Immunotherapy given before surgery caused liver cancer tumours to die off in one-third of the patients enrolled in a first-of-its-kind clinical trial, Mount Sinai researchers have reported in The Lancet Gastroenterology & Hepatology.
Liver cancer, the most common type of which is hepatocellular carcinoma (HCC), is the third-leading cause of cancer-related deaths globally. While immunotherapies have changed the prognosis of patients with advanced HCC, most patients still die from this disease. Although liver cancer surgery often appears successful, in more than half of patients the cancer comes back, due to either residual micrometastatic disease, or in some cases an entirely new tumour.
The latest phase 2 trial results suggested that neoadjuvant immunotherapy, or therapy given before surgery, might kill not only the tumour, but also microscopic cancer cells that surgery would miss and that could later cause the cancer to recur or metastasise, the researchers said. In effect, the therapy teaches the immune system to fight off any recurrences.
“Ultimately, we think it’s better for the patient to receive immunotherapy before surgery because people are healthier before metastases, and their immune systems are in better shape to fight off the cancer,” said senior author Dr Thomas Marron, director of the Early Phase Trials Unit at The Tisch Cancer Institute and Associate Professor of Medicine (Haematology and Medical Oncology) at the Icahn School of Medicine at Mount Sinai.
“This study, with neoadjuvant immunotherapy trials in many other types of tumours, supports the need for continued evaluation of perioperative immunotherapy to decrease recurrence rates.”
Marron said that typically when cancer recurs, it is no longer a curable disease.
“Larger trials in the future will aid in defining the utility, safety, and survival of neoadjuvant immunotherapy, specifically this type of PD-1 blockade.”
This study’s findings are important because to date, no therapy given before or shortly after surgery has demonstrated any real improvement in survival for liver cancer patients.
Researchers gave 21 early-stage liver cancer patients two rounds of the immunotherapy agent cemiplimab, an anti-PD-1 antibody, before their surgery in late 2020. Doctors studied tumour death and cancer-fighting immune system activation via magnetic resonance imaging and blood, tumour, and stool samples.
They found that in one-third of the patients, much of their tumours died before surgery. Patients whose immune system was already working against the cancer tended to have more of a response to the immunotherapy, which suggests that the immune system was further activated and would kill any microscopic remnants of cancer. Tumour death in response to neoadjuvant therapy is an indication for improved outcomes in many cancer types, and the researchers are currently following the patients to assess if this rings true for HCC as well.
This study was able to measure the immune system response in a novel way. Marron and colleagues used a new collaborative approach between researchers and clinicians: The neoAdjuvant Research Group to Evaluate Therapeutics or TARGET, which maximises the useful information that can be gleaned from smaller neoadjuvant clinical trials. The TARGET platform focuses on coordinating detailed, real-time profiling of the immune system’s response in patients receiving cancer immunotherapy as a neoadjuvant treatment.
The TARGET platform showed how the PD1 blockade boosted the number of activated immune cells that invade HCC tumours, induced tumour necrosis, and shrank tumours before surgery. The platform helped researchers determine that PD1 blockade is possibly beneficial in HCC, but because only some patients had a robust response, the immunotherapy might need to be used in combination with other treatments.
The aim of the in-depth analysis of tissue samples is to identify biomarkers (biological identifiers) that will help show who will and will not respond well to a
therapy. The aim of TARGET is to identify the optimal therapy for each patient, and decrease the likelihood that suboptimal treatments go into large phase 3 trials, wasting resources and the time and efforts of patients.
“You normally don’t get to study how drugs work in humans in such a detailed manner,” said Marron. “When you do simple biopsies, you get very little tissue and the analysis often doesn’t produce detailed information about the cancer or the immune system’s response. With this platform’s analysis, you get several biopsies before treatment as well as blood and stool samples. Then when the tumour is removed in surgery, we analyse that as well as more blood and stool samples, so we have a lot of detailed information on what is going on microscopically than ever before. This is an exciting platform to study in that level of detail.”
Study details
Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial.
Thomas U Marron, Maria Isabel Fiel, Pauline Hamon, Nathalie Fiaschi, Edward Kim, Stephen C Ward, Zhen Zhao, Joel Kim, Paul Kennedy, Ganesh Gunasekaran, Parissa Tabrizian, Deborah Doroshow, Meredith Legg, Ashley Hammad, Assaf Magen, Alice O Kamphorst, Muhammed Shareef, Namita T Gupta, Raquel Deering, Wei Wang, Fang Wang, Pradeep Thanigaimani, Jayakumar Mani, Leanna Troncoso, Alexandra Tabachnikova,
Christie Chang, Guray Akturk, Mark Buckup, Steven Hamel, Giorgio Ioannou, Clotilde Hennequin, Hajra Jamal, Haley Brown, Antoinette Bonaccorso, Daniel Labow, Umut Sarpel, Talia Rosenbloom, Max W Sung, Baijun Kou, Siyu Li, Vladimir Jankovic, Nicola James, Sara C Hamon, Hung Kam Cheung, Jennifer S Sims, Elizabeth Miller, Nina Bhardwaj, Gavin Thurston, Israel Lowy, Sacha Gnjatic, Bachir Taouli, Myron E Schwartz, Miriam Merad.
Published in The Lancet Gastroenterology & Hepatology on 19 January 2022
Summary
Background
Surgical resection of early stage hepatocellular carcinoma is standard clinical practice; however, most tumours recur despite surgery, and no perioperative intervention has shown a survival benefit. Neoadjuvant immunotherapy has induced pathological responses in multiple tumour types and might decrease the risk of postoperative recurrence in hepatocellular carcinoma. We aimed to evaluate the clinical activity of neoadjuvant cemiplimab (an anti-PD-1) in patients with resectable hepatocellular carcinoma.
Methods
For this single-arm, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma (stage Ib, II, and IIIb) were enrolled and received two cycles of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by surgical resection. Eligible patients were aged 18 years or older, had confirmed resectable hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate liver function. Patients were excluded if they had metastatic disease, if the surgery was not expected to be curative, if they had a known additional malignancy requiring active treatment, or if they required systemic steroid treatment or any other immunosuppressive therapy. After resection, patients received an additional eight cycles of cemiplimab 350 mg intravenously every 3 weeks in the adjuvant setting. The primary endpoint was significant tumour necrosis on pathological examination (defined as >70% necrosis of the resected tumour). Secondary endpoints included delay of surgery, the proportion of patients with an overall response, change in CD8+ T-cell density, and adverse events. Tumour necrosis and response were analysed in all patients who received at least one dose of cemiplimab and completed surgical resection; safety and other endpoints were analysed in the intention-to-treat population. Patients underwent pre-treatment biopsies and blood collection throughout treatment. This trial is ongoing.
Findings
Between Aug 5, 2019, and Nov 25, 2020, 21 patients were enrolled. All patients received neoadjuvant cemiplimab, and 20 patients underwent successful resection. Of the 20 patients with resected tumours, four (20%) had significant tumour necrosis. Three (15%) of 20 patients had a partial response, and all other patients maintained stable disease. 20 (95%) patients had a treatment-emergent adverse event of any grade during the neoadjuvant treatment period. The most common adverse events of any grade were increased aspartate aminotransferase (in four patients), increased blood creatine phosphokinase (in three), constipation (in three), and fatigue (in three). Seven patients had grade 3 adverse events, including increased blood creatine phosphokinase (in two patients) and hypoalbuminaemia (in one). No grade 4 or 5 events were observed. One patient developed pneumonitis, which led to a delay in surgery by 2 weeks.
Interpretation
This report is, to our knowledge, the largest clinical trial of a neoadjuvant anti-PD-1 monotherapy reported to date in hepatocellular carcinoma. The observed pathological responses to cemiplimab in this cohort support the design of larger trials to identify the optimal treatment duration and definitively establish the clinical benefit of preoperative PD-1 blockade in patients with hepatocellular carcinoma.
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