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Exposure-Response Relationships of Mirvetuximab Soravtansine in Patients with Folate Receptor-α Positive Ovarian Cancer: Justification of Therapeutic Dose Regimen
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  • Yaping Tu,
  • Maxime Lagraauw,
  • Michael Method,
  • Yuemei Wang,
  • Eva Hanze,
  • Lingling Li,
  • Timothy Parrott,
  • Callum Sloss,
  • Eric Westin
Yaping Tu
ImmunoGen Inc

Corresponding Author:yaping.tu@gmail.com

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Maxime Lagraauw
qPharmetra
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Michael Method
ImmunoGen Inc
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Yuemei Wang
ImmunoGen Inc
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Eva Hanze
qPharmetra
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Lingling Li
ImmunoGen Inc
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Timothy Parrott
ImmunoGen Inc
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Callum Sloss
ImmunoGen Inc
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Eric Westin
ImmunoGen Inc
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Abstract

Aims: This study aimed to investigate exposure-response (ER) relationships in efficacy and safety for mirvetuximab soravtansine (MIRV) which is a first-in-class antibody-drug conjugate approved for the treatment of folate receptor-α positive platinum-resistant ovarian cancer. Methods: MIRV was characterized in 4 clinical studies. Exposure metrics for MIRV, its payload and a metabolite were derived from a population pharmacokinetic model. Efficacy was analyzed in MIRV-treated patients (N=215) in a recent confirmatory, randomized, chemotherapy-controlled MIRASOL trial, and safety was evaluated in patients pooled across all 4 clinical studies (N=757). Results: In the MIRASOL trial, MIRV demonstrated significant benefit over chemotherapy in progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). The most common adverse events (AEs) included ocular disorders, peripheral neuropathy, and pneumonitis. For PFS, ORR and OS, the trough concentration of MIRV was the predictor consistently found in ER models for efficacy. In contrast, for ocular AEs (as well as the time to onset of ocular AEs) and peripheral neuropathy, the area under the concentration-time curve (AUC) was identified as the exposure metric in ER models for safety. No exposure parameters were found to correlate with pneumonitis. Covariates in all models did not show clinically meaningful impact on efficacy or safety. Logistic regression models for ORR and ocular AEs based on AUC were used to justify the clinical dose regimen approved for MIRV. Conclusions: The trough concentration of MIRV correlated with efficacy whereas the AUC was associated with major AEs. The ER relationships supported the selected therapeutic dose regimen.
Submitted to British Journal of Clinical Pharmacology
Submission Checks Completed
Assigned to Editor
Reviewer(s) Assigned
29 Jun 2024Review(s) Completed, Editorial Evaluation Pending
01 Jul 2024Reviewer(s) Assigned
12 Aug 2024Editorial Decision: Revise Major
20 Aug 20241st Revision Received
23 Aug 2024Submission Checks Completed
23 Aug 2024Assigned to Editor
29 Aug 2024Review(s) Completed, Editorial Evaluation Pending
30 Aug 2024Editorial Decision: Revise Minor
30 Aug 20242nd Revision Received
31 Aug 2024Submission Checks Completed
31 Aug 2024Assigned to Editor
31 Aug 2024Review(s) Completed, Editorial Evaluation Pending
01 Sep 2024Editorial Decision: Accept