ATP128 With or Without Ezabenlimab Shows Early Promise in Stage IV Colorectal Cancer

Scott Kopetz, MD, PhD

Preliminary results from the phase 1b KISIMA-01 indicate that combining the single chimeric fusion protein ATP128 with the PD-1 inhibitor, ezabenlimab, is tolerable in patients with heavily pretreated refractory stage IV colorectal cancer (CRC) and may induce immune responses.

The analysis included 15 patients who received with ATP128 alone (n = 9) of ATP128 in combination with ezabenlimab (n = 6). The cohort was assessed for the primary end point of safety and tolerability, which was measured by the incidence of treatment-emergent and serious adverse events (AEs).

According to a presentation given during the European Society of Medical Oncology (ESMO) World Congress on Gastrointestinal Cancers, only 3 grade 1 AEs occurred among the group of patients who received ATP128 alone. In the combination arm, 6 grade 1 AEs were observed, which included nausea in 2 patients, and lightheadedness, rash, injection site reaction, headache, arthralgia, flatulence, and constipation in 1 patient each. No treatment-discontinuations related to AES occurred in either treatment arm. There were also no dose-limiting toxicities or serious AEs in the overall study population.

Currently, the open-label, multicenter, non-randomized KISIMA-01 study is actively recruiting up to 32 patients in Arizona, California, New York, North Carolina, and Texas.

In an interview with Targeted Oncology™, Scott Kopetz, MD, PhD, professor, Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, explained the importance of vaccine treatment strategies in CRC, and the preliminary results from KISIMA-01.

TARGETED ONCOLOGY™: What prior research supports the use of ATP128 with or without enzabelimab, for the treatment of the stage IV CRC?

Kopetz: This study is based on an understanding that CRC is a tumor type that does not have a robust immune response, in most cases. This means that there's not preformed T cells that have antigen recognition against the tumor. So, we really have to think about clinical strategies that result in generation of a new T cell response. Classically, this has included use of vaccine strategies. Preclinical data demonstrate that vaccination with the KISIMA constructs can result in efficacy in murine models of CRC and can be augmented by PD-1 blockade. The combination is more effective than either component alone and can really provide a signal that we're following up now in the clinical trials.

What other rationale was there to carry out this study?

The recognition of a tumor antigen by vaccine really requires a mechanism delivery of the antigen and a robust mechanism to stimulate the immune response to generate that T cell. The KISIMA platform utilizes a self-adjuvant includes toll-like receptor strategies and other approaches that augment that innate response to the vaccine. So, it's a combination that were encouraged is providing good benefit for our patients.

We're selecting antigens that are highly expressed in CRC, and in the KISIMA platform, there's 3 antigens that are highly expressed in CRC providing an off-the-shelf vaccine strategy.

Can you explain the results of this study?

During ESMO GI, the presentation focused on the relative end points for this study. It demonstrated safety of the combination, and it looked at the correlative end points. There are a few key findings. One was that, indeed, there was evidence that the antigens that made up the vaccine were present in the tumors, demonstrating that the selection of these antigens was present, and that at least 2 of the 3 antigens were present in the majority of patients. The other key finding was that there was a peripheral response that was able to be manifested. We were able to see a T cell response to restimulation with the antigens in the ex vivo testing.

More strikingly, what was saw was that these T cells not only are present peripherally, but we're also seeing that these T cells are inducing a response in the tumor itself. We look at the paired samples of a small number of patients, but in the paired samples, these were able to be analyzed in this ongoing study and we saw that the T cell infiltration was increased. We also noticed that the quality of the T cells was such that that suggests that there's an immune response being generated. I think it's an encouraging finding. The study itself remains ongoing., and we're looking forward to the efficacy readouts in the future. But the preliminary evidence really does suggest that there's an immune mediated response to this treatment.

Can you discuss the analyses of this study that are ongoing?

This study is enrolling in 2 different clinical settings. Right now, we're looking at patients in the maintenance settings. This setting includes patients who received some of the first-line therapy and are now suitable a maintenance approach, which happens after approximately 4 to 6 months of initial treatment.

We also are looking at the peri hepatectomy space because we recognize that between 15 to 20% of patients with metastatic CRC are eligible for surgical resection of their metastatic disease. The focus of this is to use that period of time after neoadjuvant chemotherapy but before the patients go to liver resection to administer the vaccine and do it in a manner that will then allow an immune response to be generated in the liver metastases. As that liver metastases been resected, it provides a large amount of material to move much more in-depth characterization of the immune response, which is stronger than we're able to do in many cases with the core biopsies alone.

The peri hepatectomy setting is also a great setting for efficacy. We know that the risk of recurrence after liver resection is very high, and these are patients who in most cases harbor microscopic disease either in the remnant portions of the liver or extrahepatic. So, there is a need for novel therapies to try to eradicate the residual disease of patients. I think strategies like what's being done in this small study are really encouraging, and I think it provides an opportunity to think creatively about how we can improve outcomes for patients who are undergoing surgical resection of their disease.

What else do you think is important to mention about KISIMA-01?

KISIMA-01 is part of a larger effort to identify novel strategies to help with patients that may have minimal residual disease. The hope is that efficacy can be established. We'd love to see strategies like this move into a circulating tumor (ct)DNA setting to define the minimal residual disease. This will be for patients who've undergone surgical resection of their metastatic or locally advanced disease and have finished all the perioperative standard of care chemotherapy but are still have evidence of residual disease according to ctDNA.

I think when we're using ctDNA tests with very high positive predictive value, it enables novel therapies to be deployed. I'm hopeful that efforts like this can be deployed in patients who have very low levels of disease in their body where immune-based strategies may theoretically be more beneficial.

_Reference:

_{Kopetz S, Prenen H, Sharma S, et al. SO-11 KISIMA-01 trial: Safety, tolerability and immunogenicity of ATP128 with or without ezabenlimab (BI 754091) in patients with stage IV colorectal cancer – preliminary results from a phase 1b study. Ann Oncol. 2021;32(3): S206-S207. doi: 10.1016/j.annonc.2021.05.035}