Genomically guided Mekinist monotherapy reveals potential for precision treatment in advanced cancers

A new analysis from the IMPRESS-Norway precision medicine trial suggests that Mekinist (trametinib), a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor established in BRAF-mutant melanoma, may offer clinically meaningful disease control across a wider range of MAPK-activated tumors than previously recognized. In a heavily pretreated population with no remaining treatment options, Mekinist monotherapy achieved a 39% disease control rate at 16 weeks, including partial responses in low-grade serious ovarian cancer and select central nervous system tumors.

With almost 2 million new cases annually in the U.S. alone and recurrence or progression rates exceeding 50% in many solid tumors, advanced cancers pose a significant challenge. These cancers, which have progressed after patients have been treated with all standard therapies, continue to drive some of the highest costs and poorest outcomes in oncology. Costs often climb to $200,000 per year per patient when the last choices for treatment are being used.

Precision medicine uses genomic profiling to match treatments to changes in cancer cells that can be acted on, such as mutations, fusions or inactivations. This approach could lead to more targeted treatments, cutting down on treatments that are ineffective and improving survival for patients who are out of options or nearly so. In the long run, genomic profiling to guide treatment could also reduce costs by steering treatment with little if any chance of success. The IMPRESS-Norway experiment highlights this change, investigating off-label utilization of an approved pharmaceutical to fulfill unmet requirements across several cancer types.

A recent subgroup analysis led by Kathinka Schmidt Slørdahla, M.D., from the Department of Oncology, Oslo University Hospital in Oslo, Norway, zeroed in on Mekinist monotherapy in patients with advanced malignancies harboring MAPK-activating alterations. Conducted nationwide in Norway, the prospective study screened patients using the TruSight Oncology 500 panel or circulating tumor DNA assays. The results were published last month in Acta Oncologica. 

Eligible adults (median age 62, 63% female) had been treated with the standard lines of therapy, had ECOG performance status 0-2 and life expectancy of over three months. Predefined biomarkers were identified to allocate patients to treatment. The biomarkers included BRAF fusions, GNAQ/GNA11/GNAS mutations, NF1 inactivation (CNS tumors), NRAS/HRAS/KRAS mutations and others like MAP2K1/2.

Patients (n=65) were treated with two milligrams of Mekinist daily, with dose reductions made for toxicity, until progression, unacceptable adverse events, or withdrawal. Evaluations used RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 for solid tumors, RANO (Response Assessment in Neuro-Oncology) for brain tumors, and ELN (European LeukemiaNet) for hematological cancers, with scans at weeks 8, 16, 24 and quarterly thereafter.

Primary endpoints focused on Achieving 39% DCR in a heavily pretreated cohort, where standard options are exhausted, suggests potential to delay progression (DCR) at 16 weeks, defined as complete/partial response or stable disease, and safety. Among 52 response-evaluable patients, DCR reached 39%, with 8% partial response (no complete response) and 31% achieved stable disease. Responses occurred in low-grade serous ovarian cancer, CNS tumors (e.g., astrocytoma, pilocytic astrocytoma), uveal/mucosal melanoma, and cholangiocarcinoma, linked to alterations like KRAS G12D/V, NRAS Q61, GNAQ Q209, NF1 inactivation, and BRAF fusions. No responses were seen with NRAS amplifications or HRAS mutations. Median progression-free survival was 4 months (95% CI: 3-6), with 1-year progression-free survival at 14%; median overall survival was 9 months.

Safety data from all 65 patients showed that just under half (48%) experiencing treatment-related adverse events, including rash, elevated liver enzymes, and mucositis. Serious treatment-related adverse events affected 66% of reports, with six suspected unexpected serious adverse reactions (e.g., thromboembolism, myocardial infarction). Two treatment-related deaths occurred (thromboembolism, intra-abdominal hemorrhage), and 22% discontinued due to toxicity.

These findings may underscore Mekinist’s value in biomarker-driven care for refractory patients. Achieving 39% DCR in a heavily pretreated cohort, where standard options are exhausted, suggests potential to delay progression, reducing hospitalizations and end-of-life costs. In value-based models, genomic screening could stratify high-risk groups for targeted therapy, optimizing resource allocation.

Slørdahla noted the study’s limitations included small subgroup sizes per alteration/tumor type and high toxicity in frail patients, necessitating careful selection. She also added that the largest effect was observed in tumors where progression may be slow thus influencing the primary end point. The real-world design, however, strengthens generalizability. Future research should validate in larger cohorts, refine predictive biomarkers, and explore combinations to mitigate toxicity.