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The SARC031 study investigated the combination of selumetinib (a MEK inhibitor) and sirolimus (an mTOR inhibitor) in patients with unresectable or metastatic Malignant Peripheral Nerve Sheath Tumors (MPNST).
Despite robust preclinical data in transgenic mouse models showing tumor regression, the clinical trial failed to meet its primary efficacy endpoint, with a clinical benefit rate observed in only 2 out of 21 patients.
Early 18FDG-PET scans revealed partial metabolic responses in 24% of patients during the first cycle, yet these did not correlate with objective responses, suggesting a transient or incomplete suppression of the oncogenic signaling network.
Cell-free DNA (cfDNA) analysis demonstrated high sensitivity in detecting MPNST, highlighting its potential as a non-invasive biomarker for disease monitoring and future therapeutic stratification.
Background: The Challenge of MPNST
Malignant Peripheral Nerve Sheath Tumors (MPNST) represent one of the most formidable challenges in soft tissue oncology. These aggressive sarcomas often arise from pre-existing plexiform neurofibromas in patients with Neurofibromatosis type 1 (NF1), though they also occur sporadically or following radiation therapy. For patients with unresectable or metastatic disease, the prognosis remains dismal, with limited responses to conventional cytotoxic chemotherapy. The 5-year survival rate for metastatic MPNST is historically low, underscoring an urgent unmet medical need for targeted therapeutic strategies.
The molecular landscape of MPNST is characterized by the loss of the NF1 tumor suppressor gene, which encodes neurofibromin, a negative regulator of the RAS signaling pathway. The subsequent hyperactivation of RAS drives downstream signaling through two primary effector pathways: the Raf-MEK-ERK (MAPK) pathway and the PI3K-AKT-mTOR pathway. Given the complex crosstalk between these pathways, it has long been hypothesized that dual inhibition of MEK and mTOR could provide a synergistic therapeutic effect, overcoming the resistance mechanisms that often plague monotherapy.
Biological Rationale: Targeting the RAS Effector Pathway
The SARC031 trial was built upon compelling preclinical evidence. Transgenic mouse models of MPNST, which replicate the genetic deletions seen in human disease (such as NF1 and CDKN2A/TP53 loss), showed significant tumor regression when treated with a combination of MEK and mTOR inhibitors. In these models, blocking a single pathway often led to compensatory activation of the other, whereas dual blockade effectively shut down tumor growth and induced apoptosis.
Selumetinib (AZD6244) is a highly selective inhibitor of MEK1/2, which has previously demonstrated efficacy in reducing the volume of plexiform neurofibromas in pediatric patients. Sirolimus (rapamycin) is a well-established mTOR inhibitor. The SARC031 study aimed to translate the success seen in the laboratory into a clinical setting, testing whether this combination could achieve a meaningful clinical benefit rate (CBR) in a heavily pretreated patient population.
Study Design and Population
SARC031 was a multi-institutional, open-label, Simon 2-stage Phase 2 study. The primary objective was to determine the clinical benefit rate, defined as the sum of complete responses (CR), partial responses (PR), and stable disease (SD) lasting at least 4 months, according to RECIST 1.1 criteria.
The study enrolled 21 patients across five participating sites. The cohort included 7 females and 14 males, with a median age of 41 years (range 16–72). Critically, 14 of the 21 patients had a confirmed diagnosis of NF1. Most patients were heavily pretreated, reflecting the advanced nature of the disease in this population. Participants received a continuous 28-day cycle of selumetinib at 50 mg twice daily and sirolimus at 4 mg once daily.
Beyond clinical efficacy, the study incorporated several correlative endpoints, including patient-reported pain assessments, immune signatures in peripheral blood, and the analysis of cell-free DNA (cfDNA) to evaluate its utility as a biomarker for tumor burden and response.
Key Findings: A Disconnect Between Preclinical Promise and Clinical Reality
The results of SARC031 were sobering. In Stage 1 of the study, only 1 out of 7 patients achieved clinical benefit. In Stage 2, 1 out of 14 patients met the criteria. The median number of treatment cycles completed was only 2 (range 1–6). Consequently, the study did not meet the predefined statistical parameters required to justify further evaluation of this specific combination in MPNST.
Safety and Tolerability Profile
From a safety perspective, the combination of selumetinib and sirolimus was generally manageable. The most frequently reported adverse events (AEs) were grade 1 or 2, including gastrointestinal toxicity (diarrhea, nausea), acneiform rash, hypertriglyceridemia, mucositis, and transient elevations in transaminases. While these AEs are consistent with the known safety profiles of MEK and mTOR inhibitors, they did not lead to a high rate of treatment discontinuation, suggesting that the failure of the trial was due to lack of efficacy rather than prohibitive toxicity.
Correlative Insights: PET Imaging and cfDNA
One of the most intriguing findings of SARC031 involved the use of 18FDG-PET imaging. Early in the first cycle of treatment, 5 patients (24%) exhibited partial metabolic responses. However, these metabolic changes did not correlate with objective tumor shrinkage at the end of Cycle 2. This suggests that while the drugs were hitting their targets and temporarily dampening glucose metabolism within the tumor, this effect was insufficient to induce sustained cytoreduction or prevent disease progression.
On a more optimistic note, the correlative cfDNA studies were highly informative. The analysis was able to detect MPNST-specific genetic alterations in the peripheral blood of patients. This confirms that cfDNA is a viable tool for detecting and potentially monitoring MPNST, providing a foundation for future trials where liquid biopsies could be used to track molecular responses in real-time.
Expert Commentary: Analyzing the Translational Gap
The failure of SARC031 to replicate the dramatic results seen in mouse models highlights the persistent “translational gap” in sarcoma research. Several factors may explain this discrepancy. First, the genomic complexity of human MPNST often exceeds that of transgenic mouse models. Human tumors may harbor additional mutations (such as SUZ12 or EED loss) that alter the epigenetic landscape and provide alternative survival pathways that dual MEK/mTOR inhibition cannot address.
Furthermore, the pharmacokinetics of the drug combination in humans may not have achieved the same level of sustained pathway inhibition as seen in the preclinical setting. The metabolic responses seen on PET scans suggest a transient window of activity that the tumor quickly bypassed. Future strategies may need to consider more potent inhibitors, different dosing schedules, or the addition of a third agent to target the emerging resistance mechanisms.
Conclusion and Future Directions
While the SARC031 trial did not yield a new standard of care for MPNST, it provided essential data that will guide the next generation of clinical trials. The safety of the selumetinib/sirolimus combination was established, and the correlative studies provided a roadmap for using cfDNA and PET imaging in future research. The study emphasizes that for aggressive sarcomas like MPNST, achieving durable clinical benefit will likely require moving beyond dual-pathway inhibition toward more comprehensive, biomarker-driven therapeutic approaches.
Funding and ClinicalTrials.gov
This study was supported by the Sarcoma Alliance for Research through Collaboration (SARC) and the National Cancer Institute (NCI). ClinicalTrials.gov Identifier: NCT03433183.
References
Kim A, Ballman KV, Wolters PL, et al. SARC031: A Phase 2 Trial of Selumetinib and Sirolimus for Patients with Unresectable or Metastatic Malignant Peripheral Nerve Sheath Tumors (MPNST). Clin Cancer Res. 2026 Jan 8. doi: 10.1158/1078-0432.CCR-25-2887.
Cichowski K, et al. Mouse models of NF1-deficient MPNSTs. Cancer Cell. 2011.
Widemann BC, et al. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med. 2020;382(15):1430-1442.
