Ensituximab Shows Modest Single-Agent Activity in CRC, Combinations to Be Explored

Richard D. Kim, MD

The novel chimeric monoclonal antibody ensituximab demonstrated modest clinical activity and was found to be well tolerated in patients with heavily pretreated, refractory colorectal cancer (CRC), according to results from a phase 2 study that were published in Clinical Cancer Research.

“This drug is well tolerated, which is a good start, but we could do better in terms of efficacy,” said lead study author Richard D. Kim, MD. “The next step is to combine it with other agents, such as interleukin (IL)-15, to make it synergistic and possibly induce responses and keep the same safety profile.”

The phase 2 trial enrolled patients with advanced CRC who were refractory to chemotherapy and were treated with single-agent intravenous ensituximab at 3 mg/kg every 2 weeks. Results showed that among 57 evaluable patients, the median overall survival (OS) was 6.8 months. No responses were observed, while the stable disease rate was 21%. There were treatment discontinuations due to drug-related adverse effects (AEs).

In an interview with OncLive, Kim, assistant professor of oncology, University of South Florida College of Medicine, and medical oncologist, Department of Gastrointestinal Oncology, Moffitt Cancer Center, discussed the phase 2 findings with ensituximab in patients with refractory CRC and how its future likely lies in combination with other therapies.

OncLive: What are the treatment challenges regarding patients with chemotherapy-refractory CRC?

Kim: In patients who are refractory to standard chemotherapy, there are currently 2 oral alkaloids available for the treatment of those patients. These include TAS-102 (trifluridine/tipiracil; Lonsurf) and regorafenib (Stivarga). However, in the era of molecular profiling, we are profiling every patient diagnosed with stage IV disease. Through the use of molecular profiling, there are a few mutations that are identified. If you have any kind of mutation, such as HER2, NTRK, or even BRAF, those [targets] have come into prime time. [There are treatments for those targets that] we would use now starting in the third-line and, at times, even the second-line setting if the patient fails first-line therapy. We are getting more options than our typical oncolytic based on the profiling of the tumors.

Please discuss ensituximab and the phase 2 study with this drug in this patient population.

Ensituximab in a chimeric monoclonal antibody that targets an antigen called MUC5AC, which is expressed in colon cancer and pancreatic cancer, as well. If you look at our data, it is probably expressed 50% to 60% of the time. There was a phase 1 study where we dose-escalated the therapy and found the right dose to be studied in the larger phase 2 study setting.

This phase 2, single-agent study was in patients [with metastatic CRC] who were refractory to standard therapy. All of the patients received oxaliplatin, irinotecan, and bevacizumab (Avastin), and if they were EGFR or KRAS wild-type they received EGFR-directed therapy as well. Some even got oral oncolytics, such as regorafenib and TAS-102, as well.

What we see from this study is that the drug is very well tolerated; there are not many AEs associated with this therapy. There are perhaps a few grade 3 anemias and fatigue, but overall, it is very well tolerated.

We met the endpoint of OS, which was around 7 months. We do not want to compare 1 study to another, but [data showed that this drug] could be slightly better than [data seen in] the phase 3 study with regorafenib or TAS-102. However, there were not a lot of responses; response rates were about 20%, some of which were very durable. Based on our phase 2 study, which is about 50 patients, it shows that there may be some modest activity as a single agent and we can take advantage of that because it is well tolerated.

Moving towards the future, single-agent ensituximab is probably not the answer but the combination of it with another agent, such as IL-15, [is promising]. There are some preclinical data suggesting that IL-15 and ensituximab could be synergistic by working through natural killer cells. In the future, trying to combine different agents is where we are going. Single-agent ensituximab is well-tolerated and has modest activity, but we could do a better job by combining it with different agents.

What was the rationale for this phase 2 trial?

The rationale for this study was that this drug is a chimeric monoclonal antibody that targets MUC5AC. This is a biomarker-driven study, which is what we want to do these days. All of the patients who enrolled in the study were eligible if they were positive for MUC5AC, and they had to be positive for it for more than 20% of the study duration. We screened more than 200 patients and about 50% of them were positive and enrolled in the study. That is the rationale of using this drug as a single agent and in this biomarker-specific patient population.

Were any of the findings surprising?

What was surprising was that this was a highly refractory patient population. Some patients received more than 3 or 4 lines of therapy. Despite that, and not seeing a response rate per RECIST criteria, there were quite a few patients who had stable disease. That is a key point.

Are there any next steps for this study?

As a single agent, this drug has a modest activity that we could move forward with. The next step is to combine it with IL-15, which works with NK cells. That is where we are heading at this time and we will see how that goes in the same patient population, who are also positive for MUC5AC.

What is the importance of molecular testing and when should it be done in this patient population?

My recommendation is that unless a patient is enrolled in a study, every patient with advanced CRC should get genetic profiling done at the beginning [of their treatment course] because once we have the genetic profiling done, we have a plan for the patient. For example, if they have a positive KRAS/BRAF/HER2/NTRK status or are [mismatch repair deficient, there are drugs available to target those]. Therefore, all patients with stage IV colon cancer should get genetic testing upfront.

What is your take-home message regarding this research?

This is the first step. As you know, refractory colon cancer is a highly unmet area but we have come a long way. We now have a lot of options available but we could do a better job. One thing is that trying to maintain a good safety profile and improve outcomes [is essential].

Beyond this research, what other exciting efforts are being made in this space?

One of the hot areas that are going on right now is immunotherapy. We know that only 5% of patients are mismatch repair deficient. Therefore, those are our only patients that will respond to a single-agent checkpoint inhibitor. Now, there are a lot of ongoing research efforts to convert a cold tumor to a hot tumor by either combining it with another TKI or an immunotherapy agent. That is the future.

There were some provocative data presented at the 2019 ASCO Annual Meeting from a group from Japan, which showed an objective response rate of 30% with the combination of regorafenib plus a checkpoint inhibitor. Those are exciting data and a similar phase 1b trial us ongoing at Moffitt Cancer Center; we are trying to duplicate it.

Reference:

Kim RD, Azad NS, Morse MA, et al. Phase II study of ensituximab, a novel chimeric monoclonal antibody, in adults with unresectable, metastatic colorectal cancer [published online ahead of print, June 2, 2020]. Clin Cancer Res. doi:10.1158/1078-0432.CCR-20-0426