Phase 1 Trial of IMM-1-104 Generates Positive Topline Results in RAS-Mutant Solid Tumors

Ben Zeskind

Immuneering has announced positive topline results from the ongoing phase 1 portion of a phase 1/2a trial (NCT05585320) of IMM-1-104 in patients with RAS-mutant solid tumors.¹

At a data cutoff of February 20, 2024, IMM-1-104 was well tolerated among 41 patients who received the agent. Among the treatment-related adverse effects (TRAEs) that occurred in more than 10% of patients, no grade 4 TRAEs were reported, 1 grade 3 TRAE (a reversible, non-serious rash) was observed, and a modest number of grade 2 TRAEs were observed across categories. None of these TRAEs were deemed serious.

“In designing IMM-1-104, we sought to challenge the conventional wisdom that the MAPK pathway must be targeted narrowly and inhibited chronically, and that patients must often accept grueling toxicity,” Ben Zeskind, chief executive officer of Immuneering, stated in a press release. “Insights from our platform led us to a fundamentally new approach, Deep Cyclic Inhibition, aiming to provide better tolerability and broader, universal-RAS activity. Today’s results are an important step toward that goal…We believe these results demonstrate clear proof of concept, as IMM-1-104 shrank MAPK-dependent lesions in highly aggressive, late-line cancers, prevented acquired alterations in RAS, and has been well tolerated, showing the potential for a differentiated safety profile…[IMM-1-104 has also] shown promising initial signs of clinical activity, which we believe bodes well for the phase 2a portion of our study.”

“Preliminary topline data from the phase 1 portion of this trial with IMM-1-104 provided encouraging initial tumor activity and a well-tolerated safety profile in a refractory patient population,” added Vincent Chung, MD, FACP, a principal investigator on the phase 1/2a trial and a professor in the Department of Medical Oncology & Therapeutics Research at City of Hope in Duarte, California, added in the press release. “City of Hope looks forward to furthering clinical trials testing innovative, potentially life-saving cancer treatments and will continue to evaluate IMM-1-104 in the phase 2a portion of the study.”

The open-label, dose-exploration and -expansion phase 1/2a trial is investigating IMM-1-104 as a monotherapy in patients with first- or second-line pancreatic cancer; first-, second-, or third-line melanoma; and second- or third-line non–small cell lung cancer (NSCLC).² It is also evaluating the agent in combination with modified gemcitabine and nab-paclitaxel (Abraxane) or in combination with modified FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan, and oxaliplatin) in patients with first-line pancreatic cancer.

Eligible patients include those who are at least 18 years of age with cytologically or histologically confirmed locally advanced unresectable or metastatic solid tumors harboring a RAS activating mutation (monotherapy phase 1 cohort) or locally advanced unresectable or metastatic pancreatic ductal adenocarcinoma (PDAC), RAS-mutant melanoma, or RAS-mutant NSCLC (monotherapy phase 2a cohort). Patients in the monotherapy phase 1 cohort must be naive to prior treatment or have received at least 1 line of standard systemic treatment for advanced or metastatic disease. In the monotherapy phase 2a cohort, patients with first-line PDAC must have received no prior systemic anticancer therapy, those with second-line PDAC must have received a maximum of 1 prior systemic anticancer therapy. Patients with first-line melanoma must have received no prior systemic anticancer therapy, those with second- or third-line melanoma must have received and progressed on 1 or 2 prior systemic anticancer therapies, and patients with NSCLC must have received 1 to 2 prior lines of systemic therapy. Patients must also have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function.

The phase 1 portion of the trial is being conducted at 5 clinical sites across the US.¹ The coprimary end points of the phase 1 portion are AEs, dose-limiting toxicities, and determination of the recommended phase 2 dose (RP2D).² The primary end point of the phase 2a portion is overall response rate. Key secondary end points for phase 1/2a include the maximum observed plasma concentration, time to maximum plasma concentration, and area under the plasma concentration time curve of IMM-1-104. Other secondary end points in the phase 2a portion include disease control rate, progression-free survival, duration of response, 3-month survival rate, 6-month survival rate, and overall survival.

According to Zeskind, the phase 1 patient population comprised 8 cancer types harboring 12 different RAS mutations at the time of data cutoff.¹ Approximately 60% of patients had pancreatic cancer, approximately 80% of patients had available treatment history and had never responded to prior treatment for metastatic disease, and approximately two-thirds of patients received IMM-1-104 as a third-line or later treatment, with this population receiving a maximum of 6 prior lines of therapy.

Plasma data from 19 patients showed that IMM-1-104 at 320 mg daily inhibited pERK at levels of 90% or greater for 2.7 hours, before returning to near-zero levels before 24 hours. At the 240-mg daily dose, IMM-1-104 generated pERK inhibition at levels of 90% of greater for 1.9 hours, before returning to near-zero levels before 24 hours. Based on these findings, the 320 mg daily dose has been selected as the RP2D for the phase 2 portion of the trial.

Furthermore, 100% of evaluable patients with circulating tumor DNA profiling (n = 22) who received IMM-1-104 did not develop new acquired RAS alterations as of the data cutoff. Additionally, most patients did not develop new acquired alterations in MAPK pathway genes, excluding 2 patients who received the agent at 160 mg, which Immuneering has deemed a subtherapeutic dose. This finding indicates that there was no MAPK pathway mutation that a tumor could use to evade IMM-1-104.

In total, 53% of patients in the phase 1 portion of the study who received IMM-1-104 at either the 320 mg or 240 mg daily dose experienced regression of at least 1 target lesion. The best individual lesion regressions were –35.7% at 320 mg and –11.4% at 240 mg in the second-line setting. The best RECIST sum of longest diameters was –18.9% at 320 mg and –7.1% at 240 mg in the second-line setting. The longest duration of treatment was 162 days at the 240-mg dose, with no TRAEs observed

“IMM-1-104 demonstrated its potential to induce Deep Cyclic Inhibition, and in doing so has been well tolerated—consistent with what we observed preclinically,” Brett Hall, PhD, chief scientific officer of Immuneering, said in the press release. “We are also pleased with highly encouraging signs of activity observed among advanced RAS-mutant solid tumors.”

Further data from the ongoing phase 1 portion of the study are expected to be reported in 2024 at a future medical meeting. Additionally, the phase 2a portion of the trial is underway and expected to enroll patients in earlier lines of therapy from a maximum of 20 clinical sites. The first patient in the phase 2a portion has already been dosed.

“The phase 2a portion is studying IMM-1-104 as a single agent and in combination and could offer the clearest sign yet that IMM-1-104 has the potential to be an effective and universal treatment for RAS-mutant solid tumors,” Zeskind stated.

References

1. 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 Corporation. March 14, 2024. Accessed March 14, 2024. https://ir.immuneering.com/news-releases/news-release-details/immuneering-announces-positive-topline-results-phase-1-portion
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 March 8, 2024. Accessed March 14, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05585320