The investigational agent, ABBV-011, is showing promise, according to results from a phase 1 clinical trial.
Results from a first-in-human phase 1 trial (NCT03639194) shows that ABBV-011, a SEZ6-targeted antibody-drug conjugate (ADC), given every 3 weeks at 1 mg/kg was well-tolerated and achieved early efficacy in patients with relapsed or refractory small cell lung cancer (SCLC), according to a presentation at the 2023 ASCO Annual Meeting.1
At a data cutoff date of August 22, 2022, the maximum tolerated dose (MTD) for the agent was not yet reached through the 2-mg/kg dose level. One dose-limiting toxicity (DLT) of grade 3 fatigue was reported at the 2-mg/kg dose, and delayed onset hepatotoxicity in the form of hyperbilirubinemia and increased GGT limited long-term dosing at doses greater than 1.2 mg/kg. One mg/kg was identified as a tolerable dose for the agent, and 93% of patients had 80% or higher relative dose intensity.
In all patients (n = 98), ABBV-011 elicited a confirmed objective response rate (ORR) of 19% (95% CI, 12%-29%), with a clinical benefit rate (CBR) of 69% (95% CI, 59%-78%). Thirty-seven percent (95% CI, 27%-47%) of patients experienced a CBR that lasted for longer than 12 weeks.
In the 40 patients with SEZ6-positive SCLC who received the ADC at 1 mg/kg, the ORR was higher, at 25% (95% CI, 13%-41%), with a CBR of 65% (95% CI, 48%-79%). In this group, CBR lasted for longer than 12 weeks in 43% (95% CI, 27%-59%) of patients. The median duration of response (DOR) was 4.2 months (95% CI, 2.6-6.7).
The median progression-free survival (PFS) was 3.5 months (95% CI, 1.5-4.2) in all patients who received the agent at 1 mg/kg. In the subset of patients who received ABBV-011 as second-line (n = 12) or third- or later-line (n = 28) treatment, the median PFS was 5.4 months (95% CI, 1.4-8.3) and 2.7 months (95% CI, 1.4-4.1), respectively.
“SEZ6 should be a valid target for SCLC,” said Daniel Morgensztern, MD, lead study author, medical oncologist, and professor of medicine in the Division of Oncology, Section of Medical Oncology at the Washington University School of Medicine, in a presentation of the data. “It is a membrane protein that is highly expressed in [SCLC and other] neuroendocrine tumors with minimal expression in most normal tissues. Therefore, it warrants further investigation.”
SCLC accounts for approximately 13% of all lung cancer cases, according to Morgensztern, who added that the disease is linked with rapid tumor growth and metastatic presentation in about 70% of patients. Moreover, the prognosis for those with this diagnosis is poor. For patients with metastatic disease who have received chemotherapy and a PD-L1 inhibitor as first-line treatment, the median PFS is 5.1 months. For those who receive second-line treatment with agents such as topotecan or lurbinectedin (Zepzelca), the median PFS was about 3.5 months. No standard third-line option is available, he added.
“SEZ6 is not as popular as the HER2 family, so it deserves a little bit of explanation,” Morgensztern said. “This is a transmembrane protein encoded by the SEZ6 gene located on chromosome 17 [17q11.2]. It is involved in the normal dendritic arborization of cortical neurons.”
The main components of ABBV-011 are an anti-SEZ6 IgG1 monoclonal antibody, SC17, a noncleavable LD19.10 linker, and a calicheamicin payload, with a drug-to-antibody ratio of 2. “Calicheamicin is the payload for 2 drugs [that are] already approved: gemtuzumab ozogamicin [Mylotarg], an anti-CD33 drug used for acute myeloid leukemia, and inotuzumab ozogamicin [Besponsa], an anti-CD22 drug used for acute lymphoblastic leukemia.”
The multicenter, open-label, phase 1 study enrolled patients with relapsed or refractory SCLC who received 1 to 3 prior lines of therapy and who were at least 18 years of age and who had an ECOG performance status of 0 or 1. For the expansion phase of the research, patients were required to have SEZ6 positivity by immunohistochemistry, and this was defined as at least 25% of tumor cells with 1+ staining intensity.
The study is comprised of 4 parts: part A is a single-agent ABBV-101 dose escalation cohort, followed by part B, which is an ABBV-101 monotherapy dose-expansion cohort; and then part C, which is evaluating ABBV-101 every 3 weeks in combination with budigalimab (ABBV-181) at 375 mg every 3 weeks in an escalation and expansion cohort; and part D, which is a single-agent ABBV-101 cohort that is being done in Japan.1,2
In part A, the dose escalation is guided by Bayesian continual reassessment methods, and ABBV-101 is under evaluation at several doses, including 0.3 mg/kg (n = 3), 0.6 mg/kg (n = 4), 1.2 mg/kg (n = 5), 1.6 mg/kg (n = 5), and 2.0 mg/kg (n = 9), until the MTD and/or the recommended part B dose was identified. For part B, the initial cohort received a loading dose of 1.6 mg/kg on cycle 1, followed by maintenance 1.2 mg/kg on cycles 2 and beyond, every 3 weeks (n = 13).
“There was another cohort of 1 mg/kg every 3 weeks; this cohort was expanded to 40 patients and [this group was] the main focus of this presentation,” Morgensztern explained. “A third cohort of 0.8 mg/kg was open, at the time of data cutoff, there were only 7 patients. The cohort was expanded and completed accrual last month.”
The primary objectives of the trial include safety and tolerability, as well as to determine the MTD and recommended phase 2 dose. Secondary objectives include examining the pharmacokinetics (PK) of ABBV-101 and its antitumor activity.
Among the 445 patients who were tested for SEZ6, 86% had SEZ6 expression on 1% or more tumor cells at 1+ or above, and 55% had expression on 25% or more tumor cells at 1+ or above, which was required to enroll to the 1-mg/kg expansion cohort.
Across the total cohort and the 1-mg/kg expansion cohort, the median age was 63 years (range, 41-79) and 50.5% were female. Most patients had extensive disease (73% vs 85%, respectively) at diagnosis by Veterans Administration Lung Study group staging criteria, received prior PD-1/PD-L1 therapy (77% vs 88%), and had an ECOG performance status of 1 (80%, both). About 32.5% of patients across cohorts had brain metastases at baseline.
In the total cohort, 33% of patients received 1 prior line of therapy, 41% received 2 prior lines, 23% received 3 more lines, and 3% received more than 3 prior lines; these rates were 30%, 55%, 15%, and 0%, respectively, in the 1-mg/kg cohort. In the total cohort, the chemotherapy-free interval (CTFI) was less than 90 days in 34% of patients, 90 days or longer in 63% of patients, and unknown for 3% of patients. In the 1-mg/kg cohort, 30% and 65% of patients had CTIFs of less than 90 days or 90 days or greater, respectively; this information was unknown for 5% of patients.
At the time of data cutoff, 8% of patients in the 1-mg/kg cohort were still receiving treatment with ABBV-011. The median duration of treatment with the ADC was 12 weeks (range, 2-63).
Additional efficacy data showed that in all 40 patients in the 1-mg/kg cohort, the 3-month estimated PFS rate was 54% (95% CI, 37%-68%); the 6-month and 9-month rates were 20% (95% CI, 9%-34%) and 3% (95% CI, 0%-14%), respectively.
In the subset of patients who received 1 prior line of treatment, the estimated PFS rates at 3, 6, and 9 months were 73% (95% CI, 38%-91%), 42% (95% CI, 13%-69%), and 14% (95% CI, 1%-45%), respectively. In the group of patients who previously received 2 or more lines of therapy, the 3- and 6-month PFS rates were 46% (95% CI, 27%-63%) and 12% (95% CI, 3%-27%), respectively.
Antitumor activity was also examined by first-line platinum sensitivity in this cohort. In those who had a CTIF of less than 90 days (n = 12), or those who were platinum resistant, the confirmed ORR with ABBV-011 was 25% (95% CI, 5%-57%), with a CBR of 58% (95% CI, 28%-85%). For 33% (95% CI, 10%-65%) of these patients, the CBR lasted for longer than 12 weeks. The median PFS in this group was 3.0 months (95% CI, 1.2-3.9).
In those with a CTIF of 90 days or longer (n = 26), in those who were platinum sensitive, the confirmed ORR with the ADC was 27% (95% CI, 12%-48%), with a CBR of 69% (95% CI, 48%-86%). Half of these patients had a CBR that lasted for longer than 12 weeks. Additionally, the median PFS in this group was 4.1 months (95% CI, 1.5-5.8).
Any-grade treatment-emergent adverse effects (TEAEs) were reported in 98% of those in the 1-mg/kg cohort and 97% of those in the total population; grade 3 or higher TEAEs occurred in 65% and 64% of patients, respectively. Serious TEAEs were experienced by 45% of those who received the agent at 1 mg/kg and 41% of those in the total population.
Moreover, treatment-related AEs (TRAEs) were experienced by 78% and 77% of those in the 1-mg/kg cohort and the total population, respectively. TRAEs resulted in discontinuation for 8% and 13% of patients, respectively; they resulted in dose reductions for 15% and 8% of patients, respectively, and dose interruptions in 30% and 29% of patients, respectively.
No deaths related to study treatment occurred, and no on-target neurotoxicity was observed.
The most common TEAEs observed in 20% or more of patients in the 1-mg/kg cohort included fatigue (all-grade, 48%; grade ≥3, 10%), nausea (45%; 3%), decreased appetite (38%; 0%), decreased platelet count (38%; 10%), vomiting (35%; 3%), increased aspartate aminotransferase (15%; 0%), constipation (28%; 0%), and increased GGT (13%; 5%).
Additional hepatotoxicity TEAEs of special interest included hyperbilirubinemia (18%; 3%), ascites (10%; 0%), veno-occlusive liver disease (3%; 3%), and portal hypertension (3%; 3%).
Across the dose range of 0.3 mg/kg to 2.0 mg/kg, the PK for ABBV-011 were approximately dose proportional, according to Morgensztern. The elimination half-life for the agent was 4.6 days. In the 1-mg/kg cohort, the mean Tmax was 0.5h (0.5-24.0), Cmax was 24.2 µg/mL (25.6-34), and AUC21d was 92.2 µg/day/mL (98.1-40).
1. Morgensztern D, Ready NE, Johnson ML, et al. First-in-human study of ABBV-011, a seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate, in patients with small cell lung cancer. J Clin Oncol. 2023;41(suppl 16):3002. doi:10.1200/JCO.2023.41_suppl.16.3002
2. A study of ABBV-011 alone and in combination with budigalimab (ABBV-181) in participants with relapsed or refractory small cell lung cancer. ClinicalTrials.gov. Updated May 16, 2023. Accessed June 5, 2023. https://www.clinicaltrials.gov/ct2/show/NCT03639194