ABBV-706 Demonstrates Tumor Shrinkage, Tolerability in Pretreated R/R SCLC

Updated findings from the dose-optimization part of a first-in-human phase 1 trial (NCT05599984) showed that ABBV-706, a seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate (ADC), yielded high response rates with an acceptable safety profile in heavily pretreated patietns with relapsed/refractory small cell lung cancer (SCLC). These results were shared at the IASLC 2025 World Conference on Lung Cancer (WCLC).1 In the total population (n = 80), the confirmed overall response rate (cORR) was 58%. Responses were seen across key patient subgroups, as well as patients with platinum-refractory/resistant disease and those with brain metastases. Among patients who had received 2 prior lines of therapy (n = 30) or at least 3 prior lines of therapy (n = 50), the cORRs were 77% and 46%, respectively. Among patients with prior chemotherapy-free intervals of 90 days or longer (n = 30), less than 90 days (n = 41), and less than 30 days (n = 19), the cORRs were 57%, 59%, and 53%, respectively. Among patients with (n = 28) and without (n = 36) brain metastases at baseline, the cORRs were 57% and 69%, respectively. Notably, SEZ6 expression levels were similar between responders and nonresponders. Among patients treated at the 1.8-mg/kg dose (n = 41), the cORR was 56%. Of patients who had received 2 prior lines of therapy (n = 16) or at least 3 prior lines of therapy (n = 25), the cORRs were 81% and 40%, respectively. Among patients with prior chemotherapy-free intervals of 90 days or longer (n = 12), less than 90 days (n = 24), and less than 30 days (n = 11), the cORRs were 58%, 54%, and 46%, respectively. Among patients with (n = 16) and without (n = 16) brain metastases at baseline, the cORRs were both 63%. Among patients treated at the 2.5-mg/kg dose (n = 39), the cORR was 59%. Of patients who had received 2 prior lines of therapy (n = 14) or at least 3 prior lines of therapy (n = 25), the cORRs were 71% and 52%, respectively. Among patients with prior chemotherapy-free intervals of 90 days or longer (n = 18), less than 90 days (n = 17), and less than 30 days (n = 8), the cORRs were 56%, 65%, and 63%, respectively. Among patients with (n = 12) and without (n = 20) brain metastases at baseline, the cORRs were 50% and 75%, respectively. “ABBV-706 has manageable safety and promising efficacy in heavily pretreated patients with relapsed/refractory SCLC, with most patients receiving durable clinical benefit, including those patients with platinum-refractory disease,” lead study author Lauren A. Byers, MD, emphasized in the presentation. Byers is a professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston. What Data Have Been Previously Shown With ABBV-706 in SCLC? SEZ6 is a type I transmembrane protein and neuroendocrine lineage marker that is highly expressed in SCLC. It has a proprietary topoisomerase 1 payload, a stable linker attachment, and a drug-to-antibody ratio of 6. Previously, data from the phase 1 study (NCT05599984) showed that ABBV-706 monotherapy elicited a median DOR of 6.37 months (95% CI, 4.4-9.46) and a median PFS of 7.62 months (95% CI, 5.52-8.31) in patients with SCLC and neuroendocrine carcinomas (n = 65).2,3 The present analysis expanded on these findings in patients with SCLC.1 What Is the Design of the Phase 1 Trial Investigating ABBV-706 in Relapsed/Refractory SCLC? This phase 1 trial enrolled patients at least 18 years of age with histologically or cytologically documented extensive-stage SCLC (ES-SCLC) who had received at least 1 prior line of therapy with at least 1 platinum-based chemotherapy regimen. Patients also needed to have an ECOG performance status of 0 or 1 and at least 1 measurable lesion per RECIST 1.1 criteria. Patients with prior untreated or treated stable brain metastases were permitted to enroll. Patients were excluded if they had received prior therapy with SEZ6-targeted ADCs or ADCs with a topoisomerase 1 payload. During the dose-escalation portion, patients with ES-SCLC, high-grade neuroendocrine neoplasms, or central nervous system tumors received ABBV-706 at doses ranging from 1.3 mg/kg to 3.5 mg/kg (n = 60). Following dose escalation, in the dose-optimization portion, patients with SCLC were randomly assigned 1:1 to receive ABBV-706 at 1.8 mg/kg or 2.5 mg/kg IV every 3 weeks in 21-day cycles until disease progression or unacceptable toxicity. The primary end points included safety and tolerability, pharmacokinetics, and identification of the recommended phase 2 dose (RP2D). Antitumor activity end points included investigator-assessed ORR, duration of response (DOR), and progression-free survival (PFS); overall survival (OS); and clinical benefit. Exploratory end points included SEZ6 expression by immunohistochemistry, as well as the identification of pharmacodynamic and predictive biomarkers. What Were the Baseline Characteristics of the Dose-Optimization SCLC Population in the Phase 1 Trial Investigating ABBV-706? In the total SCLC patient population, at baseline, the median age was 65 years (range, 48-85), 55% of patients were male, 80% of patients had an ECOG performance status of 1, and 35% of patients had brain metastases. Patients had received a median of 2 prior lines of systemic therapy (range, 1-6), and 63% of patients had received at least 2 prior lines of systemic therapy. Chemotherapy-free intervals lasted at least 90 days, less than 90 days, and less than 30 days in 38%, 51%, and 24% of patients, respectively; this information was missing for 11% of patients. A total of 29% and 4% of patients had previously received prior topoisomerase 1–directed chemotherapy and tarlatamab-dlle (Imdelltra), respectively. Additionally, 75% of patients had received prior anti-PD-(L)1–directed therapy. At a data cutoff date of January 3, 2025, 12 and 10 patients were ongoing treatment in the 1.8 mg/kg and 2.5 mg/kg arms, respectively. Fifty-eight patients discontinued treatment due to progressive disease (1.8 mg/kg arm, n = 20; 2.5 mg/kg arm, n = 22), treatment-emergent adverse effects (TEAEs; n = 6; n = 5), death (n = 9; n = 9), and withdrawal of consent (n = 3; n = 0). The median treatment durations in these respective arms were 6.21 months (range, 0.7-10.9) and 5.52 months (range, 0.7-11.3). The median follow-ups were 9.0 months and 8.3 months, respectively. What Additional Efficacy Data Were Seen in the Dose-Optimization Phase? In the total population, the median DOR was 5.6 months (95% CI, 4.2-6.9). Among patients who received ABBV-706 as their second line of therapy and those with a chemotherapy-free interval of less than 30 days, the median DORs were 6.9 months (95% CI, 3.2-7.1) and 5.7 months (95% CI, 2.8-7.5), respectively. Overall, among patients who received the agent in the second-line setting or later, only 1 did not respond to ABBV-706 on the first scan. Treatment with ABBV-706 led to rapid responses at both tested dose levels. In the 1.8 mg/kg cohort, the median DOR was 6.2 months (95% CI, 4.2-not evaluable [NE]) overall, 6.9 months (95% CI, 3.0 months-NE) among patients treated in the second-line setting, and 6.2 months (95% CI, 2.8-NE) among patients with a chemotherapy-free interval of less than 30 days.In the 2.5 mg/kg cohort, the median DORs in these respective populations were 4.4 months (95% CI, 3.5-6.9), 5.2 months (95% CI, 2.7 months-NE), and 5.0 months (95% CI, 3.2-7.0). In the overall population, the median PFS was 5.7 months (95% CI, 4.9-7.0); the median PFS was 6.8 months (95% CI, 4.4-8.4) in the second-line population and 5.7 months (95% CI, 3.9-7.5) in the population of patients with a chemotherapy-free interval of less than 30 days. OS data were immature at the time of the presentation; however, the estimated 9-month OS rate was 0.6% (95% CI, 0.5%-0.7%). The median PFS was longer in the 1.8 mg/kg cohort compared with the 2.5 mg/kg cohort, at 6.8 months (95% CI, 4.0-8.2) vs 5.6 months (95% CI, 4.4-7.0). The median PFS also trended toward further improvement in the second-line setting with the lower dose, at 7.5 months (95% CI, 4.0-8.4) vs 5.4 months (95% CI, 2.8-NE), respectively. Among patients with a chemotherapy-free interval of less than 30 days, these respective values were 7.0 months (95% CI, 2.0-NE) and 4.4 months (95% CI, 2.2-7.0). The estimated 9-month OS rates in these respective arms were 0.6% (95% CI, 0.4%-0.7%) and 0.6% (95% CI, 0.4%-0.7%). “The ABBV-706 efficacy profile in terms of ORR, DOR, and PFS is similar to that of the first-line standard of care (platinum-etoposide-checkpoint inhibitor) even if given in a later line of treatment,” Byers and coauthors wrote in the presentation. What Is the Safety Profile of ABBV-706? In the total population, any-grade treatment-related AEs (TRAEs) were reported in 90% of patients. Grade 3 or higher TRAEs and serious AEs occurred in 63% and 14% of patients in the 1.8 mg/kg and 2.5 mg/kg groups, respectively. TRAEs led to dose interruption, reduction, and discontinuation in 44%, 28%, and 9% of patients in these respective patient populations. At a median follow-up of 8.4 months, the median treatment duration was 5.8 months (95% CI, 0.7-11.3), and the relative dose intensity was 92%. Overall, Byers noted that the safety profile of ABBV-706 was more favorable at the 1.8-mg/kg dose vs the 2.5-mg/kg dose, including fewer grade 3 or higher TRAEs, dose interruptions, and dose reductions. In the 1.8 mg/kg arm, any-grade TRAEs, grade 3 or higher TRAEs, and serious AEs were reported in 85%, 49%, and 17% of patients, respectively, as opposed to 95%, 77%, and 10% of patients, respectively, in the 2.5 mg/kg arm. TRAEs led to dose interruption, reduction, and discontinuation in 24%, 20%, and 10% of patients, respectively, in the 1.8 mg/kg arm vs 64%, 36%, and 8% in the 2.5 mg/kg arm. The relative dose intensities in these respective arms were 99% vs 85%. Hematological AEs were dose dependent. In the 1.8 mg/kg arm, the most common hematological TEAEs included anemia (any-grade, 54%; grade ≥ 3, 42%), neutropenia (27%; 20%), thrombocytopenia (22%; 20%), and leukopenia (17%; 5%). In the 2.5 mg/kg arm, TEAEs rates were as follows: anemia (any-grade, 74%; grade ≥ 3, 62%), neutropenia (44%; 31%), thrombocytopenia (41%; 23%), and leukopenia (26%; 21%). The most common nonhematologic TEAEs in the 1.8 mg/kg arm were fatigue (any-grade, 42%; grade ≥ 3, 5%), nausea (37%; 0%), decreased appetite (20%; 2%), and dyspnea (29%; 2%). In the 2.5 mg/kg arm, the rates of these TEAEs were as follows: fatigue (any-grade, 44%; grade ≥ 3, 5%), nausea (36%; 2%), decreased appetite (46%; 2%), and dyspnea (23%; 8%). Furthermore, any-grade adjudicated interstitial lung disease (ILD) was reported in 7 patients, including 4 in the 1.8 mg/kg arm and 3 in the 2.5 mg/kg arm. Two patients in each arm had grade 3 or higher ILD. “ABBV-706 provides high response rates, quick tumor shrinkage, and rapid symptomatic relief,” Byers and study coauthors wrote in the concluding slide of the presentation. Based on the benefit-risk profile of ABBV-706, 1.8 mg/kg every 3 weeks was determined to be the RP2D for the agent as monotherapy in patients with SCLC. References