A Phase 1 Study Evaluating Rovalpituzumab Tesirine in Frontline Treatment of Patients With Extensive-Stage SCLC

Abstract

Introduction: Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, a Notch pathway ligand highly expressed on SCLC cells. Rova-T was evaluated alone or in combination with platinum-based chemotherapy (cisplatin or carboplatin combined with etoposide [CE]) in frontline treatment of extensive-stage SCLC.Methods: One cycle of CE pre-enrollment was permitted (later mandated). The following four cohorts were enrolled: Rova-T monotherapy (0.3 mg/kg, every 6 [q6] wk  2; cohort 1; n ¼ 4); Rova-T induction (0.3 mg/kg, q6 wk  2) followed by CE every 21 days (q21)  4 (cohort 2; n ¼ 5); Rova-T (0.1 or 0.2 mg/kg, q6 wk  2) overlapping with CE q21  4 (cohort 3; n ¼ 14); and Rova-T maintenance (0.3 mg/kg, q6 wk  2) after CE q21  4 (cohort 4; n ¼ 3).Results: A total of 26 patients were dosed (cohort 3: 14; cohorts 1, 2, and 4 combined: 12). Median age was 66 years, and 73% had Eastern Cooperative Oncology Group performance status of 1. In cohort 3, seven patients (50%) had

Dissecting Immunotherapy Strategies for Small Cell Lung Cancer: Antibodies, Ionizing Radiation and CAR-T

“…Rovalpituzumab tesirine (Rova-T) is an IgG1 which binds DLL-3 and it has been conjugated with the cytotoxic pyrrolobenzodiazepine (PDB) dimer [ 101 , 102 ]. Rova-T has been evaluated in different settings and schedules (alone or in combination with platinum-based chemotherapy or immunotherapy) for the treatment of SCLC, however, many toxicities or efficacy issues were highlighted, and its development was discontinued [ 103 , 104 , 105 , 106 , 107 ]. In particular, Rova-T monotherapy failed in demonstrating its effectiveness as a second line treatment (compared with topotecan) in a phase 3 trial and as a maintenance treatment after first-line chemotherapy (compared with placebo) [ 104 , 106 ].…”

Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives

“…Another phase I/II CT evaluated the tolerability of agents in delta-like protein 3-expressing advanced solid tumors (melanoma, medullary thyroid cancer, glioblastoma, various NET) and revealed some signs of context-dependent benefit, expressed as 4.3-22.6% objective response rate (ORR) (NCT02709889). Due to the suboptimal results of clinical trials, its development has been terminated [246]. The third DLL3-targeting approach (NCT03392064) uses CAR-T cells modified to recognize DLL3-positive cells and opens the road for the development of personalized therapies in NETs overexpressing this Notch ligand [247].…”

“…The phase II trial assessing the addition of etoposide and OMP-59R5 to cisplatin or carboplatin as the first-line therapy for extensive SCLC showed a lower frequency of disease progression or death in the group of tarextumab+etoposide addition to cisplatin/carboplatin compared to placebo during 1 year observation; however, it was not considered as an improved PFS, and it did not correspond to the increase in the frequency of ORR, confirming the controversial benefit of Notch inhibition in this lung cancer (NCT01859741). Moreover, the combination of Rova-T, composed of a human DLL3-specific mAb and the DNA-crosslinking agent and cisplatin + etoposide, did not add benefit to chemotherapy alone in terms of ORR and OS (NCT02819999), did not improve OS after the first-line platinum-based therapy (NCT03033511), and had worse OS and PSF compared to topotecan as the second-line approach (NCT03061812) [240,241,246]. A detailed description of the above-mentioned CT is shown in Table 2.…”

Treatment of small cell lung cancer: recent advances

“…Following these observations, DLL3 might be correlated with neuroendocrine phenotype and helps to neuroendocrine tumorigenesis. A phase 1 study investigated rovalpituzumab tesirine (Rova-T) alone or with chemotherapy as frontline therapy of ES-SCLC [38]. Low-doses of Rova-T may be related to decreased adverse events, however, there was no favorable outcomes with the addition of Rova-T.…”