"In this trial, we are only giving roughly three weeks of therapy prior to surgery," Dr. Thomas Marron of the Icahn School of Medicine at Mount Sinai in New York City told Reuters Health by email. "The goal was not necessarily to kill the tumor we were going to remove - these patients are going to the operating room regardless - but rather to prime the immune system as to what the tumors look like, so it can recognize and eliminate any microscopic disease that remains elsewhere in the body that will eventually lead to recurrence."
"In roughly a third of patients there was already significant tumor killing after just a few weeks," he noted. "This was not necessarily surprising, as neoadjuvant trials in other tumor types (lung cancer, in particular) had already demonstrated that these therapies work faster than we anticipated, but it was gratifying nonetheless."
"This is particularly true as we think that tumor necrosis correlates with increased likelihood that these patients will remain cancer free," he said. "This is possibly MOST important in liver cancer where 1) the recurrence rate following surgery is as high as 70%, and 2) we have NO standard pre-operative or post-operative therapies that have proven ability to decrease the risk of the cancer coming back."
As reported in The Lancet Gastroenterology and Hepatology, for this single-arm, open-label, phase 2 trial, patients with resectable HCC (stage Ib, II, and IIIb) were enrolled and received two cycles of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks, followed by surgical resection.
After resection, patients received an additional eight cycles of adjuvant cemiplimab 350 mg intravenously every 3 weeks.
The primary endpoint was significant tumor necrosis on pathological examination (defined as >70% necrosis of the resected tumor).
Twenty-one patients were enrolled and received neoadjuvant cemiplimab. Twenty underwent successful resection, of whom four (20%) had significant tumor necrosis; three (15%) had a partial response, and the others maintained stable disease.
Twenty (95%) patients had a treatment-emergent adverse event of any grade during neoadjuvant treatment. The most common of any grade were increased aspartate aminotransferase (four patients), increased blood creatine phosphokinase (three), constipation (three), and fatigue (three).
Seven patients had grade 3 adverse events, including increased blood creatine phosphokinase (in two) and hypoalbuminemia (in one). No grade 4 or 5 events occurred.
One patient developed pneumonitis, which led to a two-week delay in surgery.
The authors conclude, "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."
Dr. Marron said, "One of the notable parts of this trial is that this pre-operative therapy did not significantly delay surgery, which is a common concern among clinicians and patients alike. Given scheduling--particularly in the era of COVID--often takes weeks before a patient can get into the operating room, brief therapies like this could offer patients significant benefit with relatively low likelihood of side effects."
Dr. James Harding of the Gastrointestinal Oncology and Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York City commented on the study in an email to Reuters Health. "The results continue to support the antitumor activity of immune checkpoint inhibitors in patients with HCC."
"The novelty here is that this study is one of a group of several trials that seek to use immune checkpoint inhibitors alone or in combinations at earlier stages of disease," he said. "The preliminary results of this small study are quite interesting, but of course larger, randomized studies will be required and are ongoing to confirm if perioperative approaches will become a standard of care or not in patients with earlier stages of disease."
"The paradigm for HCC treatment is advancing and clinicians and patients should follow closely, as from my vantage point, the field is changing rapidly," Dr. Harding concluded.
The study was funded by Regeneron Pharmaceuticals. Dr. Marron and a number of coauthors receive fees from the company and 17 coauthors are employees and shareholders.
SOURCE: https://bit.ly/3uajcki The Lancet Gastroenterology and Hepatology, online January 19, 2022.
By Marilynn Larkin
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