IMM-1-104 Earns FDA Fast Track Designation for First-Line PDAC

The FDA has granted fast track designation to IMM-1-104 as a potential therapeutic option in the first-line treatment of patients with pancreatic ductal adenocarcinoma (PDAC).¹

The oral agent designed to promote universal RAS activity via deep cyclic inhibition of the MAPK pathway previously received fast track designation in February 2024 for patients with PDAC whose disease progressed after 1 line of therapy.²

IMM-1-104 is currently being evaluated in a phase 1/2a trial (NCT05585320) in patients with advanced solid tumors harboring RAS mutations.

“[Patients with] first-line pancreatic cancer are eligible and actively enrolling in our phase 2a study in two arms evaluating IMM-1-104 in combination with chemotherapy,” Ben Zeskind, PhD, co-founder and chief executive officer of Immuneering, stated in a news release.¹ “With fast track designation now granted for IMM-1-104 in both first and second-line pancreatic cancer, we have the potential to help a broader population of patients impacted by one of the most difficult to treat cancers. Our phase 2a study also includes an arm evaluating IMM-1-104 as monotherapy in [patients with] first and second-line pancreatic cancer, along with monotherapy arms focused on RAS-mutant melanoma and RAS-mutant non–small cell lung cancer [NSCLC]. We look forward to sharing initial data from multiple arms of the study this year.”

Topline data from the phase 1 portion of the study showed that patients with RAS-mutated advanced solid tumors treated with IMM-1-104 (n = 41) did not experience any grade 4 or higher treatment-related adverse effects (TRAEs); 1 grade 3 TRAE occurred, which was a reversible non-serious rash. No serious TRAEs were reported.³

Efficacy data showed that 53% of patients treated with IMM-1-104 at either 320 mg or 240 mg per day achieved regression in at least 1 target lesion. The best target lesion regression was –35.7% at the 320-mg dose and –11.4% at the 240-mg dose. The best reduction in the sum of longest diameters of a target lesion per RECIST 1.1 criteria was –18.9% at the 320-mg dose and –7.1% at the 240-mg dose. The longest duration of therapy was 162 days in a patient treated with the 240-mg dose, and this patient did not experience any TRAEs.

The multicenter, open-label, nonrandomized dose-escalation and -expansion study is enrolling patients at least 18 years of age with unresectable, locally advanced or metastatic solid tumors harboring RAS mutations.⁴

For the monotherapy cohorts, those enrolled in phase 1 needed to have any RAS-mutated solid tumor, and those in phase 2a are required to have PDAC, melanoma, or NSCLC. In phase 1, at least 1 prior line of systemic therapy for locally advanced or metastatic disease was required. In phase 2a, patients with PDAC and melanoma must have treatment-naive disease, and for those with NSCLC, at least 1 and no more than 2 prior lines of therapy are required.

During both phases, patients with previously untreated, locally advanced or metastatic PDAC harboring RAS mutations are also allowed to enroll in combination cohorts evaluating IMM-1-104 plus chemotherapy.

Key inclusion criteria for all patients include measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function.

In the monotherapy cohorts, IMM-1-104 was evaluated at escalating doses in phase 1. Notably, 240 mg per day and 320 mg per day were the prospective doses for phase 2a, and 320 mg was selected as the recommended phase 2 dose (RP2D).³ In the chemotherapy cohorts, patients are receiving IMM-1-104 in combination with gemcitabine at 1000 mg/m² and nab-paclitaxel (Abraxane) at 125 mg/m²; or in combination with FOLFIRINOX, consisting of folinic acid at 400 mg/m², fluorouracil at 2400 mg/m², irinotecan at 150 mg/m², and oxaliplatin at 85 mg/m².⁴

During phase 1, the primary end points were safety, dose-limiting toxicities, and identifying the RP2D. Overall response rate is serving as the primary end point in phase 2.

Additional data from phase 1 showed that patients treated with IMM-1-104 evaluated for circulating tumor DNA (n = 22) did not acquire any new RAS alterations. Except for 2 patients treated at 160 mg of IMM-1-104—a dose deemed subtherapeutic by Immuneering—no new MAPK pathway alterations were reported.³

Initial data from multiple arms of the phase 2a portion of the study are expected to read out in the second half of 2024.¹

References

1. Immuneering granted FDA fast track designation for IMM-1-104 in first-line pancreatic cancer. News release. Immuneering. July 31, 2024. Accessed August 1, 2024. https://ir.immuneering.com/news-releases/news-release-details/immuneering-granted-fda-fast-track-designation-imm-1-104-first
2. Immuneering receives FDA fast track designation for IMM-1-104 in pancreatic cancer. Immuneering. February 20, 2024. Accessed August 1, 2024. https://ir.immuneering.com/news-releases/news-release-details/immuneering-receives-fda-fast-track-designation-imm-1-104
3. Immuneering announces positive topline results from phase 1 portion of its phase 1/2a clinical trial of IMM-1-104 in RAS-mutant solid tumors. News release. Immuneering. March 14, 2024. Accessed August 1, 2024. https://ir.immuneering.com/news-releases/news-release-details/immuneering-announces-positive-topline-results-phase-1-portion
4. A phase 1/​2a study of IMM-1-104 in participants with previously treated, RAS-mutant, advanced or metastatic solid tumors. ClinicalTrials.gov. Updated July 1, 2024. Accessed August 1, 2024. https://clinicaltrials.gov/study/NCT05585320