KEY TAKEAWAYS
- SG, an antibody-drug conjugate composed of anti-Trop-2 antibody and SN-38 payload via a hydrolyzable linker, was evaluated in a phase 1/2 trial (IMMU-132-01) and phase 3 trial (ASCENT).
- Higher values of average exposure of SG (CAVGSG) were significantly associated with an increase in the probability of complete response (CR).
- The probability of Grade ≥1 evaluated adverse events (AEs), the risk of dose reductions, and dose delays were found to increase significantly with increasing CAVGSG.
- The developed models were used to estimate the efficacy and safety outcomes for the 8 mg/kg vs. 10 mg/kg SG dose levels.
- Baseline Trop-2 expression level was not statistically correlated with the magnitude of clinical response based on the limited available Trop-2 data.
SG is an anti-Trop-2 antibody combination containing the cytotoxic SN-38 payload attached to the antibody via a proprietary, hydrolyzable linker. Patients with mTNBC undergoing>1 previous chemotherapy are eligible for SG. In patients with mTNBC, we examined the associations between SG exposure, free SN-38, and total antibody (tAB) after SG treatment and its effectiveness and safety results. Patients with mTNBC who had had 2 prior therapies (> 1 in the metastatic setting; n = 253) and patients with mTNBC from the phase 1/2 IMMU-132-01 study (relapsed/refractory pts; n = 24) were assessed for general exposure effectiveness and safety data.
Patients in the IMMU-132-01 study were given either 8 or 10 mg/kg SG on days 1 and 8 of every 21-day cycle, while patients in the ASCENT study were given 10 mg/kg SG on days 1 and 8 of every process. Survival, progression-free survival, time until first dose reduction, and time until first dose delay were analyzed using Cox proportional hazards models, while the effect of exposure on CR, ORR, and evaluated AEs of vomiting, diarrhea, hypersensitivity reactions, nausea, and neutropenia were analyzed using logistic (CR, ORR) or ordinal logistic (AE) regression models. The effect of other factors was defined within the modeling framework. Various exposure metrics relating to the PK of SG, free SN-38, and tAB were investigated as predictors of SG efficacy and safety.
It was found that higher values of the cumulative exposure throughout therapy (CAVG) for SG (CAVGSG) were significantly linked with an increased probability of CR and ORR and that higher values of the CAVG for tAB (CAVGtAB) were significantly associated with prolonged OS and PFS. In addition, it was discovered that as CAVGSG increased, so did the likelihood of Grade 1 assessed AEs, the risk of dosage decreases, and the potential for dose delays. Only neutropenia was found to have a statistically significant relationship between exposure and the likelihood of Grade 3 assessed AEs.
None of the examined endpoints showed statistically significant correlations between exposure and the likelihood of Grade 4 AEs. Results from applying the created models to predict efficacy and safety outcomes at the 8 mg/kg and 10 mg/kg SG dose levels showed that the 10 mg/kg dose level had a more favorable risk/benefit profile, which was driven by the higher estimated efficacy. In addition, the available Trop-2 data did not show a statistically significant correlation between baseline Trop-2 expression level and the degree of the clinical response.
Patients with mTNBC showed exposure-response relationships for all evaluated efficacy and safety endpoints for SG, 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.
Source: https://meetings.asco.org/abstracts-presentations/210129
Clinical trial: https://clinicaltrials.gov/ct2/show/NCT01631552
Singh, I., Sathe, A.G., Singh, P., Diderichsen, P.M., Fauchet, F., Maringwa, J., Pierrillas, P., Phan, S.-C., Girish, S. and Othman, A.A. (2022). Exposure-response analyses of sacituzumab govitecan (SG) efficacy and safety in patients (pts) with metastatic triple-negative breast cancer (mTNBC). Journal of Clinical Oncology, 40(16_suppl), pp.1076–1076. doi:https://doi.org/10.1200/jco.2022.40.16_suppl.1076.
