The combination of NT-I7 and pembrolizumab showed significant clinical activity in checkpoint inhibitor–naïve, relapsed/refractory microsatellite stable colorectal cancer and pancreatic cancer without liver metastasis.
Aung Naing, MD, FACP
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.