Final Analysis from AMPECT, an Open-Label Phase 2 Registration Trial of nab-SIROLIMUS for Patients With Advanced Malignant Perivascular Epithelioid Cell Tumors (PEComa)

Background

• mTOR pathway activation is common in PEComa.
• PEComa are associated with alterations of TSC1 or TSC2, which are negative regulators of the mTOR signaling pathway.¹
• Nab-sirolimus is a­­n mTOR inhibitor (mTORi) with significantly higher anti-tumor activity, significantly higher intratumoral drug accumulation, and significantly higher mTOR target (pS6 and p4EBP1) suppression in preclinical models.

Methods

• Sample Size: Overall response rate (ORR) of ~30% in 30 evaluable patients to exclude the lower bound of the 95% CI of 14.7%
• Efficacy Evaluable Patients: Must receive 1 dose or more of nab-sirolimus; must have centrally confirmed PEComa
• Primary End point: ORR by independent radiology review (RECIST v1.1)
  • CT/MRI every 6 weeks for the first year, every 12 weeks thereafter
• Secondary End points:
  • Duration of response (DOR), progression-free survival (PFS) at 6 months, median PFS, median overall survival
  • Safety
• Key Exploratory End points: Investigator response assessment
  • Biomarker were mutational analysis (NGS, IHC, FISH)
• Baseline Demographics, Characteristics, and Disposition:
  • Median follow-up was 22 months (range 1, 58)
  • Thirty of thirty-four patients discontinued treatment; the main reason was PD (59%). Other reasons included adverse event (AE), surgery, withdrew consent, and death
  • Four patients have ongoing treatment (all responders)
  • Six patients are in post-treatment, on-study follow-up for survival

Results

• Two patients converted from a partial response (PR) to a complete response (CR) after 11 months and 34 months of treatment, respectively
• Median DOR has not been reached, 50% of patients had a DOR of more than 36.1 months (range 5.6, 55.5+ months)
• No grade 4 or 5 treatment-related AEs
• No unexpected AEs or new safety signals
• Pneumonitis in 7 out of 34 (21%) patients was grade (G)1/G2 only
• Discontinuation due to AEs: 2 out of 34 (6%) patients (G2 anemia and G1 cystitis)
• Treatment-related Serious Adverse Events were:
  • Dehydration in 6% of patients and 3% each of acute kidney injury, acute coronary syndrome, abdominal pain, diarrhea, edema, enteritis, and pancytopenia
    • All recovered / resolved

Conclusions

• This registrational trial met its primary end point; the independently assessed confirmed ORR was 39% (95% CI 22%-58%), 2 CRs and 10 PRs, with durable responses and acceptable safety profile
• Median DOR has not been reached; 50% of patients had a response exceeding 36 or more months (range: 5.6, 55.5+)
• Disease control (CR/PR/stable disease [SD] ≥ 12 weeks) was achieved in 71% of patients
• No new safety signals were observed despite relatively high doses of nab-sirolimus compared with other mTORis
• Mutational Analysis Versus Response:
  • TSC2 mutations: 89% (8/9) of patients had confirmed ORR (1/9 had an unconfirmed response)
  • Responses also occurred in some patients with TSC1 or no TSC1/TSC2 or unknown mutational status.
  • This first prospective study in advanced malignant PEComa suggests that nab-sirolimus is active in a rare and aggressive sarcoma for which there are no approved therapies.
  • A tumor-agnostic study is planned for patients with pathogenic inactivating TSC1 or TSC2 alterations.

1. Wagner A, Ravi V, Riedel RF, et al. Final Analysis from AMPECT, an open-label phase 2 registration trial of nab-sirolimus for patients with advanced malignant perivascular epithelioid cell tumors (PEComa). Abstract presented at: 2021 Connective Tissue Oncology Society, November, 10-13. Abstract #108747