1318MO First-in-human Study of ABBV-637, an EGFR-targeting BCL-XL–inhibiting Antibody-Drug Conjugate Combined with Osimertinib (OSI) in Relapsed/refractory, EGFR-mutated Non-Small Cell Lung Cancer (NSCLC)

ABBV-637 is an antibody-drug conjugate consisting of an epidermal growth factor receptor (EGFR)–targeting antibody and BCL-XLinhibitor. Preclinical data demonstrate potent antitumor activity of ABBV-637 plus OSI in mutant EGFR NSCLC through reactivation of the apoptotic pathway. This phase 1 dose escalation and expansion study (NCT04721015) explored the safety and preliminary efficacy of ABBV-637 as second- (2L) and third-line (3L) combination therapy with OSI. Enrolled adults had relapsed/refractory (RR) NSCLC with EGFR mutation, ECOG 0–1, and prior response and subsequent disease progression on OSI. Enrolled patients being treated at 2L and 3L had no inclusion/exclusion criteria for specific targetable mutations. ABBV-637 (12 or 20 mg/kg) was dosed IV Q4W; OSI (80 mg) was given daily in 28-day cycles. Endpoints included the rates of treatment-emergent adverse events (TEAEs), objective response (ORR), disease control (DCR), and best overall response. Disease- and drug-related biomarkers were evaluated. Forty-two patients were treated; median age was 65 (range: 44–79), and 64% had ≥2 prior lines of therapy. Median duration of ABBV-637 treatment was 113 days (range: 28–288). Most common TEAEs were increases in aspartate (38%) and alanine aminotransferase (33%), nausea (33%), and fatigue (21%). The ORR was 14% in 3L cohorts and 10% in 2L (Table). DCR was 73% and 65% in 3L and 2L, respectively. In 2L, confirmed responders did not have targetable bypass alterations.Table: 1318MOCharacteristicTotal (N=42)Safety, n (%)TEAEs41 (98)Grade ≥317 (40)ABBV-637-related deaths0 (0)Preliminary efficacy, n (%)Cohort A†+ Bi‡ (3L) (n=22)Cohort Bii§ (2L) (n=20)Best overall response*Complete response (CR)0 (0)0 (0)Partial response – all (PR)5 (23)3 (15)Partial response – confirmed (cPR)3 (14)2 (10)Stable disease (SD)11 (50)10 (50)Progressive disease6 (27)7 (35)Objective response rate (CR+cPR)3 (14)2 (10)Disease control rate (PR+SD)16 (73)13 (65)*Based on RECIST 1.1; †dose escalation (3L; n=5); ‡dose expansion (3L; n=17); §dose expansion (2L). 2L, 2nd-line therapy (post osimertinib alone); 3L, 3rd-line therapy (post osimertinib and platinum chemotherapy). Open table in a new tab *Based on RECIST 1.1; †dose escalation (3L; n=5); ‡dose expansion (3L; n=17); §dose expansion (2L). 2L, 2nd-line therapy (post osimertinib alone); 3L, 3rd-line therapy (post osimertinib and platinum chemotherapy). ABBV-637 plus OSI showed clinical activity and a manageable safety profile in patients with RR NSCLC. Biomarker data suggest that response to ABBV-637 plus OSI may be enriched by excluding patients with targetable bypass mechanisms; ongoing research is needed to confirm association of mutation and patient selection.