IMM-1-104 Plus Chemo Generates Responses in First-Line Pancreatic Cancer

The addition of IMM-1-104, a deep cyclic MEK inhibitor, to modified gemcitabine and nab-paclitaxel (Abraxane) led to responses and disease control as first-line therapy for patients with pancreatic cancer, according to data from phase 2a trial (NCT05585320).

Updated results from the phase 2a portion of the trial showed that IMM-1-104 plus modified gemcitabine and nab-paclitaxel generated an overall response rate (ORR) of 43% and a disease control rate (DCR) of 86% in evaluable patients (n = 7). Among responders, 1 patient had a complete response, and 3 patients achieved a partial response (PR). Three patients had stable disease.

"We are excited to report an updated ORR of 43% and DCR of 86% for IMM-1-104 in combination with modified gemcitabine/nab-paclitaxel in [patients with] first-line pancreatic cancer. For reference, the benchmark reported for gemcitabine/nab-paclitaxel in this setting [was] an ORR of 23% and DCR of 48%,” Ben Zeskind, PhD, chief executive officer of Immuneering, stated in a news release.

Initial data from another cohort of the phase 2a study evaluating IMM-1-104 in combination with modified FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) demonstrated that all evaluable patients (n = 4) experienced tumor shrinkage. One patient had 100% tumor shrinkage and a confirmed PR . One other patient had an unconfirmed PR, and 2 patients had stable disease.

“Today we are also sharing initial data from IMM-1-104 in combination with modified FOLFIRINOX in [patients with] first-line pancreatic cancer,” Zeskind added. “We observed target lesion shrinkage across all evaluable patients, including a 100% reduction, a rare event in this patient population.”

In another phase 2a cohort, IMM-1-104 monotherapy generated an ORR of 5% in patients with second-line pancreatic cancer (n = 21). The DCR was 52%.

The open-label, nonrandomized phase 1/2 trial enrolled patients at least 18 years of age with histologically or cytologically locally advanced unresectable or metastatic solid tumors harboring a RAS activating mutation to receive IMM-1-104 monotherapy during the phase 1 portion; in phase 2a, patients needed to have locally advanced unresectable or metastatic pancreatic ductal adenocarcinoma (PDAC), RAS-mutant melanoma, or RAS-mutant non–small cell lung cancer (NSCLC) to receive the agent alone.2 Patients with locally advanced or metastatic PDAC were allowed to enroll to receive IMM-1-104–based combinations in both phases of the study. All patients needed to have measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function.

The study included 3 treatment groups: IMM-1-104 monotherapy given once per day for those with first- or second-line PDAC, first-, second-, or third-line melanoma, or second- or third-line NSCLC; IMM-1-104 plus modified gemcitabine and nab-paclitaxel for first-line PDAC; and IMM-1-104 plus modified FOLFIRINOX for first-line PDAC.

The primary end point of phase 2 was ORR. Secondary end points included DCR, progression-free survival, duration of response, 3- and 6-month overall survival (OS), and OS.

Safety data for patients with PDAC treated with IMM-1-104 alone in the second-line setting (n = 21) showed that the most common treatment-related adverse effects (TRAEs) that occurred in at least 10% of patients included rash (29%), diarrhea (24%), fatigue (19%), nausea/vomiting (14%), and blurred vision (14%).1

“No grade 3 or grade 4 [TRAEs] were observed [with IMM-1-104 monotherapy], and only a handful of grade 2 [TRAEs] were observed,” Brett Hall, PhD, chief scientific officer of Immuneering, stated in a news release.

Immuneering is planning to expand the phase 2a trial to include 3 additional combination arms. These additional arms will evaluate IMM-1-104 plus a BRAF inhibitor for patients with melanoma; and IMM-1-104 plus checkpoint inhibitors for patients with melanoma or NSCLC. Additional phase 2a data are expected to readout in the second quarter of 2025.

“The maturing safety profile for IMM-1-104 gives us confidence that Immuneering may have developed a better tolerated MEK-inhibitor with exciting potential for vertical, immune-modifying, and orthogonal combinations. We expect to share expanded development plans for IMM-1-104 beyond pancreatic cancer, as we continue to explore options with investigators and third parties,” Hall added.