Neoadjuvant Cemiplimab Shows Promise as HCC Treatment

Thomas Marron, MD, PhD

Recent clinical trial data suggest there may be hope for the treatment of patients with hepatocellular carcinoma (HCC) after surgery. In the current landscape, the majority of HCC tumors recur after hepatic resection and no other preoperative intervention has demonstrated an improvement in survival. The novel intervention that may be a solution is neoadjuvant immunotherapy, which has shown benefit in multiple tumor types, according to data presented at the American Association of Cancer Research (AACR) Annual Meeting 2021.

The multicenter exploratory study (NCT03916627) evaluated whether neoadjuvant cemiplimab (Libtayo) could improve outcomes over hepatic resection in HCC, non-small cell lung cancer, and head and neck squamous cell carcinoma. The data presented at the 2021 AACR Annual meeting focused on cohort B, the HCC cohort, which enrolled 21 individuals. Prior to surgery, patients received 2 cycles of neoadjuvant cemiplimab. After surgical resection, patients received an additional 8 adjuvant cycles. All but 1 of the patients underwent resection as they were found to have metastatic disease at the time of surgery and resection was aborted.

The primary end point of the study was significant tumor necrosis, meaning 70% or more necrosis of the resected tumor. Secondary end points included surgery delays, overall response rate, adverse events (AEs) and changes in lymphocyte infiltration.

In total, 90.5% of patients experienced any grade treatment-emergent AE (TEAE) and 28.6% experienced a grade 3 TEAE. One patient’s surgery was delayed for 2 weeks by grade 2 pneumonitis during neoadjuvant surgery. Twenty percent of patients met the primary end point, 75% of which had a pathological complete response.

In an interview with Targeted Oncology, Thomas Marron, MD, PhD, an assistant director of Immunotherapy and Early Phase Trials at The Tisch Cancer Institute, and assistant professor of Medicine, Hematology and Medical Oncology at the Icahn School of Medicine at Mount Sinai, discussed neoadjuvant cemiplimab for the treatment of HCC.

TARGETED ONCOLOGY: Can you tell me what led to this trial?

MARRON: We have 1 of the largest HCC programs in the country, and our surgeons do over 100 surgeries a year. But unfortunately, the vast majority of patients recur and that is local regional recurrence that’s not typically at the surgical margin. We believe the recurrence is due to the existence of micro metastatic disease. However, to date, there haven't been any trials that have demonstrated a survival advantage to using either pre-operative or post-operative, neoadjuvant or adjuvant therapy of any sort. So, as we are seeing the development of the neoadjuvant immunotherapy space in many different types of cancer, and we have clinical trials going on in that space and in most types of cancer, we really think that HCC is the optimal space because there's no standard neoadjuvant or adjuvant therapy to decrease the likelihood of recurrence. What we do know is that the recurrence rate is very high and we also see rising rates of HCC, both due to hepatitis B infection and also rising rates of nonalcoholic steatohepatitis (NASH), which are growing problems in the United States. So, I think that it's an opportune time to try to intercede early in HCC. We're doing better job of screening patients and identifying early-stage lesions that are amenable to resection. But we want to make sure that once those patients go through surgery that is the definitive therapy.

Can you explain study design and what methods are used in this study?

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 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.

What were the key goals that you were looking at in the study?

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.

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.

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.

Was there anything unique about these results or anything that surprised you with the analysis?

I think that it's very reassuring to see this impressive pathologic response rate. I was reassured that we had 21 patients, and all 21 of them eventually made it to the operating room. Twenty of them didn't have any preoperative issues, per se. There was one patient that had a little bit of pneumonitis and so their surgery was delayed by 2 weeks. But it was reassuring to see that this was a pretty well-tolerated intervention. And I think that when we're thinking about the neoadjuvant space, and we're looking for possible therapies, there's a balance between, efficacy, and looking at surrogates of efficacy, and obviously tolerability. These patients that have very short, very relatively easy treatment ahead of surgery that didn't significantly delay their curative intent therapy. So, I think that it was very reassuring to see how well tolerated the treatment was.

I think that what's going to be very exciting is to look further at some of the multiplex immunohistochemistry that's coming up. We're using 2 different platforms. We're using RNA scope and the MICs platform, which is developed in house here at Mount Sinai. Also, we're just now starting to get back some of the final single-cell sequencing that's really going to allow us to do a deep dive and look at the phenotypes of the T cells, particularly the T cells that we believe are tumor specific. I think that's going to not only inform further iterations of neoadjuvant trials in HCC, but also potentially inform more rational combinatorial approaches, bringing in additional therapies that hopefully are not more toxic, but maybe significantly more efficacious at stimulating a T cell response.

This is the largest study to date of PD-1 monotherapy and HCC. I think that even with long term outcomes, we're not going to be able to say too much definitively about the impact of this therapy and survival because it is a relatively small population. But I look forward to significantly larger trials that will hopefully validate the use of neoadjuvant immune therapy and the treatment of HCC patients who have early stage lesions that have been identified that are surgical candidates.

_REFERENCE:

_{Marron T, Gunasekaran G, Tabizian P, et al. Neoadjuvant cemiplimab demonstrates complete pathological responses in hepatocellular carcinoma. April 10, 2021. Accessed May 18, 2021. Presented at AACR Annual Meeting 2021. https://bit.ly/2Sb6VuQ}