Abstract
Objectives:
This phase 1 study investigated safety/tolerability, pharmacokinetics, and preliminary efficacy of SC-002, a delta-like ligand 3-directed antibody-drug conjugate, in advanced small cell lung cancer and large cell neuroendocrine carcinoma
Materials and Methods:
Eligible patients received SC-002 at 1 of 7 dose levels during the dose-escalation portion of the study.
Results:
Thirty-five enrolled patients received ≥1 dose of SC-002. Twenty-three (66%) patients experienced serious adverse events (AEs), 37% considered related to SC-002. Grade 3/4 AEs occurred in 21 (60%) and 2 (6%) patients; most common were effusion and hypoalbuminemia. One grade 5 AE occurred in 1 patient. Five (14%) patients achieved a partial response; no patients achieved a complete response.
Conclusion:
SC-002 treatment was associated with systemic toxicity and limited efficacy.
Keywords: Antibody-drug conjugate, delta-like ligand 3, large cell neuroendocrine carcinoma, SC-002, small cell lung cancer, pyrrolobenzodiazepine
1. Introduction
High-grade pulmonary neuroendocrine tumors, including small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), represent approximately 20% of primary lung tumors and predominantly affect older patients with a smoking history [1], Both tumor types have a poor prognosis, with limited effective available therapies. Novel therapeutic options are urgently needed to alter the natural disease course and improve survival outcomes.
The Notch signaling network is a highly conserved pathway well known for its role in cell renewal and differentiation [2]. Dysregulation of the pathway has been implicated in numerous cancer types, including neuroendocrine tumors, small cell bladder cancer, and ovarian cancer [2–4], Among the components of the network, delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is minimally expressed in normal tissues, but highly expressed in SCLC and LCNEC [1,5]. DLL3 is thought to mediate Notch pathway inhibition and facilitate tumorigenesis via regulation of transcription downstream of the ASCL1 oncogenic driver in neuroendocrine tumor cells [3]. DLL3 protein is typically exclusively intracellular, expressed in the Golgi apparatus. Due to its markedly elevated expression in SCLC, DLL3 becomes aberrantly cell-surface expressed, and is then a target for antibody-based therapy [1].
SC-002 is a bioengineered, DLL3-directed antibody-drug conjugate (ADC) that delivers the cytotoxic pyrrolobenzodiazepine (PBD) dimer warhead, SC-DR002, to cells expressing DLL3. SC-002 was engineered to facilitate a uniform drug-to-antibody ratio of 2 through site-specific conjugation of SC-DR002 via a plasma-stable valine-alanine dipeptide linker. Membrane binding of SC-002 results in internalization of the complex and release of SC-DR002 via cathepsin-mediated proteolysis within the endosomal compartment. Rovalpituzumab tesirine (Rova-T), another DLL3-targeted ADC bearing the same antibody and warhead as SC-002 (SC-DR002) but a different linker, was investigated in a phase 1 trial where it showed encouraging single-agent antitumor activity in patients with SCLC [6], A subsequent phase 2 study in patients with recurrent metastatic SCLC treated in the third line and beyond confirmed antitumor activity of Rova-T, but was notable for grade 3–5 adverse events (AEs) in 63% of patients [7]. Compared with Rova-T, SC-002 has a more uniform drug-antibody ratio (95% 2) due to the introduction of 2 site-specific cysteine residues, as well as a modified linker-drug, SC-LD002. These changes were hypothesized to yield improved pharmacokinetics (PK) and safety profiles compared with Rova-T. Herein we report the findings of a first-in-human phase 1 study of SC-002 in which the safety, tolerability, PK, and preliminary efficacy of this novel agent was investigated in patients with advanced SCLC and LCNEC.
2. Material and Methods
2.1. Study design
This multicenter, open-label phase 1a/1b trial evaluated the safety, tolerability, PK, and preliminary efficacy of SC-002 as a single agent in patients with relapsed and/or refractory SCLC or LCNEC (NCT02500914). In the phase 1a dose-escalation phase, patients were sequentially enrolled to receive SC-002 at 1 of 7 dose levels (0.025–0.4 mg/kg) according to a conventional 3+3 design, with a minimum of 3 evaluable patients treated in each cohort [8]. Primary endpoints included safety, tolerability, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase 1b dose. Secondary endpoints were PK and immunogenicity of SC-002, as well as preliminary evidence of antitumor activity (objective response rate [ORR]). Exploratory endpoints included evaluation of DLL3 expression and measurement of additional biomarkers. In the phase 1b dose-expansion, patients screened for DLL3-high expression (≥75% DLL3-positive cells determined by immunohistochemistry [Ventana DLL3 rabbit antibody (SP347)]) were treated with single-agent SC-002 at doses less than or equal to the MTD. Primary endpoints of safety and ORR and secondary endpoints of duration of response, progression-free survival, PK profile, safety/immunogenicity, and DLL3 expression were evaluated.
The study was conducted according to national and local regulatory guidelines, Good Clinical Practice International Conference on Harmonization guidelines, the National Statement on Ethical Conduct in Human Research 2007, and the Declaration of Helsinki. All patients provided written informed consent.
2.2. Patients
Patients age ≥18 years with histologically or cytologically confirmed SCLC (either limited or extensive disease) or LCNEC that had relapsed or was refractory to treatment following ≥1 prior systemic chemotherapy and for which no curative therapy was available were eligible for the phase 1a dose-escalation. Eligibility criteria for the phase 1b dose-expansion were similar to dose-escalation and included patients with relapsed/refractory SCLC or LCNEC. Tissue sample for retrospective DLL3 assessment was optional in dose escalation. All patients enrolled in the phase 1b study were required to have DLL3-high (≥75%) expressing SCLC or LCNEC as determined by immunohistochemistry on archival or fresh tissue. Other major inclusion criteria were measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0 or 1, life expectancy of ≥12 weeks, adequate hematologic status, and adequate hepatic and renal function. A complete list of inclusion and exclusion criteria can be found at ClinicalTrials.gov [9].
2.3. Treatment schedule and procedures
During single-agent dose-escalation, patients initially received their assigned dose of SC-002 given intravenously (IV) on day 1 of a 3-week (Q3W) cycle. Dosing interval could be extended to longer (e.g., 9 weeks [Q9W]) upon emergence of treatment-related toxicities necessitating dose delay. Following enrollment of the first 3 patients in phase 1a, dose advancement proceeded through successive cohorts only in the absence of DLTs in cycle 1. All 3 patients in each cohort were required to complete the initial 3-week cycle, with the final patient observed for 7 days following completion of the cycle before enrollment commenced for the next cohort.
A DLT was defined as any of the following treatment-emergent AEs (TEAEs) not clearly related to the underlying disease and that occurred in the first 3-week cycle: grade 4 thrombocytopenia (or grade 3 thrombocytopenia with bleeding) lasting >7 days and/or requiring platelet transfusion; grade 4 neutropenia lasting >7 days and/or requiring hematopoietic growth factor rescue, or any febrile neutropenia defined as grade 3 or 4 neutropenia with concurrent fever ≥38.3° C; clinically significant grade 3 or 4 laboratory abnormality; grade 3 or 4 nonlaboratory toxicity (including infusion reactions) excluding manageable constitutional symptoms (e.g., fatigue, asthenia, nausea); or any other toxicity requiring treatment discontinuation, excluding symptoms related to disease progression.
MTD was defined as the dose level immediately below which ≥2 of either 3 or 6 patients experienced a DLT during cycle 1. At least 6 patients were required to be treated at the putative MTD, with no more than 1 DLT at that dose level. A minimum of 6 and maximum of 48 patients were planned for enrollment into phase 1a, and up to 60 patients with DLL3-high expressing SCLC or LCNEC were planned for enrollment into phase 1b. A safety monitoring committee checked data throughout the study.
2.4. Assessments
TEAEs were recorded, rated for severity according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03, and assessed for relationship to study drug by the investigator. AEs were collected from the time of informed consent until 70 days after the last dose or until the start of another anticancer therapy. Assessments of measurable and nonmeasurable disease were performed locally by the investigator on the basis of RECIST version 1.1. Antitumor activity evaluation occurred every 6 weeks for the first 24 weeks (± 1 week), and every 12 weeks thereafter. Blood samples were collected to estimate the PK of SC-002, including intact ADC (SC-002), free toxin (SC-DR002), and total antibody. Immunohistochemical methods were used to measure DLL3-high expression on the basis of fresh or formalin-fixed, paraffin-embedded archived tumor tissue samples collected at enrollment. An end-of-treatment visit occurred 30 days after the last dose of study drug or before initiation of another anticancer therapy.
2.5. Statistical analyses
Data were analyzed using descriptive statistics and summarized on the basis of the number and percentage of patients who experienced the reported AE by Medical Dictionary for Regulatory Activities system organ class and preferred term. Safety and efficacy data were analyzed using the full analysis set, which consisted of all patients who received ≥1 dose of SC-002. PK analyses were performed on the basis of the PK-evaluable set, which included all treated patients with adequate blood sampling to estimate ≥1 PK parameter. PK parameters were calculated from concentration-time data using noncompartmental analyses. ORR was estimated on the basis of the proportion of patients with best objective response of complete response (CR) or partial response (PR).
3. Results
3.1. Patients and disposition
Overall, 35 patients (phase 1a, n = 34; phase 1b, n = 1) were enrolled in this study and received ≥1 dose of study drug, which constituted the full analysis set. Only 1 patient was screened and enrolled in the phase 1b portion of the study. Baseline demographics and clinical characteristics are summarized in Table 1. Overall, 54% of patients were male, and the median age of all patients was 66 years (range, 46–81).
Table 1.
Patient demographics and baseline characteristics
| Characteristic | SC-002 dose escalation 0.025–0.4 mg/kg Q3W; 0.4 mg/kg Q9W (N = 34) | SC-002 dose expansion 0.2 mg/kg Q6W (N = 1) | Overall (N = 35) |
|---|---|---|---|
| Age, years, median (range) | 66.5 (46.0–81.0) | 62.0 (62.0–62.0) | 66.0 (46.0–81.0) |
|
Sex, n (%) | |||
| Male | 18 (53) | 1 (100) | 19 (54) |
| Female | 16 (47) | 0 | 16 (46) |
|
Race, n (%) | |||
| White | 33 (97) | 0 | 33 (94) |
| Asian | 1 (3) | 1 (100) | 2 (6) |
|
Stage at diagnosis, n (%) | |||
| Extensive | 25 (74) | 1 (100) | 26 (74) |
| Limited | 9 (26) | 0 | 9 (26) |
| Prior lines of systemic therapy, n (%) | |||
| 1 | 15 (44) | 0 | 15 (43) |
| 2 | 12 (35) | 1 (100) | 13 (37) |
| 3 | 7 (21) | 0 | 7 (20) |
|
History of brain metastases, n (%) | |||
| Yes | 26 (76) | 0 | 26 (74) |
| No | 8 (24) | 1 (100) | 9 (26) |
Q, every; W, weeks.
The most common reason for discontinuing treatment was disease progression (n = 18; 51%). Other reasons for treatment discontinuation were AE (n = 8; 23%), investigator decision (n = 6; 17%), and patient decision to withdraw (n = 3; 9%). The most common reason for study discontinuation was death (n = 25; 71%), followed by disease progression (n = 2; 6%), withdrawal of consent (n = 2; 6%), and other (n = 5; 14%).
3.2. Safety
Dose escalation proceeded from the cohort 1 dose of 0.025 mg/kg Q3W to 0.4 mg/kg IV Q3W. While no cycle 1 DLTs were observed at 0.4 mg/kg Q3W, all 3 patients treated in this cohort experienced pleural effusion shortly after completing cycle 2; thus, this dosing regimen was considered to exceed the MTD. To assess the effect of a longer dosing interval on safety and antitumor activity, an additional cohort was enrolled at 0.4 mg/kg IV Q9W. One DLT of photosensitivity reaction (grade 3) occurred in 1 patient treated at a dose of 0.4 mg/kg Q9W. With 1 DLT observed out of 8 total patients treated at this dose, 0.4 mg/kg Q9W was declared the MTD.
TEAEs of any grade and deaths occurring during the study are presented in Table 2. All patients experienced ≥1 TEAE, including 28 (80%) patients with ≥1 drug-related TEAE. Twenty-three (66%) patients experienced ≥1 serious adverse event (SAE) and in 13 (37%) of those patients, SAEs were considered drug related. Most common SAEs (≥3 patients; irrespective of relation to study drug) were pleural effusion (n = 9; 26%) and fatigue (n = 3; 9%). Of the 25 deaths, 11 (44%) were considered by the investigator to be due to the underlying disease, unknown in another 11 (11%) patients, and due to sepsis and/or respiratory failure in 2 (6%) patients. In 1 (3%) patient, the cause of death was a SAE of pneumonia that was considered to be possibly related to study drug.
Table 2.
Summary of adverse events
| Adverse event, n (%) | All patients (N = 35) |
|---|---|
| ≥1 TEAE | |
| Any | 35 (100) |
| Drug related | 28 (80) |
| ≥1 SAE | |
| Any | 23 (66) |
| Drug related | 13 (37) |
| ≥1 TEAE leading to dose reduction | |
| Any | 2 (6) |
| Drug related | 2 (6) |
| ≥1 TEAE leading to dose interruption | |
| Any | 11 (31) |
| Drug related | 8 (23) |
| ≥1 TEAE leading to dose withdrawal | |
| Any | 10 (29) |
| Drug related | 7 (20) |
| Deaths | |
| Any | 25 (71) |
| Underlying disease | 11 (44) |
| Unknown | 11 (11) |
| AE | 2 (6) |
| Drug related | 1 (3) |
AE, adverse event; SAE, serious AE; TEAE, treatment-emergent adverse event.
The most commonly occurring TEAEs (≥25%) were dyspnea (43%), pleural effusion (43%), decreased appetite (34%), fatigue (31%), peripheral edema (31%), constipation (29%), cough, and pericardial effusion (26% each). TEAEs are summarized according to dose group in Table 3. Grade 3 and grade 4 AEs occurred in 21 (60%) and 2 (6%) patients; a grade 5 AE occurred in 1 (3%) patient. All patients (100%) on the Q3W schedule experienced TEAEs of any grade, and 17 (65%) patients reported grade ≥3 AEs (most common: pleural effusion; 19%). All patients (100%) on the Q9W schedule experienced TEAEs of any grade, and 88% experienced grade ≥3 AEs (most common: dyspnea, pleural effusion, thrombocytopenia, and anemia; 25% each).
Table 3.
Treatment-emergent adverse events by preferred term occurring in ≥15% (any) or ≥5% (grade ≥3) of patients treated with SC-002
| AEs, n (%) | Dose-escalation phase | Dose-expansion phase | Total (N = 35) | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0.025 mg/kg Q3W (n = 4) | 0.05 mg/kg Q3W (n = 3) | 0.1 mg/kg Q3W (n = 7) | 0.2 mg/kg Q3W (n = 3) | 0.3 mg/g Q3W (n = 6) | 0.4 mg/kg, Q3W (n = 3) | 0.4 mg/kg Q9W (n = 8) | 0.2 mg/kg Q6W (n = 1) | |||||||||||
| Any | Gr ≥3 | Any | Gr ≥3 | Any | Gr ≥3 | Any | Gr ≥3 | Ay | Gr ≥3 | Any | Gr ≥3 | Any | Gr ≥3 | Any | Gr ≥3 | Any | Gr ≥3 | |
| Patients with ≥1 AE | 4 (100) | 2 (50) | 3 (100) | 1 (33) | 7 (100) | 4 (57) | 3 (100) | 3 (100) | 6 (100) | 4 (67) | 3 (100) | 3 (100) | 8 (100) | 7 (88) | 1 (100) | 0 | 35 (100) | 24 (69) |
| Dyspnea | 2 (50) | 0 | 1 (33) | 0 | 3 (43) | 0 | 2 (67) | 0 | 2 (33) | 0 | 1 (33) | 0 | 4 (50) | 2 (25) | 0 | 0 | 15 (43) | 2 (6) |
| Pleural effusion | 0 | 0 | 0 | 0 | 3 (43) | 1 (14) | 2 (67) | 1 (14) | 2 (33) | 1 (17) | 3 (100) | 2 (67) | 5 (63) | 2 (25) | 0 | 0 | 15 (43) | 7 (20) |
| Decreased appetite | 0 | 0 | 1 (33) | 0 | 2 (29) | 0 | 2 (67) | 0 | 5 (83) | 0 | 1 (33) | 0 | 1 (13) | 0 | 0 | 0 | 12 (34) | 0 |
| Fatigue | 3 (75) | 1 (25) | 0 | 0 | 2 (29) | 1 (14) | 2 (67) | 0 | 1 (17) | 0 | 1 (33) | 0 | 2 (25) | 0 | 0 | 0 | 11 (31) | 2 (6) |
| Peripheral edema | 0 | 0 | 0 | 0 | 2 (29) | 0 | 0 | 0 | 4 (67) | 1 (17) | 1 (33) | 0 | 4 (50) | 0 | 0 | 0 | 11 (31) | 1 (3) |
| Constipation | 2 (50) | 0 | 0 | 0 | 0 | 0 | 2 (67) | 0 | 2 (33) | 0 | 1 (33) | 0 | 3 (38) | 1 (13) | 0 | 0 | 10 (29) | 1 (3) |
| Cough | 0 | 0 | 1 (33) | 0 | 3 (43) | 0 | 1 (33) | 0 | 1 (17) | 0 | 0 | 0 | 3 (38) | 0 | 0 | 0 | 9 (26) | 0 |
| Pericardial effusion | 0 | 0 | 0 | 0 | 0 | 0 | 1 (33) | 0 | 2 (33) | 0 | 2 (67) | 1 (33) | 4 (50) | 0 | 0 | 0 | 9 (26) | 1 (3) |
| Nausea | 2 (50) | 0 | 0 | 0 | 0 | 0 | 1 (33) | 0 | 3 (50) | 0 | 1 (33) | 0 | 1 (13) | 0 | 0 | 0 | 8 (23) | 0 |
| Pyrexia | 1 (25) | 0 | 1 (33) | 0 | 0 | 0 | 0 | 0 | 3 (50) | 0 | 1 (33) | 0 | 2 (25) | 0 | 0 | 0 | 8 (23) | 0 |
| Photosensitivity reaction | 0 | 0 | 0 | 0 | 1 (14) | 0 | 1 (33) | 0 | 2 (33) | 0 | 0 | 0 | 3 (38) | 1 (13) | 0 | 0 | 7 (20) | 1 (3) |
| Hypoalbuminemia | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 (50) | 0 | 3 (100) | 2 (67) | 0 | 0 | 0 | 0 | 6 (17) | 2 (6) |
| Hypotension | 0 | 0 | 1 (33) | 0 | 1 (14) | 0 | 1 (33) | 0 | 1 (17) | 0 | 2 (67) | 0 | 0 | 0 | 0 | 0 | 6 (17) | 0 |
| Thrombocytopenia | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 (67) | 0 | 3 (38) | 2 (25) | 0 | 0 | 5 (14) | 3 (9) |
| Anemia | 0 | 0 | 0 | 0 | 1 (14) | 1 (14) | 0 | 0 | 0 | 0 | 0 | 0 | 3 (38) | 2 (25) | 0 | 0 | 4 (11) | 3 (9) |
| Decreased platelet count | 0 | 0 | 0 | 0 | 2 (29) | 1 (14) | 0 | 0 | 1 (17) | 0 | 1 (33) | 1 (33) | 0 | 0 | 0 | 0 | 4 (11) | 2 (6) |
| Hyponatremia | 0 | 0 | 0 | 0 | 0 | 0 | 2 (67) | 1 (33) | 1 (17) | 1 (17) | 1 (33) | 1 (33) | 0 | 0 | 0 | 0 | 4 (11) | 3 (9) |
| Pneumonia | 0 | 0 | 0 | 0 | 0 | 0 | 2 (67) | 1 (33) | 0 | 0 | 2 (67) | 1 (33) | 0 | 0 | 0 | 0 | 4 (11) | 2 (6) |
| Increased blood alkaline phosphatase | 1 (25) | 1 (25) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (33) | 1 (33) | 0 | 0 | 1 (100) | 0 | 3 (9) | 2 (6) |
| Pulmonary embolism | 0 | 0 | 1 (33) | 1 (33) | 0 | 0 | 1 (33) | 1 (33) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 (6) | 2 (6) |
AE, adverse event; Gr, grade; Q, every; W, weeks.
Nineteen AEs led to treatment discontinuation in 13 patients (37%). Among these, 6 patients experienced pleural effusion that was considered to have at least a reasonable possibility of being treatment related, including 4 patients with grade 3 serious pleural effusion (1 each in 0.1-, 0.3-, 0.4-mg/kg Q3W and 0.4-mg/kg Q9W dose groups) and 2 patients (1 each in 0.4-mg/kg Q3W and Q9W dose groups) with grade 2 nonserious pleural effusion. Two patients (1 each in the 0.4-mg/kg Q3W and Q9W dose groups) experienced a grade 2 pericardial effusion that was considered to have at least a reasonable possibility of being treatment related, with the Q3W group event considered serious. The remaining events occurred in 1 patient each. Serious events possibly related to treatment were grade 5 pneumonia, grade 3 confusional state in the 0.4-mg/kg Q3W group, and 1 patient with grade 2 hypoalbuminemia and acute kidney injury receiving 0.3 mg/kg Q3W. Serious AEs not considered to have reasonable possibility of being treatment related included grade 3 altered mental status and grade 2 atrial fibrillation in the 0.4-mg/kg Q9W dose group and grade 2 hypercalcemia in the 0.05-mg/kg Q3W dose group. The remaining events were nonserious. Grade 2 events of photophobia in the 0.2-mg/kg Q3W group and increased blood creatinine in the 0.3-mg/kg Q3W group and grade 1 fatigue in the 0.4-mg/kg Q9W dose group were considered possibly related to treatment. Grade 1 edema in the 0.4-mg/kg Q9W group was not considered to have reasonable possibility of being treatment related.
3.3. Pharmacokinetics
Preliminary PK analyses demonstrated dose-proportional maximum plasma concentration and area under the concentration-time curve, and an estimated terminal half-life of ∼9–13 days.
3.4. Efficacy
All patients (N = 35) were included in response analyses. Five patients (14%) overall achieved a PR per investigator assessment, with no patients achieving a CR. One patient each had a PR in the 0.2-and 0.3-mg/kg Q3W dose groups, and 3 patients in the 0.4-mg/kg Q9W dose group, Fourteen (40%) patients achieved stable disease as their best overall response, and 5 had no or an non-evaluable posttreatment scan. Eleven patients had progressive disease, including 1 patient enrolled in the dose expansion (0.2 mg/kg Q6W).
Nineteen patients had tumor samples that were able to be assessed for DLL3 expression by immunohistochemistry. DLL3-positive expression by immunohistochemistry (DLL3 >0%) was confirmed in 17 patients; 5 were DLL3 high (≥75% DLL3-positive cells). Of DLL3-positive patients, 2 (11.8%) achieved a PR, including 1 patient in the 0.2-mg/kg Q3W cohort and 1 DLL3-high patient in the 0.4-mg/kg Q9W cohort. The remaining patients had stable disease (n = 5, 29.4%; including 1 DLL3-high patient), progressive disease (n = 8, 47.1%; including 2 DLL3-high patients), or data were missing (n = 2, 11.8%; including 1 DLL3-high patient). Of the 2 patients with DLL3 = 0%, 1 had best response of SD and one had PD.
4. Discussion
In this first-in-human phase 1 study, we investigated the safety and preliminary efficacy of SC-002, an ADC designed to deliver the small-molecule toxin SC-DR002 to DLL3-expressing tumor cells. Our findings show that tolerability of SC-002 was reduced at higher doses that were associated with increased response. Overall safety findings revealed a high occurrence of grade 3 AEs, including AEs of pleural and pericardial effusion that frequently led to treatment discontinuation. In addition, 1 patient died due to pneumonia that was considered by the investigator to be treatment related. Collectively, these findings suggested that the toxicity profile of SC-002 was not substantially better than that of Rova-T. Therefore, the phase 1b expansion was stopped.
DLL3 is highly expressed in SCLC, but not in normal lung tissue, with an estimated 76% of SCLC tumor samples demonstrating cytoplasmic and/or membranous immunoreactivity for this Notch pathway inhibitory ligand [10]. Recent findings also suggest that DLL3 regulates the proliferation, migration, and invasion of SCLC cells, implicating it as a factor in neuroendocrine tumorigenesis [11]. Recent data suggest that DLL3 expression on circulating SCLC tumor cells could serve as a dynamic biomarker for treatment response and disease progression [12]. These and other preclinical findings provide rationale for targeting DLL3 with ADCs. Rova-T is the first ADC in which DLL3 was investigated as a therapeutic target in patients with previously treated SCLC [6]. In a phase 1 trial, Rova-T demonstrated encouraging single-agent antitumor activity with manageable safety in patients with SCLC. However, in subsequent studies, modest activity combined with associated toxicities led to the discontinuation of Rova-T [7]. SC-002 was designed to circumvent some of the liabilities of Rova-T through an improved conjugation strategy between antibody and warhead. However, the clinically observed toxicity profile of SC-002 was similar to that of Rova-T, specifically the association with pleural and pericardial effusion, edema, skin reactions, and thrombocytopenia. These AEs are believed to be the result of either premature cleavage of the PBD linker resulting in systemic release of the PBD payload, and/or potential back-release into circulation of the PBD warhead from lysed tumor or other cells [7]. Definitive data supporting these or other hypotheses are lacking, but these may explain why SC-002 did not have a reduction in toxicity compared with Rova-T.
In conclusion, our data suggest that the systemic toxicity and limited efficacy of SC-002, similar to the Rova-T ADC, indicate that this drug is unlikely to achieve the requisite level of benefit in this difficult-to-treat patient population. No further development is planned.
Highlights.
SC-002 is an antibody-drug conjugate targeting cells expressing delta-like ligand 3
SC-002 was designed for improved pharmacokinetics and safety compared with Rova-T
First-in-human phase 1 study of SC-002 in patients with advanced SCLC and LCNEC
SC-002 had toxicity and efficacy similar to Rova-T
No further development of SC-002 is planned
Acknowledgments
AbbVie and the authors thank the patients who participated in this clinical trial and all the study investigators, coordinators, and support staff for their contributions, including Bilal Tariq and Shekman Wong (pharmacokinetic analyses). Medical writing support was provided by Mary L. Smith, PhD, CMPP, Aptitude Health, Atlanta, GA, funded by AbbVie.
Financial support
AbbVie Inc. provided financial support for the study (NCT02500914) and participated in the design, study conduct, analysis and interpretation of data, as well as the writing, review, and approval of the manuscript.
Abbreviations
- ADC
antibody-drug conjugate
- AE
adverse event
- CR
complete response
- DLL3
delta-like ligand 3
- DLT
dose-limiting toxicity
- IV
intravenous
- LCNEC
large cell neuroendocrine carcinoma
- MTD
maximum tolerated dose
- ORR
objective response rate
- PBD
pyrrolobenzodiazepine
- PK
pharmacokinetics
- PR
partial response
- Q
every
- RECIST
Response Evaluation Criteria In Solid Tumors
- Rova-T
rovalpituzumab tesirine
- SAE
serious adverse event
- SCLC
small cell lung cancer
- TEAE
treatment-emergent adverse event
- W
weeks
Footnotes
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Trial registration number: NCT02500914
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Conflict of interest statements
Daniel Morgensztern: Consultant fees: AbbVie, Bristol-Myers Squibb, PharmaMar, Boehringer Ingelheim, Takeda.
Melissa Johnson: Research funding to institution: AbbVie, Acerta, Adaptimmune, Apexigen, Array BioPharma, AstraZeneca, Atreca, BeiGene, Birdie, Boehringer Ingelheim, Checkpoint Therapeutics, Corvus Pharmaceuticals, CytomX, Daiichi Sankyo, Dynavax, Lilly, EMD Serono, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Merck, Mirati Therapeutics, Neovia Oncology, Novartis, OncoMed Pharmaceuticals, Pfizer, Regeneron Pharmaceuticals, Sanofi, Shattuck Labs, Stemcentrx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, University of Michigan, WindMIL, TCR2 Therapeutics, Arcus Biosciences, Ribon Therapeutics, Amgen; consulting/advisory role (spouse): contract lobbyist for Astellas, contract lobbyist for Otsuka Pharmaceuticals; consulting/advisory role (self) — all to institution: AbbVie, Achilles Therapeutics, AstraZeneca, Atreca, Boehringer Ingelheim, Calithera Biosciences, Genentech, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Incyte, Janssen, Lilly, Loxo Oncology, Merck, Mirati Therapeutics, Novartis, Pfizer, Ribon Therapeutics, Sanofi, Association of Community Cancer Centers; food/beverage/travel expenses: AbbVie, Astellas, AstraZeneca, Boehringer Ingelheim, Clovis, Daiichi Sankyo, EMD Serono, Bristol-Myers Squibb, Exelixis, Genentech/Roche, Incyte, Merck, Pfizer, Sysmex Inostics, Vapotherm, Janssen, Lilly, Novartis, Sanofi.
Charles M. Rudin: Consultant for: AbbVie, Amgen, Ascentage, AstraZeneca, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Loxo, PharmaMar, and Vivotek. Scientific advisory boards of Bridge Medicines and Harpoon Therapeutics.
Michael Rossi, Mirella Lazarov, Daniel Brickman, Abraham Fong: AbbVie employees and may own stock.
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