FDA Fast Tracks IMM-1-104 for PDAC Treatment

• IMM-1-104, a novel drug targeting the MAPK pathway, received a fast track designation from the FDA for the treatment of pancreatic cancer after first-line therapy failure.

• An ongoing phase 1/2a clinical trial (NCT05585320) is assessing IMM-1-104’s safety, efficacy, and other properties in various advanced cancers with RAS mutations.

• Experts hope this well-tolerated oral medication can improve treatment outcomes for patients with pancreatic cancer and potentially benefit individuals with other RAS-driven cancers.

The FDA has granted fast track designation to IMM-1-104 for the treatment of patients with pancreatic ductal adenocarcinoma (PDAC) who have progressed after 1 line of treatment.¹

IMM-1-104–an investigational drug with a novel mechanism–targets the MAPK pathway, aiming to effectively inhibit the growth of these cancers. By specifically targeting cancer cells, it minimizes impact on healthy cells. This unique approach, utilizing deep cyclic inhibition, potentially overcomes resistance mechanisms seen with other therapies, offering hope for broader efficacy against RAS-mutant tumors.

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

“We welcome the FDA’s decision to grant fast track designation for IMM-1-104,” said Ben Zeskind, co-founder and chief executive officer of Immuneering, in a news release.¹ “Our phase 1/2a study is designed to evaluate IMM-1-104 in pancreatic cancer, as well as a number of other tumor types associated with the RAS pathway. We look forward to a data-rich 2024 as we plan to provide multiple readouts from our study this year.”

cancer of pancreas : © Dr_Microbe - stock.adobe.com

Enrollment in the trial is open to patients aged 18 years or older with measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function.² In the monotherapy phase 1 portion of the trial, those with a histologically or cytologically confirmed locally advanced unresectable or metastatic solid tumor harboring a RAS activating mutation will be included. The monotherapy phase 2a part of the trial will consist of patients with locally advanced unresectable or metastatic PDAC, RAS-mutant melanoma, or RAS-mutant NSCLC. In the combination arms, patients must have locally advanced, unresectable or metastatic or PDAC.

For the phase 1 monotherapy arm, all patients must have received at least 1 line of systemic standard-of-care therapy. Of those with PDAC in the phase 2a monotherapy arm, first-line patients must have received no prior systemic anticancer therapy while second-line patients must have received no more than 1 prior systemic anticancer therapy. Further, those in the combination arms must have received no prior systemic anticancer therapy for their advanced or metastatic disease.

Patients were divided into 3 groups:

• Group A received once-daily IMM-1-104 alone in 28-day cycles.
• Group B included patients with PDAC only, who received IMM-1-104 combined with modified gemcitabine/nab-paclitaxel in 28-day cycles.
• Group C also included patients with PDAC only, who received IMM-1-104 combined with modified leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) in 28-day cycles.

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

Findings from the phase 1 portion previously showed there to be no DLTs among patients treated with IMM-1-104. For pharmacokinetics, the plasma half-life of IMM-1-104 was approximately 2 hours, and the plasma Cmax free-fractions were about 1 to 3 uM, and a near 0 drug trough and pERK inhibition of over 90% was seen.³

Based on these findings, the RP2D was determined to be 240 mg or 320 mg once daily.

“The FDA’s decision reinforces the importance of developing effective, novel treatments to improve the health outcomes of patients with PDAC,” said 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, in the press 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.”

REFERENCES

1. Immuneering receives FDA fast track designation for IMM-1-104 in pancreatic cancer. News release. Immuneering Corporation. February 20, 2024. Accessed February 21, 2024. http://tinyurl.com/3jhatjhy

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 al. 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. Abstract A134