Ascentage Pharma announced that it has released the latest clinical data of its dual Bcl-2/Bcl-xL inhibitor, APG-1252 (pelcitoclax), combined with osimertinib for the treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC) in a Mini Oral at the 2023 European Society of Medical Oncology (ESMO) Congress. Developed by Ascentage Pharma, pelcitoclax is a potential best-in-class novel dual Bcl-2/Bcl-xL inhibitor that can restore the apoptosis of cancer cells by selectively inhibiting Bcl-2 and Bcl-xL proteins, thus delivering its therapeutic effects on a range of solid tumors and hematologic malignancies The clinical data presented at the ESMO Congress this year demonstrated promising therapeutic utility of pelcitoclax combined with osimertinib in patients with EGFR-mutant NSCLC. Those results show that among the 26 EGFR-tyrosine kinase inhibitor (TKI)-naïve patients, 21 partial responses (PRs) were observed, resulting in an objective response rate (ORR) of 80.8%; while among the 16 EGFR-TKI naïve patients with TP53 and EGFR-mutations, 14 PRs were observed, resulting in an ORR of 87.5%.

Highlights This open-label, multi-center, Phase Ib study being conducted in China was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of pelcitoclax in combination with osimertinib in patients with EGFR-mutant NSCLC. As of April 21, 2023, 64 patients were enrolled with a median age of 56 years. To the 13 patients enrolled in the dose escalation phase, pelcitoclax was administered intravenously once weekly (QW) at 160 mg (n=6) and 240 mg (n=7); while osimertinib was orally administered once daily (QD) at 80 mg, in 21-day cycles.

After establishing 160 mg as the recommended Phase II dose (RP2D) of pelcitoclax, the study enrolled another 51 patients into the dose-expansion phase that divided the 64 patients into 3 cohorts: Cohort 1 included patients with disease resistant to first-generation EGFR-TKIs (n=8), Cohort 2 included patients with disease resistant to third-generation EGFR-TKIs (n=29), Cohort 3 included patients whose disease was previously untreated with EGFR-TKIs (n=27). Efficacy results: In the 26 efficacy-evaluable EGFR-TKI-naïve patients, 21 partial responses (PRs) were observed, resulting in an ORR of 80.8%. In the 16 EGFR-TKI- naïve patients with TP53 and EGFR mutations, 14 PRs were observed, resulting in an ORR of 87.5% and a median progress-free survival (mPFS) of 16.39 months (95%Cl, 8.11-NR).

Furthermore, preliminary biomarker data from patients resistant to third-generation EGFR-TKIs suggest that the combination regimen can potentially prolong the PFS of patients with high Bcl-xL expressions. Safety results: A total of 59 patients (92.2%) experienced treatment-emergent adverse events (TEAEs), of whom only 13 (20.3%) experienced grade=3 AEs. The most common TEAEs included increased aspartate aminotransferase (68.8%) and alanine aminotransferase (64.1%), reduced platelet counts (43.8%), increased serum amylase (29.7%), and increased blood creatinine (28.1%).

Conclusions: According to the preliminary results, pelcitoclax in combination with osimertinib showed favorable tolerability in patients with EGFR-mutant NSCLC, and the potential for improving the prognosis of EGFR-TKI-naïve patients with TP53- and EGFR-mutant NSCLC. In patients resistant to third-generation EGFR-TKIs, those with higher Bcl-xL expressions achieved better responses. These encouraging findings warrant further clinical investigations.