BCL-2/BCL-xL inhibitor pelcitoclax with osimertinib for EGFR-mutated advanced non-small-cell lung cancer: a phase 1b trial.
Overcoming tyrosine kinase inhibitor (TKI) resistance improves survival in advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). We therefore examined the safety and preliminary efficacy of pelcitoclax, a B-cell lymphoma-2 (BCL-2)/BCL-extra-large (BCL-xL) inhibitor, and osimertinib in patients with EGFR-mutated advanced NSCLC.
Enrolled patients included Cohort 1 (previously progressed after third-generation TKI treatment+chemotherapy), Cohort 2 (previously progressed after first-generation or second-generation TKI treatment+chemotherapy), and Cohort 3 (TKI treatment-naive±prior chemotherapy). Patients received intravenous pelcitoclax (160 mg in dose-expansion and either 160 or 240 mg in dose-escalation) weekly and oral osimertinib 80 mg daily. Primary endpoints were safety and recommended phase 2 dose (dose-escalation), objective response rate (ORR) and safety (dose-expansion).
64 patients were enrolled (13, dose-escalation; 51, dose-expansion): 29 patients in Cohort 1, 8 in Cohort 2, and 27 in Cohort 3. One dose-limiting toxicity occurred at pelcitoclax 240 mg, and the recommended phase 2 dose was 160 mg plus osimertinib 80 mg. The ORR was 10.7% and median progression-free survival (mPFS) 2.7 months in patients previously progressed after third-generation TKI treatment+chemotherapy (Cohort 1) and 80.8% and 16.4 months in TKI treatment-naïve patients±prior chemotherapy (Cohort 3). mPFS was longer in Cohort 1 patients with high expression of BCL-xL (4.2 vs 2.7 months, p=0.058).
Pelcitoclax combined with osimertinib showed promising safety and antitumor activity in EGFR-mutated NSCLC.
NCT04001777.
Enrolled patients included Cohort 1 (previously progressed after third-generation TKI treatment+chemotherapy), Cohort 2 (previously progressed after first-generation or second-generation TKI treatment+chemotherapy), and Cohort 3 (TKI treatment-naive±prior chemotherapy). Patients received intravenous pelcitoclax (160 mg in dose-expansion and either 160 or 240 mg in dose-escalation) weekly and oral osimertinib 80 mg daily. Primary endpoints were safety and recommended phase 2 dose (dose-escalation), objective response rate (ORR) and safety (dose-expansion).
64 patients were enrolled (13, dose-escalation; 51, dose-expansion): 29 patients in Cohort 1, 8 in Cohort 2, and 27 in Cohort 3. One dose-limiting toxicity occurred at pelcitoclax 240 mg, and the recommended phase 2 dose was 160 mg plus osimertinib 80 mg. The ORR was 10.7% and median progression-free survival (mPFS) 2.7 months in patients previously progressed after third-generation TKI treatment+chemotherapy (Cohort 1) and 80.8% and 16.4 months in TKI treatment-naïve patients±prior chemotherapy (Cohort 3). mPFS was longer in Cohort 1 patients with high expression of BCL-xL (4.2 vs 2.7 months, p=0.058).
Pelcitoclax combined with osimertinib showed promising safety and antitumor activity in EGFR-mutated NSCLC.
NCT04001777.
Authors
Ma Ma, Wu Wu, Zhao Zhao, Cui Cui, Huang Huang, Fang Fang, Yang Yang, Zhao Zhao, Yang Yang, Pan Pan, Xiong Xiong, Men Men, Wang Wang, Yang Yang, Zhai Zhai, Zhang Zhang, Zhao Zhao
View on Pubmed