FDA Grants Fast Track Designation to IMM-1-104 in NRAS+ Advanced Melanoma

The FDA has granted fast track designation to IMM-1-104 for the treatment of patients with unresectable or metastatic NRAS-mutant melanoma who experience disease progression or are intolerant to PD-1/PD-L1–based immune checkpoint inhibitors.1

IMM-1-104 is a MEK inhibitor designed to induce deep cyclic inhibition of the MAPK pathway to produce universal RAS activity and selectively affect cancer cells over healthy cells. The agent is currently being evaluated in a phase 1/2a trial (NCT05585320) in patients with RAS-mutated advanced solid tumors, including melanoma.

Preliminary data from the phase 1 portion of the study presented at the 2024 ESMO Congress showed that the agent was well tolerated at doses of 240 mg and 320 mg once per day in patients with advanced solid tumors.2 The most common any-grade treatment-related adverse effects reported in at least 10% of patients treated between the 2 dose levels (n = 54) were rash (26%), diarrhea (22%), nausea (17%), fatigue (17%), vomiting (15%), subretinal fluid (13%), and retinopathy (11%).

Although no responses per RECIST 1.1 criteria were reported, signs of clinical activity were reported in a heterogeneous population that included patients with pancreatic ductal adenocarcinoma (PDAC; n = 34), colorectal cancer (n = 8), lung cancer (n = 5), melanoma (n = 2), appendiceal cancer (n = 2), cholangiocarcinoma (n = 1), and other (n = 2). Investigators noted deepening regressions in RECIST target lesions, and reductions in CA 19-9 levels and other relevant circulating tumor DNA biomarkers.

“Immune checkpoint inhibitors play a vital role in the treatment of [patients with] melanoma, yet patients who progress on or are intolerant to them have limited options,” Ben Zeskind, PhD, co-founder and chief executive officer of Immuneering, stated in a news release.1 “Targeted therapies including MEK and RAF inhibitors have shown promise in melanoma but historically are severely limited by toxicity. As we presented at the [2024 ESMO Congress], IMM-1-104 is a new kind of MEK inhibitor that was observed to be uniquely well tolerated in our phase 1 trial, relative to MEK inhibitors currently used to treat melanoma. We believe this creates opportunities for IMM-1-104 to benefit [patients with] melanoma both alone and in combination with RAF inhibitors and/or immune checkpoint inhibitors.”

In the phase 2a portion of the study, investigators are enrolling patients at least 18 years of age with locally advanced unresectable or metastatic PDAC, RAS-mutant melanoma, or RAS-mutant non–small cell lung cancer.3 Patients with melanoma are allowed to have treatment-naive disease or disease that has progressed on 1 to 2 prior lines of therapy. Other key inclusion criteria consist of measurable disease defined as at least 1 target lesion per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function.

In both phases of the study, investigators are also evaluating IMM-1-104 in combination with chemotherapy for the first-line treatment of patients with PDAC.

Key exclusion criteria comprise symptomatic, untreated, or actively progressing known central nervous system metastases; a history or concurrent evidence of retinal vein occlusion (RVO) or risk factors for RVO; a history of serous retinopathy, retinal edema, or retinal pigment epithelial detachment; and impaired cardiovascular function or clinically significant cardiac disease.

In the single-arm cohorts, IMM-1-104 is being administered once per day in 28-day cycles until treatment discontinuation criteria are met.

The primary end point of phase 2a is overall response rate. Key secondary end points in this portion of the trial include pharmacokinetics, disease control rate, progression-free survival, duration of response, and overall survival.

“We are pleased with the FDA’s decision to grant Fast Track designation for IMM-1-104 in advanced melanoma, an area of significant unmet need,” Zeskind added in the news release.1 “[Patients with] melanoma are actively enrolling in one of the five arms of our phase 2a clinical trial, and this designation follows our announcements earlier this year that IMM-1-104 has also been granted fast track designations for the treatment of both first and second-line pancreatic cancer.”

References

1. Immuneering granted FDA fast track designation for IMM-1-104 in advanced melanoma. News release. Immuneering. December 12, 2024. Accessed December 12, 2024. https://ir.immuneering.com/news-releases/news-release-details/immuneering-granted-fda-fast-track-designation-imm-1-104
2. Chung V, Spira AI, Pavlick AC, et al. Preliminary phase I safety and activity of IMM-1-104, an orally dosed universal RAS inhibitor that drives deep cyclic inhibition of the MAPK pathway at MEK, in patients with advanced unresectable or metastatic solid tumors. Ann Oncol. 2024;35(suppl 2):S930-S931. doi:10.1016/j.annonc.2024.08.1587
3. A phase 1/​2a study of IMM-1-104 in participants with previously treated, RAS-mutant, advanced or metastatic solid tumors. ClinicalTrials.gov. Updated August 21, 2024. Accessed December 12, 2024. https://clinicaltrials.gov/study/NCT05585320