Updated study results of pelcitoclax (APG-1252) in combination with osimertinib in patients (pts) with EGFR-mutant non–small cell lung cancer (NSCLC).

9116 Background: Investigational agent pelcitoclax is a dual BCL-2/BCL-xL inhibitor, which enhanced antitumor effects of osimertinib in preclinical models. A report presented at International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer demonstrated that the combination of pelcitoclax and osimertinib at the recommended phase 2 dose (RP2D) was safe, and preliminary efficacy was observed in some patients whose disease failed prior osimertinib or other third-generation EGFR-TKI treatments. Here, we further provide safety and efficacy results of this combination therapy. Methods: After RP2D was determined to be pelcitoclax 160 mg per week plus osimertinib 80 mg QD, pts were enrolled into 3 expansion cohorts of 20 pts each: Cohort 1 (EC-1) included those with disease resistant to third-generation EGFR-TKIs; Cohort 2 (EC-2) included those with osimertinib-naïve, EGFR-sensitive or T790M-positive mutations; and Cohort 3 (EC-3) included those with the EGFR exon 20 insertion mutation. Results: At the data cutoff date of January 6, 2022, 61 pts (median age, 56 years [69% female]) had been treated with pelcitoclax plus osimertinib. Among them, 13 were in dose escalation cohorts, 20 in EC-1, 20 in EC-2, and 8 in EC-3. Sixteen pts in EC-2 were EGFR-TKI naïve, and 4 were T790M positive with prior TKI treatment. All pts in EC-2 experienced treatment-related adverse events (TRAEs) but only 4 (20%) had grade ≥ 3. Common TRAEs included increased aspartate aminotransferase (90%) and alanine aminotransferase (85%) levels, reduced platelets (40%), diarrhea (40%), and increased lipase (35%). Among 20 evaluable pts, 17 PRs (85%) were observed and 16 (80%) confirmed. The median (range) time to response was 1.4 (1.2-7.0) months, and the median duration of response (DOR) was not reached. The DOR rate at 9 months after first response was 71.4% (95% CI 25.8-92.0). Seven pts had brain metastases at baseline in EC-2; 2 CRs and 3 PRs were observed intracranially. Conclusions: Osimertinib in combination with targeted therapies has been of clinical interest to improve the outcomes of patients with EGFR-mutant NSCLC. Pelcitoclax plus osimertinib was well tolerated and showed comparable efficacy in TKI-naïve pts. Further randomized control trials are warranted to elucidate the role of pelcitoclax when combined with osimertinib. Clinical trial information: NCT04001777.