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Population Pharmacokinetics and Exposure-Response Analyses for Telisotuzumab Vedotin in Patients With c-Met Protein
Heiko Babel1, Priya Brunsdon2, Benjamin Engelhardt1
1Clinical Pharmacology, AbbVie Deutschland GmbH Co. KG, North Chicago, Illinois, USA.
Abstract:
Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate that delivers a cytotoxic microtubule inhibitor monomethyl auristatin E (MMAE) payload to c-Met-expressing tumor cells. It received accelerated approval from the US FDA for the treatment of adults with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) with high c-Met protein overexpression (≥ 50% of tumor cells with strong [3+] staining) at a dose of 1.9 mg/kg every 2 weeks (Q2W; maximum 190 mg for patients ≥ 100 kg) as an intravenous infusion. Population pharmacokinetic (PK) modeling used pooled data from a phase 1 (N = 35) and phase 2 study (N = 269) to describe the Teliso-V conjugate and unconjugated MMAE PK and evaluate the impact of intrinsic and extrinsic factors on exposures in patients with solid tumors. Body weight, race, albumin, and anti-drug antibody status were identified as significant covariates on Teliso-V conjugate clearance, but did not result in clinically meaningful changes in exposure. The exposure-response evaluations for efficacy (based on the pivotal phase 2 study) showed significant correlations between conjugate exposure and overall response rates. Higher conjugate exposures were also correlated with improved progression-free survival and overall survival, demonstrating meaningful clinical benefit with the 1.9 mg/kg Q2W dosing regimen. Exposure-safety evaluations showed significant relationships between conjugate exposures and grade ≥ 2 and grade ≥ 3 peripheral neuropathy, and grade ≥ 2 corneal epitheliopathy. Unconjugated MMAE payload exposures were correlated with a greater probability of grade ≥ 3 treatment-emergent adverse events. The 1.9 mg/kg Q2W dose maximized efficacy while balancing adverse events in patients with c-Met overexpressing NSCLC.
Insights
Telisotuzumab vedotin (Teliso-V) is an antibody-drug conjugate for c-Met overexpressing non-small cell lung cancer. The 1.9 mg/kg Q2W dose maximizes efficacy while balancing safety, demonstrating clinical benefit.
Area of Science:
- Oncology
- Pharmacology
- Translational Medicine
Background:
- Telisotuzumab vedotin (Teliso-V) is an antibody-drug conjugate targeting c-Met.
- It delivers monomethyl auristatin E (MMAE) to c-Met-expressing tumor cells.
- Teliso-V received accelerated FDA approval for advanced non-squamous non-small cell lung cancer (NSCLC) with high c-Met overexpression.
Purpose of the Study:
- To describe the population pharmacokinetics (PK) of Teliso-V and unconjugated MMAE.
- To evaluate the impact of intrinsic and extrinsic factors on Teliso-V exposure.
- To assess the exposure-response relationships for efficacy and safety in patients with solid tumors.
Main Methods:
- Population PK modeling using pooled data from Phase 1 (N=35) and Phase 2 (N=269) studies.
- Analysis of intrinsic factors (body weight, race, albumin, anti-drug antibodies) and extrinsic factors on Teliso-V clearance.
- Exposure-response modeling for efficacy (overall response rate, progression-free survival, overall survival) and safety (peripheral neuropathy, corneal epitheliopathy).
Main Results:
- Body weight, race, albumin, and anti-drug antibody status were significant covariates on Teliso-V clearance but did not cause clinically meaningful exposure changes.
- Conjugate exposure significantly correlated with overall response rates, progression-free survival, and overall survival, indicating clinical benefit.
- Higher conjugate exposures were linked to peripheral neuropathy and corneal epitheliopathy, while unconjugated MMAE exposure correlated with severe treatment-emergent adverse events.
Conclusions:
- The 1.9 mg/kg Q2W intravenous dose of Teliso-V maximizes efficacy in c-Met overexpressing NSCLC.
- This dosing regimen balances efficacy with manageable adverse events, including peripheral neuropathy and corneal epitheliopathy.
- Population PK modeling supports the established dosing regimen for Teliso-V in NSCLC patients.
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