Exposure-response analyses of sacituzumab govitecan (SG) efficacy and safety in patients (pts) with metastatic triple-negative breast cancer (mTNBC).
Authors: Singh Indrajeet , Sathe Abhishek G. , Singh Pratap , Diderichsen Paul M. , Fauchet Floris , Maringwa John , Pierrillas Philippe , Phan See-Chun , Girish Sandhya , Othman Ahmed A. 
Published: June 2022

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Background: SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG is approved for pts with mTNBC who received ≥2 prior chemotherapies (> 1 in the metastatic setting). The relationships between exposure of SG, free SN-38, and total antibody (tAB) following SG administration and its efficacy and safety outcomes were evaluated in pts with mTNBC. Methods: Available exposure efficacy and safety outcomes from the mTNBC cohort of the phase 1/2 IMMU-132-01 study (relapsed/refractory pts; n = 24) and mTNBC pts from the phase 3 ASCENT study who had received ≥2 prior therapies (> 1 in the metastatic setting; n = 253) were analyzed. Pts in IMMU-132-01 received 8 or 10 mg/kg SG and pts in ASCENT received 10 mg/kg SG on d1 and d8, of every 21d cycle. Effect of exposure on CR, ORR and the evaluated adverse events (AEs) of vomiting, diarrhea, hypersensitivity reactions, nausea, and neutropenia were analyzed using logistic (CR, ORR) or ordinal logistic (AE) regression models while OS, PFS, time to first dose reduction and time to first dose delay were analyzed using Cox PH models. Several exposure metrics related to the PK of SG, free SN-38, and tAB were evaluated as predictors of SG efficacy and safety and the most statistically significant exposure metric was retained in the model; effect of other covariates was characterized within the modeling framework. Results: Higher values of the average exposure over the treatment duration (CAVG) for SG (CAVGSG) were significantly associated with an increase in the probability of CR and ORR and higher CAVG values for tAB (CAVGtAB) were significantly associated with longer OS and PFS. The probability of Grade ≥1 evaluated AEs, the risk of dose reductions and dose delays were found to increase significantly with increasing CAVGSG. Neutropenia was the only AE where the effect of exposure was significantly associated with the probability of Grade ≥3 evaluated AEs. No statistically significant associations between exposure and the probability of Grade 4 AEs were observed for any of the evaluated endpoints. The developed models were used to estimate the efficacy and safety outcomes for the 8 mg/kg vs 10 mg/kg SG dose levels and the results indicated a more favorable risk/benefit profile for the 10 mg/kg dose level driven by the higher estimated efficacy. Baseline Trop-2 expression level was not statistically correlated with magnitude of clinical response based on the limited available Trop-2 data. Conclusions: Exposure-response relationships were observed for all evaluated efficacy and safety endpoints for SG in patients with mTNBC, and the higher efficacy (as assessed by CR, ORR, OS and PFS) achieved with the exposures associated with the 10 mg/kg SG dose regimen and its manageable safety profile support the appropriateness of the approved regimen of SG. Clinical trial information: NCT02574455, NCT01631552.