Novel Agent Yields Promising Results in MAPK-Associated Solid Tumors

Partial responses and stable disease were observed with PAS-004 in patients with advanced solid tumors harboring RAS, NF1, or RAF mutations.

Positive interim phase 1 data (NCT06299839) were reported when assessing PAS-004 for patients with advanced MAPK pathway-associated solid tumors, according to a press release from Pasithea Therapeutics.1

PAS-004 is a next-generation macrocyclic oral MEK inhibitor indicated for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN). The phase 1 trial is a first-in-human that is evaluating PAS-004 in patients with MAPK pathway-driven advanced solid tumors who have a RAS, NF1, or RAF mutation. Additionally, this treatment is available for patients who progressed on prior BRAF/MEK inhibition.

Of the 21 evaluable patients, an unconfirmed partial response with a 31.9% tumor reduction occurred in cohort 4A when giving a 15 mg capsule to a patient with BRAF V600E-mutated melanoma. Additionally, this patient has remained on trial for more than 11 months. A disease control rate of 71.4% (n = 5/7) was observed in patients with BRAF-mutated tumors who had achieved stable disease or partial responses, and 42.8% (n = 9/21) achieved stable disease or partial responses overall. In cohort 6, a second patient with BRAF V600E melanoma who had been treated with a prior MEK plus BRAF combination had stable disease plus a tumor shrinkage of –1.6%, and they have remained on trial for more than 6 months.

Regarding safety and tolerability, 27 patients were dosed through the dose-limiting toxicity period of day 28 through the cutoff date of November 10, 2025. Investigators found that PAS-004 given once daily was well-tolerated across all dose levels. There were no dose-limiting toxicities or discontinuations.

Treatment-related adverse effects (AEs) that were at least possibly related to PAS-004 were all grade 1/2. These included nausea (18.5%), vomiting (14.8%), rash (7.4%), and diarrhea (7.4%). Additionally, there were no ocular retinal abnormalities or cardiovascular toxicities.

Pharmacokinetics (PK) were observed through cohort 6. This included linear PK and dose-proportionality, a PK curve with Cmax/Cmin ratio of less than 2, and a long half-life of approximately 60 hours. Additionally, in cohort 6, where patients were given 30 mg capsules, the area under the curve (AUC) was approximately 5480 ng·h/mL, Cmax was 249 ng/mL, and Cmin was 215 ng/mL.

“I find it very encouraging that even when used as a monotherapy in [patients with] advanced recurrent cancer, PAS-004 has demonstrated early signals of efficacy, but more importantly exhibited such a favorable safety profile that no dose interruptions or modifications were required. Maintaining [patients with] NF1-PN on treatment for extended periods of time is paramount to achieving maximum tumor control. I believe that PAS-004’s early efficacy signals combined with the low rate of [AEs] may translate into better tolerability and longer time-on-treatment for plexiform neurofibromas associated with NF1, compared with current FDA-approved therapies’ discontinuation rates estimated as high as 40% to 50% before year 2,” Rebecca Brown, MD, director of the Neurofibromatosis and Schwannomatosis Program at University of Alabama Birmingham, said in the press release.1

The primary end points of the trial included evaluation of dose-limiting toxicities, AEs, AEs leading to discontinuation, and evaluation of hematology laboratory parameters.2 Secondary end points included apparent terminal elimination half-life in plasma, peak plasma concentration, plasma pre-dose through concentration, and time of maximum plasma concentration.

PAS-004 capsules were given at either 1 mg, 4 mg, or 10 mg strength once daily. PAS-004 tablets were given at 4 mg strength tablets once daily. In the capsule arm, patients received dose escalation at 2 mg, 4 mg, 8 mg, 15 mg, 22 mg, 30 mg, 37 mg, and 45 mg.

Patients were eligible for treatment if they were able to swallow oral medication, had histologically or cytologically diagnosed MAPK pathway-driven advanced solid tumors, had an estimated life expectancy of at least 12 weeks, had adequate organ function, and maintained abstinence or used the highest form of birth control.

Patients were excluded from the trial if they had participated in another therapeutic trial within 3 weeks of enrollment; received chemotherapy, radiotherapy, major surgery, targeted therapy, or immunotherapy within 21 days of enrollment; had known or active nervous system metastases; or had unresolved toxicity from prior antitumor therapy.

References

1. Pasithea Therapeutics announces positive phase 1 data including partial response, demonstrating monotherapy clinical activity and favorable safety profile for PAS-004 in advanced cancer study. News release. Pasithea Therapeutics. November 20, 2025. Accessed November 21, 2025. https://tinyurl.com/2uxbyc6m
2. PAS-004 in patients with advanced solid tumors. ClinicalTrials.gov. Updated August 21, 2025. Accessed November 21, 2025. https://tinyurl.com/mrx6p84h