NT-I7/Pembrolizumab Combo Shows Clinical Efficacy in MSS CRC and Pancreatic Cancer Without Liver Metastasis

The combination of NT-I7 (efineptakin alfa) and pembrolizumab (Keytruda) showed significant clinical activity in checkpoint inhibitor–naïve, relapsed/refractory microsatellite stable (MSS) colorectal cancer (CRC) and pancreatic cancer without liver metastasis, according to data from the phase 1/2 NIT-110 study (NCT04332653) that were presented during the 2022 SITC Annual Meeting.

Patients with no liver metastasis had a higher objective response rate (ORR) with the combination (15.4%, RECIST v1.1 criteria; 30.8%, iRECIST criteria) vs those with them (0.0% and 2.7%, respectively). The disease control rate (DCR) via RECIST v1.1 criteria was 53.9% and was 69.2% via iRECIST criteria in those without liver metastasis, and 21.6% and 24.3%, respectively, in those with liver metastasis. The median overall survival (OS) was not reached in those without liver metastasis.

“These promising findings warrant further exploration of the NT-I7 plus pembrolizumab combination,” said Aung Naing, MD, FACP, a professor in the Department of Investigational Cancer Therapeutics, at The University of Texas MD Anderson Cancer Center, in a presentation during the meeting.

MSS CRC or pancreatic cancer, which are immunologically cold tumors, are challenging to treat with the standard of care being chemotherapy. Those with relapsed/refractory MSS disease is an even greater challenge, as checkpoint inhibitors have limited activity. This subgroup also has a high incidence of liver metastasis, which is prone to even less efficacy with immunotherapy, Naing explained.

However, tumor-infiltrating lymphocytes in liver biopsies have prognostic value. NT-I7 is a long-acting interleukin-7, which is a T-cell homeostatic cytokine that is fundamental for lymphocyte development and survival that can enhance T-cell immunity.

NT-I7 is said to favor CD8-positive T-cell infiltration when used in combination with pembrolizumab in heavily pretreated, immunologically cold MSS CRC and pancreatic cancer.

In the open-label NIT-110 study, investigators evaluated the combination of NT-I7 and pembrolizumab in patients with relapsed/refractory solid tumors. The treatment was given until disease progression or unacceptable toxicity.

The dose-expansion phase was stratified by 2 groups: checkpoint inhibitor-naïve (CPI-naïve) and CPI–pretreated patients. The CPI-naïve group was stratified further to be in relapsed/refractory MSS CRC or pancreatic cancer, with 25 patients in each.

The CPI-pretreated cohort includes patients with relapsed/refractory triple-negative breast cancer, non–small cell lung cancer, and small cell lung cancer.

NT-I7 was given at 1200 µg/kg intramuscular injection every 6 weeks plus intravenous pembrolizumab at 200 mg every 3 weeks in 21-day cycles for up to 35 cycles. Investigators sought to assess the ORR, DCR, and OS by RECIST v1.1 and iRECIST criteria, as well as tumor biopsies pre- and on-treatment.

Data from the CPI-naïve gastrointestinal cancer cohort was presented at the 2022 SITC Annual Meeting. The median age across both the MSS CRC and pancreatic cancer groups was 60.0 years (range, 31-81), and 44.0% of patients were female. Most (68.0%) had an ECOG performance status of 1 and had received 2 or more prior therapies. Seventy-four percent of patients had liver metastasis.

Tumor mutational burden was calculated for a subset of 17 patients, and all patients were TMB-low with the median being 3.21 mutations/megabase (mut/Mb; range, 0.96-6.5). A total 41.2% of patients had TMB >3 mut/MB and 58.8% had TMB between 3 and 10 mut/MB.

Efficacy was stratified by patients with MSS CRC or pancreatic cancer, both with liver metastasis. The ORR in patients with MSS CRC was 5.0% and the DCR was 30.0%; in pancreatic cancer, these rates were 0.0% and 17.7%, respectively.

Additional findings showed that immunohistochemistry staining confirmed that NT-I7 combined with pembrolizumab boosts CD8+ T-cell infiltration in subjects with or without liver metastasis and increases TCF-1+lymphoid aggregates. CD8+ T-cell infiltration is also correlated with higher OS, as seen in all patients (P<.0001) and in those with liver metastasis (P = .0012).

NT-I7–driven T-cell infiltration into the tumor, regardless of the tissue location, could account for the efficacy observed with this combination treatment, even in those with liver metastasis, Naing added.

Reference

1. Naing A, Ferrando-Martinez S, Ware MB, et al. NT-I7, a long-acting IL-7, plus pembrolizumab favors CD8 T-cell infiltration in liver metastases of heavily pre-treated, immunologically cold, MSS-colorectal and pancreatic cancer. Presented at: 2022 SITC Annual Meeting; November 8-12, 2022; Boston, MA. Abstract 657