Population Pharmacokinetics and Exposure‐Response Analyses for Telisotuzumab Vedotin in Patients With c‐Met Protein Overexpressing Tumors

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.