FDA Grants Fast Track Designation to IMM-1-104 for Advanced Melanoma

Updated Thursday, December 12 at 4:04 PM.

The FDA granted a fast track designation to IMM-1-104 (Immuneering Corp.) to treat patients with unresectable or metastatic NRAS-mutant melanoma whose disease progressed or is intolerant to PD-1-/PD-L1-based immune checkpoint inhibitors.¹ Currently, the treatment is undergoing evaluation in a phase 2a clinical trial (NCT05585320)², which enrolled patients with advanced solid tumors, including melanoma.¹

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IMM-1-104 is a novel oral dual MEK1/2 inhibitor that aims to achieve a universal-RAS activity that selectively impacts cancer cells to a greater extent than healthy cells. It is administered once daily and achieves deep cyclic inhibition of the MAPK pathway.^1,2

“Immune checkpoint inhibitors play a vital role in the treatment of melanoma, yet patients who progress on or are intolerant to them have limited options. Targeted therapies including MEK and RAF inhibitors have shown promise in melanoma but historically are severely limited by toxicity,” said Ben Zeskind, PhD, co-founder and CEO of Immuneering, in a news release.¹

IMM-1-104 is currently undergoing evaluation in the phase 2 portion of an open-label, dose-exploration, and expansion phase 1/2a clinical trial (NCT05585320) which aims to determine the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity when administered as a monotherapy or in combination with approved agents in patients with RAS-mutated or RAS/MAPK activated advanced or metastatic solid tumors. The phase 2a portion is evaluating patients with locally advanced or metastatic solid tumor malignancies, including pancreatic ductal adenocarcinoma (PDAC), RAS-mutant melanoma, and RAS-mutant non-small cell lung cancer (NSCLC). In some study arms, IMM-1-104 will be studied alone, in combination with modified gemcitabine and nab-paclitaxel (Abraxane; Bristol Myers Squibb), or in combination with folfirinox.²

The trial’s primary end points include adverse events (AEs), dose-limiting toxicities, and recommended phase 2 dose for the phase 1 portion, and overall response rate for the phase 2a portion. Additionally, secondary end points include maximum observed plasma concentration (Cmax), time to reach Cmax, and area under plasma concentration time curve of IMM-1-104 for phase 1/2a, as well as disease control rate, progression-free survival, duration of response, and overall survival for phase 2a.²

Results of the phase 1 portion were published in Annals of Oncology found that IMM-1-104 disrupted the MAPK-pathway of tumors and was well tolerated, while also demonstrating lesion and molecular level responses as a monotherapy. At the time of May 1, 2024, the phase 1 study had enrolled 45 patients, including 30 with PDAC, 5 with colorectal cancer, 5 with NSCLC, 2 with melanoma, and 1 with cholangiocarcinoma, as well as 2 with other cancer types. IMM-1-104 was evaluated in 2 candidate optimal doses, 240 mg and 320 mg, both of which were administered orally once per day.³

According to the findings, early signs of clinical activity in this heavily pretreated, advanced metastatic patient population were considered promising. Paired CT scans (32) and circulating tumor DNA ctDNA; 27) revealed that approximately 66% (n = 21) had RECIST SLD below 20% and 25% (n = 8) had SLD 0% or below. Additionally, about 41% (n = 13) had 1 or more target lesion regressions (-4.8% to -50.0%), and reductions in mean ctDNA were observed in 33% (n = 9) of patients (-24% to -81%). Further, no new variants in RAS ctDNA were observed.³

Treatment-related AEs (TRAEs) were observed in at least 10% of patients, but these were primarily grades 1 and 2 in severity and short in duration. No dose-limiting toxicities or serious TRAEs were noted by the study authors.³

“As presented at the European Society for Medical Oncology 2024 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 melanoma patients both alone and in combination with RAF inhibitors and/or immune checkpoint inhibitors,” said Zeskind in the news release. “…we are pleased with the FDA’s decision to grant [a] fast track designation for IMM-1-104 in advanced melanoma, an area of significant unmet need.”¹

REFERENCES

1. Immuneering. Immuneering granted FDA fast track designation for IMM-1-104 in advanced melanoma. News release. 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. A hase 1/​2a study of IMM-1-104 in participants with previously treated, RAS-mutant, advanced or metastatic solid tumors. ClinicalTrials.gov identifier: NCT05585320. Updated August 21, 2024. Accessed December 12, 2024. https://clinicaltrials.gov/study/NCT05585320

3. Chung V, Spira AI, Pavlick AC, et al. 1524P 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(Supplement 2):S930 - S931 doi:10.1016/j.annonc.2024.08.1587