ICT01 With or Without Pembrolizumab Shows Early Safety, Activity in Advanced Solid Tumors

ICT01, a humanized anti-BTN3A monoclonal antibody that selectively activates γ9δ2 T cells, has demonstrated early signs of biological activity when given as a single agent or in combination with pembrolizumab (Keytruda) in patients with advanced solid tumors, according to data from the phase 1/2 EVICTION trial (NCT04243499) presented during the 2021 SITC Annual Meeting.¹

Six of 19 patients who received ICT01 monotherapy achieved stable disease; this included 2 patients with breast cancer, 1 with colorectal cancer (CRC), 1 with ovarian cancer, 1 with melanoma, and 1 with prostate cancer. No RECIST-defined responses to treatment were reported in this cohort.

Moreover, 5 of 8 patients who received the combination of ICT01 and pembrolizumab achieved stable disease. Notably, 2 patients who were refractory to checkpoint inhibitors achieved partial responses to the regimen; 1 of these patients had bladder cancer and 1 had non–small cell lung cancer (NSCLC).

“ICT01 seems to be safe as monotherapy, and in combination with pembrolizumab. We have encouraging signs of biological activity; the drug does what it is supposed to,” Martin Wermke, MD, Medical Faculty Carl Gustav Carus, Technical University, NCT/UCC ECTU, Dresden, Germany, said in a presentation on the data. “We also have a preliminary signal that might suggest that the drug combination can have intracranial efficacy, but this warrants further study.”

ICT01 targets 3 isoforms of BTN3A that are expressed on the surface of innate (γδ T cells and natural killer [NK] cells) and adaptive immune cells (T cells and B cells), and are overexpressed on several solid tumors, including bladder cancer, CRC, melanoma, ovarian cancer, pancreatic cancer, and lung cancer, and hematologic malignancies like leukemia and lymphoma.²

BTN3A has proven to be a critical component of activating the antitumor immune response of γ9δ2 T cells. The investigative agent was designed to selectively activate circulating γ9δ2 T cells; this results in the migration of these T cells out of circulation and into target tissue and activates the γ9δ2 T cells inside the tumor.

The first-in-human, open-label, phase 1/2a EVICTION trial is comprised of 2 parts. The first part, which is the dose-escalation phase of the trial, is examining the safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of ICT01 monotherapy in those with solid tumors (Group A) and those with hematologic malignancies (Group B). It is also examining ICT01 in combination with pembrolizumab in those with solid tumors (Group C).

Patients enrolled to group A had bladder, breast, colorectal, gastric, ovarian, prostate, or pancreatic cancers, or melanoma. Group B was comprised of patients with acute myeloid leukemia, acute lymphoblastic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. Group C enrolled patients with bladder cancer, head and neck squamous cell carcinoma (HNSCC), melanoma, and NSCLC.

For the presentation during the meeting, Wermke focused on reporting data from the phase 1 dose-escalation portion of the trial—specifically the ICT01 monotherapy all-comer solid tumor cohort and the combination cohort.

Additional data from the monotherapy cohort showed that the concentration of γ9δ2 T cells within the peripheral blood quickly decreased following treatment with ICT01. “You see that even for very low doses, and the effect gets more pronounced with increasing doses,” Wermke noted. “It tends to be more sustainable if you look at just the 2 highest dose levels of 75 mg and 200 mg.”

This was accompanied by a decrease in CD8-positive T cells, which my be attributed to a redistribution of the T cells into the peripheral tumor tissues, according to Wermke. “Again, they seem to be a bit more pronounced and sustained at higher dose levels,” he added. “We seem to have similar data for NK cells.”

Additionally, the drug was found to increase the infiltration of pan-γδ T cells, CD3-positive T cells, and CD8-positive T cells in the tumor tissue of patients with melanoma and gastric cancer. “There are more data on file to corroborate these data,” Wermke said.

Safety data from the monotherapy cohort showed that the drug was safe, with no dose-limiting toxicities (DLTs) or new safety signals reported. Overall, 52% of the 33 total patients experienced pyrexia, 27% reported chills, 18% had asthenia, 15% had arthralgia, 15% had nausea, 12% experienced vomiting, 9% reported fatigue, 6% had hypotension, 6% had anemia, 6% had diarrhea, 6% reported a rash, and 6% experienced infusion-related reactions.

“However, they were all grade 2 [at most] and did not pose a significant problem for the treating investigators,” Wermke noted. “They are all well explained with the mode of action of the drug.”

Additional findings from the combination cohort showed that in 1 patient with metastatic melanoma that was refractory to ipilimumab (Yervoy) and nivolumab (Opdivo), some liver metastases increased in size at the time of the first CT scan, but later decreased in size. “More importantly, this patient had intracranial asymptomatic brain metastases, and this completely disappeared under treatment with ICT01 and pembrolizumab,” Wermke said.

Regarding safety, 18% of the 11 patients experienced asthenia with the doublet, and 18% reported pyrexia. Again, no DLTs or new safety signals were observed.

Dose-escalation is ongoing in the combination cohort.

The phase 2 portion of the trial will include 5 expansion cohorts in which the agent will be examined: as a monotherapy in 40 patients with ovarian cancer, a monotherapy in 40 patients with HNSCC, a monotherapy in patients with hematologic malignancies, in combination with pembrolizumab in patients with NSCLC, and in combination with pembrolizumab in a population that is yet to be determined.

“We will open the expansion cohorts pretty soon,” Wermke concluded.

References

1. Wermke M, Marabelle A, Jungels C, et al. Clinical activity of ICT01, an anti-BTN3A-targeted, γ9δ2 T cell-activating mAb, alone and in combination with pembrolizumab in patients with advanced solid tumors: EVICTION trial. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington DC. Abstract 503. https://bit.ly/3ngQLgE
2. About ICT01: anti-BTN3A mAb that selectively activates γ9δ2 T cells for IO. ImCheck Therapeutics website. Accessed November 15, 2021. https://bit.ly/3HlXSMV