FDA Grants Fast Track Status to IMM-1-104 for Pancreatic Cancer

The FDA has given fast track designation to IMM-1-104 for use as a therapeutic option in patients with pancreatic ductal adenocarcinoma (PDAC) who have progressed on 1 line of treatment.¹

IMM-1-104 provides deep cyclic inhibition of the MAPK pathway, translating to universal anti-RAS activity.

“We welcome the FDA’s decision to grant fast track designation for IMM-1-104,” Ben Zeskind, cofounder and chief executive officer of Immuneering, stated in a news release. “Our phase 1/2a study [NCT05585320] is designed to evaluate IMM-1-104 in pancreatic cancer, as well as a number of other tumor types associated with the RAS pathway.”

The open-label, dose-exploration and -expansion phase 1/2a trial is evaluating the safety, tolerability, pharmacodynamics, pharmacokinetics, and preliminary antitumor activity of IMM-1-104 as monotherapy or in combination with FDA-approved agents in patients with RAS-mutated or RAS/MAPK–activated pretreated advanced or metastatic solid tumors, including PDAC, malignant cutaneous melanoma, and non–small cell lung cancer (NSCLC).²

Patients with first- or second-line PDAC, first- through third-line melanoma, or second- or third-line NSCLC were enrolled in Treatment Group A and received once-daily IMM-1-104 in 28-day cycles as monotherapy. Patients with first-line PDAC could also have been randomly assigned to receive once-daily IMM-1-104 in 28-day cycles in combination with modified gemcitabine/nab-paclitaxel (Abraxane; Treatment Group B), or in combination with modified FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin; Treatment Group C).

The primary end points of the phase 1 portion of the trial were the number of patients with adverse effects, the number of patients with dose-limiting toxicities (DLTs), and the determination of the recommended phase 2 dose (RP2D). The primary end point of the phase 2a portion is overall response rate. Secondary end points in the phase 1/2a portion include the Cmax, Tmax, and area under the plasma concentration time curve of IMM-1-104. Secondary end points in the phase 2a portion only are disease control rate, progression-free survival, duration of response, landmark 3-month survival, landmark 6-month survival, and overall survival.

Eligible patients include those at least 18 years of age with a histologically or cytologically confirmed locally advanced unresectable or metastatic solid tumor harboring a RAS activating mutation (monotherapy phase 1); locally advanced unresectable or metastatic PDAC, RAS-mutant melanoma, or RAS-mutant NSCLC (monotherapy phase 2a); and locally advanced unresectable or metastatic or PDAC (combination arms). In the monotherapy phase 1 arm, patients must have received at least 1 line of systemic SOC therapy. Among the patients with PDAC in the monotherapy phase 2a arm, first-line patients must have received no prior systemic anticancer therapy, and second-line patients must have received no more than 1 prior systemic anticancer therapy. In the combination arms, patients must have received no prior systemic anticancer therapy for their advanced or metastatic disease. All patients must have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function.

In the phase 1 portion, investigators observed no DLTs, the plasma half-life of IMM-1-104 was approximately 2 hours, and the plasma Cmax free-fractions were approximately 1 to 3 uM.³ Furthermore, the agent achieved a near 0 drug trough and pERK inhibition of over 90%. The RP2D was determined to be 240 mg or 320 mg once daily.

Previously, a preclinical study investigated IMM-1-104 in approximately 190 cancer-specific, patient-aligned cell lines using the humanized 3D-Tumor Growth Assay (3D-TGA). Among the sensitive (n = 20), intermediate (n = 20), and resistant (n = 20) 3D-TGA pancreatic cancer models, dose responses were observed in 35.0%, 55.0%, and 10.0%, of models respectively. These findings support the broad potential of IMM-1-104 as a monotherapy and in combinations for patients with cancers harboring MAPK pathway mutations upstream of MEK. Furthermore, the antitumor activity of IMM-1-104 was enhanced when 1 uM of the agent was combined with gemcitabine and paclitaxel in models of KRAS G12V– and KRAS G12D–mutated PDAC.

“The FDA’s decision reinforces the importance of developing effective, novel treatments to improve the health outcomes of patients with PDAC,” Vincent Chung, MD, FACP, principal investigator of the phase 1/2a trial and a professor in the Department of Medical Oncology and Therapeutics Research at City of Hope in Duarte, California, added in the news release.1 “The development of well-tolerated oral medicines would improve the lives of these patients. City of Hope offers many clinical trials testing innovative treatments for people with pancreatic cancer.”

“We look forward to a data-rich 2024 as we plan to provide multiple readouts from our study this year,” Zeskind said in the new release.

References

1. Immuneering receives FDA fast track designation for IMM-1-104 in pancreatic cancer. Immuneering Corporation. February 20, 2024. Accessed February 20, 2024. https://ir.immuneering.com/news-releases/news-release-details/immuneering-receives-fda-fast-track-designation-imm-1-104
2. A phase 1/2a study of IMM-1-104 in participants with previously treated, RAS-mutant, advanced or metastatic solid tumors. ClinicalTrials.gov. Updated February 14, 2024. Accessed February 20, 2024. https://clinicaltrials.gov/study/NCT05585320
3. Nair P, Kolitz S, Funt J, et a. Predicting activity of IMM-1-104 as single agent and in combination for patients with RAS or RAF mutant tumors. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023. Orlando, FL.