmaceuticals, has received consulting fees from AstraZeneca, Exelixis, Genentech, Replimune, Hepion, and Lantheus; and has received research funding through Johns Hopkins from Bristol Myers Squibb, Exelixis, Incyte, and Genentech.

Highlights of prescribing information
Sorafenib (Nexavar®; Bayer Pharmaceuticals)[Prescribing Information]
Cabozantinib (Cabometyx®; Excelixis)[Prescribing information]
Nivolumab (Opdivo®; Bristol-Myers Squibb)[Prescribing Information]
Cemiplimab (Libtayo®; Regeneron Pharmaceuticals)[Prescribing Information]
Nivolumab and relatlimab-rmbw (Opdualag™; Bristol-Myers Squibb)[Prescribing Information]

Clinical trials
Feasibility and Efficacy of Neoadjuvant Cabozantinib Plus Nivolumab (CaboNivo) Followed by Definitive Resection for Patients With Locally Advanced Hepatocellular Carcinoma (HCC)
– ClinicalTrials.gov ID NCT03299946.
Neoadjuvant Cemiplimab for the Treatment of Resectable NSCLC, HCC, and HNSCC in Adult Patients – ClinicalTrials.gov ID NCT03916627.
Feasibility and Efficacy of Perioperative Nivolumab With or Without Relatlimab for Patients With Potentially Resectable Hepatocellular Carcinoma (HCC)
ClinicalTrials.gov ID NCT04658147

Reference
[1] Mari Nakazawa, Mike Fang, Tyrus Vong, Jane Zorzi, Paige Griffith, Robert A. Anders, Kiyoko Oshima, Amy K. Kim, Jacqueline Laurin, Kelly J. Lafaro, Christopher R. Shubert, William R. Burns, Jin He, Richard A. Burkhart, Benjamin Philosophe, Jeffrey Meyer, Robert P. Liddell, Christos Georgiades, Kelvin Hong, Won Jin Ho, Marina Baretti, Alexandra T. Strauss, Mark Yarchoan. Impact of Neoadjuvant Immunotherapy on Recurrence-Free Survival in Patients with High-Risk Localized HCC. Cancer Research Communications 1 August 2024; 4 (8): 2123–2132. [Article]
[2] National cancer Institute (NCI) Cancer Stat Facts: Liver and Intrahepatic Bile Duct Cancer. Online.  Last accesses on August 13. 2024.
[3] Truty MJ, Vauthey JN. Surgical resection of high-risk hepatocellular carcinoma: patient selection, preoperative considerations, and operative technique. Ann Surg Oncol. 2010 May;17(5):1219-25. doi: 10.1245/s10434-010-0976-5. Epub 2010 Apr 20. PMID: 20405326; PMCID: PMC4103783.

Featured image: Surgeon with surgical instruments performs liver surgery. Photo courtesy: © 2016 – 2024 Fotolia/Adobe. Used with permission.

DOI: 10.14229/onco.2024.08.15.001

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