Determining the Efficacy of Neoadjuvant Cemiplimab in Hepatocellular Carcinoma

Thomas Marron, MD, PhD an assistant professor of hematology and medical oncology at Mount Sinai Hospital, discusses the study design and key goals of adding perioperative cemiplimab (Libtayo), an anti-PD-1 antibody, to surgical resection for hepatocellular carcinoma (HCC) (NCT03916627).

According to Marron, patients included had tumors that could be excised immediately at the time of enrollment. However, instead of going to the operating room initially, patients were given 2 rounds go cemiplimab prior to surgery. Cemiplimab is given ever 3 weeks. Four weeks after surgery ended, patients were given 8 cycles of adjuvant cemiplimab.

In total, 21 patients were enrolled and 20 underwent surgery. Of the 20 that underwent surgery, 4 had a tumor necrosis of 70% or more, meeting the study’s primary end point. Of the 4 patients who responded, 3 had a complete response. Additionally, tumor necrosis of 50% or more were seen in 7 of the 20 patients. According to Marron, the purpose of adding cemiplimab to therapy prior to surgery isn’t to kill the tumor, but to shrink the tumor to make surgery easier. 

Study Design to Determine the Efficacy of Neoadjuvant Cemiplimab in HCC

0:08 | We have patients that were identified that were deemed surgical candidates. They had tumors that could be excised, and they could have gone straight to the operating room, and they were enrolled. And what they did was they underwent some pretreatment biospecimen collection. We got core needle biopsies of their tumor and we collected a large amount of blood and stool so that we could have some baseline biospecimens to analyze. They then received 2 cycles of the PD-1 antibody, cemiplimab. It's given every 3 weeks as the standard dosing that's used throughout the clinical trials. And it's also FDA approved for a few indications at this point. Cemiplimab is given every 3 weeks. We see them on a regular basis so that we can get routine blood work and also collect research bloods. Then, most of the patients went to the operating room soon after the second dose of cemiplimab was administered. So roughly 4 weeks after starting therapy, so it's a relatively short neoadjuvant intervention. After patients recovered from surgery, typically around 4 weeks after the day of operation, they came back to the cancer center and they started adjuvant therapy and all of the patients, or nearly all the patients, received 8 cycles of adjuvant cemiplimab. Here we're really only focusing on the data up to the time of surgery.

Key Goals of the Study Evaluating Neoadjuvant Cemiplimab in HCC

1:28| Our primary end point was significant tumor necrosis, which we defined as greater than 70% necrosis, unlike other cancer types, like lung cancer, where we have major pathologic response. This is then validated to correlate with overall survival, or in breast cancer, where we have pathologic complete response. Pathologic complete responses correlate well with overall survival in liver cancer because there's no standard neoadjuvant therapy, and there are no validated markers of response that correlate with survival. We came up with significant tumor necrosis looking at a small study from France, where they had resected patients following trans arterial chemoembolization. There, they show that around a 70% necrosis in the tumor that was resected correlated with a survival advantage. So, it's a totally different type of therapy. I am the first to admit that it is not a perfect endpoint, but we needed something to shoot for. So that was our primary end point. Our secondary end points dealt with delay of surgery, disease-free survival, overall response rate, and overall survival, and adverse events that were experienced.

2:39 | What we saw was basically the tumors were resected, and they were analyzed by 3 expert hepatic pathologists, and 4 of the patients that were analyzed. Again, 21 patients were enrolled, 21 went to the operating room after receiving 3 cycles of cemiplimab. One patient that operation was actually aborted because they found some peritoneal spread of their cancer that hadn't been seen extensively on MRI, but 20 patients had tumors excised and were evaluable for the primary end point. Of those 20 patients, 4 had a significant tumor necrosis. So that's 20% of patients met the primary endpoint. Actually 3 had complete pathologic responses with no residual evidence of tumor cells. But interestingly, as I mentioned, the 70% cut off is something that in many ways we made up. But we saw that more than 50% tumor necrosis was seen in 7 of the 20 patients. And so that was very reassuring, because we assume that if we're seeing tumor necrosis, and especially an increase in the tumor necrosis over baseline, that that is going to correlate with an elimination of any sort of residual micro metastatic disease and prolong survival.

3:54 | I think that what's going to be very interesting to do now is we're doing extensive single-cell analysis of the immune infiltrate within the tumor and in some patients and draining lymph nodes. And we're going to be able to do a characterization of those T cells to see if we see expansion of tumor reactive T cells. So, potentially even in the other 65% of patients who didn't have this, whopping necrosis in the excised tumors, we, we think that there's a possibility that we might actually be still having some sort of vaccinal effect. So, priming a T-cell response, because, these patients have tumors that can be excised and cured with surgery, we just know that a lot of them are going to recur. It’s always reassuring and nice to see when there's a lot of necrosis especially if it downstage the tumors, and we have seen some patients who had huge tumors shrink significantly before surgery, and potentially even have a less morbid surgery. So that's reassuring. But really, the goal is not to kill the tumor that's there, because we're going to take that anyway. It's really about priming an immune response to eliminate all the microscopic residual disease elsewhere in the liver or elsewhere in the body, to further decrease the likelihood that the cancer is going to come back after surgery.