Rova-T (rovalpituzumab tesirine) / AbbVie - LARVOL DELTA

Bispecific antibody drug conjugates (bsADCs) targeting DLL3 and B7-H3 demonstrated potent anti-tumor activity in preclinical models of small cell lung cancer (SCLC) (AACR 2025) - "Tarlatamab, a T cell engager targeting DLL3, was recently approved for SCLC...In vitro, the bsAbs showed superior internalization in double positive cell lines than the parental monovalent arms and outperformed the naked antibodies of DS-7300 and rovalpituzumab (Rova)...The bsAbs for our lead bsADCs exhibited excellent stability under stress conditions, suggesting their suitability for CMC development. In summary, our DLL3xB7H3 bsADCs showed promising and superior in vitro and in vivo preclinical activities with first-in-class potential for SCLC treatment."

Preclinical • Brain Cancer • CNS Tumor • Endocrine Cancer • Glioblastoma • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • CD276 • DLL3

AI-guided engineering and preclinical development of biparatopic anti-DLL3 antibody-drug conjugates (ADCs) (AACR 2025) - "An anti-DLL3 x CD3 bispecific T-cell engager, tarlatamab, has demonstrated significant clinical benefits and was recently approved by the US FDA for the treatment of DLL3-expressing SCLC. On the other hand, Rova-T, the first antibody-drug conjugate (ADC) targeting DLL3 entered advanced clinical development, failed in phase III studies due to insufficient efficacy and an unfavorable safety profile...The ADCs showed selective cytotoxicity towards multiple tumor cell lines with varying levels of DLL3 expression in vitro, and potently inhibited the growth of several DLL3-expressing tumor xenografts in animal models. Taken together, our findings underscore the significance of AI-guided antibody engineering and optimization, and provide support for the further development of the biparatopic anti-DLL3 ADCs in patients with DLL3-expressing tumors such as SCLC and other neuroendocrine tumors."

Preclinical • Endocrine Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • DLL3

Advances in adoptive cell therapies in small cell lung cancer. (PubMed, Explor Target Antitumor Ther) - "While investigated therapies such as rovalpituzumab tesirine (Rova-T) have failed, several insights from these trials have led to the development of compelling new agents such as sacituzumab govitecan (SG), ifinatamab deruxtecan (I-DXd), tarlatamab, and DLL3-targeted CAR-T cells. Advancing development of molecular testing and improving targeted approaches remain integral to pushing forward the progress of adoptive cell therapies in SCLC."

IO biomarker • Journal • Review • Gene Therapies • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • CD276 • DLL3

Comparison of two immunotoxins against DLL3 receptor; as an inhibitor for small cell lung cancer. (PubMed, Front Mol Biosci) - "In this study, we investigated the binding ability, cytotoxicity, apoptosis induction rate, and permeability of two immunotoxins based on the rovalpituzumab antibody...The designed immunotoxins in prokaryotic hosts exhibit good anticancer performance in A549 lung cancer cells. Additionally, the bacterial toxin-based immunotoxin has a greater ability to induce apoptosis compared to human enzymes and can be considered as a therapeutic option for SCLC cancer."

Journal • Infectious Disease • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • DLL3

Advances in DLL3-targeted therapies for small cell lung cancer: challenges, opportunities, and future directions. (PubMed, Front Oncol) - "The review highlights the challenges encountered in translating these promising approaches into clinical practice, including the setbacks faced by early DLL3-targeted therapies like Rovalpituzumab Tesirine (Rova-T)...The integration of cutting-edge technologies and interdisciplinary collaboration is proposed as a path forward to optimize DLL3-targeted therapies and improve outcomes for SCLC patients. This comprehensive overview provides insights into the current state and future directions of DLL3-targeted therapies, underscoring their potential to revolutionize SCLC treatment paradigms."

Journal • Review • Developmental Disorders • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • DLL3

Advances in DLL3-Targeted Therapies for Small Cell Lung Cancer: Challenges, Opportunities, and Future Directions (Front Oncol) - "The review highlights the challenges encountered in translating these promising approaches into clinical practice, including the setbacks faced by early DLL3-targeted therapies like Rovalpituzumab Tesirine (Rova-T). We also explore potential strategies to overcome these obstacles, emphasizing the need for a more nuanced understanding of DLL3 biology and its role in SCLC pathogenesis."

Review • Small Cell Lung Cancer

DB-1314, a novel DLL3-targeting ADC with DNA topoisomerase I inhibitor, exhibits promising therapeutic efficacy and safety profile in preclinical (EORTC-NCI-AACR 2024) - "DB131401 exerted high affinity and specificity to DLL3, and showed higher internalization activity than Rovalpituzumab...Our preclinical data provide a strong scientific rationale for the further development of DB-1314 for treatment of DLL3-positive cancers, including SCLC and NEPC."

Preclinical • Genito-urinary Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • DLL3

DB-1314, a novel DLL3-targeting ADC with DNA topoisomerase I inhibitor, exhibits promising safety profile and therapeutic efficacy in preclinical small cell lung cancer models. (PubMed, J Transl Med) - "These results suggest that DB-1314 may be a candidate ADC targeting DLL3 for the treatment of DLL3-positive SCLC, supporting further evaluation in the clinical setting."

Journal • Preclinical • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • DLL3

Antibody-drug conjugates treatment of small cell lung cancer: advances in clinical research. (PubMed, Discov Oncol) - "Although toxicities exceeding expectations have been observed with Rova-T, drugs targeting TROP-2 (Sacituzumab Govitecan), B7-H3 (DS-7300), and SEZ6 (ABBV-011) have shown exciting clinical benefits. In this review, we collect the latest clinical evidence to describe the therapeutic efficacy and safety of ADCs in SCLC and discuss prospects and challenges."

Journal • Review • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • CD276 • DLL3 • NCAM1 • SEZ6

FZ-AD005, A Novel DLL3-Targeted Antibody-drug Conjugate with Topoisomerase I Inhibitor, Shows Potent Antitumor Activity in Preclinical Models. (PubMed, Mol Cancer Ther) - "Rovalpituzumab tesirine (Rova-T) was the first DLL3-targeted antibody-drug conjugate (ADC) to enter clinical studies. The safety profile of FZ-AD005 was favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys. In conclusion, FZ-AD005 has the potential to be a superior DLL3-targeted ADC with a wide therapeutic window and is expected to provide clinical benefits for the treatment of SCLC patients."

Journal • Preclinical • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • DLL3

DLL3-guided therapies in small-cell lung cancer: from antibody-drug conjugate to precision immunotherapy and radioimmunotherapy. (PubMed, Mol Cancer) - "Although rovalpituzumab tesirine (Rova-T) showed promise in a phase II study, it failed to produce favorable results in subsequent phase III trials, leading to the cessation of its development...Tarlatamab, for instance, demonstrated enhanced response rates and progression-free survival compared to the standard of care in a phase II trial; its biologics license application (BLA) is currently under US Food and Drug Administration (FDA) review...DLL3-targeted therapies hold substantial potential for SCLC management. Future clinical trials will be crucial for comparing treatment outcomes among various approaches and exploring combination therapies to improve patient survival outcomes."

Journal • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ASCL1 • DLL3

Dr Leal on the Development of DLL3-Targeted Agents in SCLC (OncLive) - "Ticiana Leal, MD...sheds light on the DLL3-targeted agents in development for patients with small cell lung cancer (SCLC) and neuroendocrine tumors...Cytokine release syndrome (CRS) is a common toxicity with tarlatamab, HPN328, and BI 765432; however, most instances of CRS with these agents have been grade 1 or 2 and can be managed with supportive care and tocilizumab (Actemra), when necessary, Leal concludes."

Video

Unlocking New Horizons in Small-Cell Lung Cancer Treatment: The Onset of Antibody-Drug Conjugates. (PubMed, Cancers (Basel)) - "Despite the negative results of rovalpituzumab tesirine (Rova-T), other ADCs targeting different antigens, such as B7-H3, seizure-related homolog 6 (SEZ6), and CEACAM5, have also been investigated in clinical trials, including for SCLC, and their results suggest preliminary activity, either alone or in combination with other therapies. More recently, sacituzumab govitecan, an anti-TROP2 ADC, demonstrated promising activity in lung cancer, including SCLC. Furthermore, an anti-B7-H3 (CD276), ifinatamab deruxtecan (DS7300A), showed a high response rate and durable responses in heavily pretreated SCLC...Further studies are needed to determine their efficacy and safety and the best location in the treatment algorithm for SCLC. In this review, we aim to collect and describe the results regarding the past, the present, and the future of ADCs in SCLC."

Journal • Review • CNS Disorders • Epilepsy • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • CD276 • CEACAM5 • SEZ6

Novel nomogram based on the expression of DLL3 and PD-L1 for predicting the prognosis of small cell lung cancer patients (ESMO 2023) - "Delta-like ligand 3 (DLL3)-targeted drug Rova-T was terminated due to insufficient efficacy, considering other factors that may affect efficacy...In addition, patients were divided into low-risk and high-risk for survival analysis based on the best cut-off value of 49.11 for nomogram, indicating that the model had great discrimination ability (mOS 13.33 vs. 7.80m, p<0.001). Table: 2018P Conclusions The OS prediction model for SCLC patients in this study has excellent predictive performance in predicting the 12-m survival probability and may assist clinicians in making more accurate judgments and guiding therapy of SCLC patients."

Clinical • IO biomarker • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • DLL3 • PD-L1

Delta-like ligand 3 in small cell lung cancer: potential mechanism and treatment progress. (PubMed, Crit Rev Oncol Hematol) - "The Phase III clinical trials of Rova-T, a drug targeting DLL3, have not yielded the expected results. However, other drugs that target DLL3, such as AMG119, AMG757 and DLL3-targeted NIR-PIT, bring new ideas for SCLC treatment. Overall, DLL3 remains a valuable target for SCLC."

Journal • Review • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • DLL3

Dr. Tagawa on the Evolution of ADCs in mCRPC (OncLive) - "Scott Tagawa, MD, MS, FACP, discusses the evolution of antibody-drug conjugates in metastatic castration-resistant prostate cancer, as well as potential future targets for ADC development in this space."

Video

Emerging therapies targeting the delta-like ligand 3 (DLL3) in small cell lung cancer. (PubMed, J Hematol Oncol) - "First, we discuss the clinical experience with rovalpituzumab tesirine (Rova-T), a DLL3-targeting ADC, the development of which was halted due to a lack of efficacy in phase 3 studies, with a view to understanding the lessons that can be garnered for the rapidly evolving therapeutic landscape in SCLC. We then review preclinical and clinical data for several DLL3-targeting agents that are currently in development, including the TCE molecules-tarlatamab (formerly known as AMG 757), BI 764532, and HPN328-and the CAR T-cell therapy AMG 119. We conclude with a discussion of the future challenges and opportunities for DLL3-targeting therapies, including the utility of DLL3 as a biomarker for patient selection and disease progression, and the potential of rational combinatorial approaches that can enhance efficacy."

IO biomarker • Journal • Review • Endocrine Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • DLL3

DLL3 Targeting Agents (IASLC-WCLC 2019) - P1, P2, P3; "An active phase 3 trial of Rova-T in the maintenance setting (MERU) is ongoing (NCT03033511).Other DLL3-targeting therapies under active investigation include the bispecific T cell engager (BiTE) AMG 757 (NCT03319940), and a chimeric antigen receptor CAR-T AMG119 (NCT03392064). Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol 18, 42-51, doi:10.1016/S1470-2045(16)30565-4 (2017)."

IO biomarker • IO Companion diagnostic • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer

A phase 1/2 study on safety of rovalpituzumab tesirine in combination with nivolumab or nivolumab + ipilimumab in small cell lung cancer (ESMO 2017) - P1/2; "1. Rudin et al., Lancet Oncol, 2016."

Biomarker • Clinical • Combination therapy • P1/2 data • Neuroendocrine Tumor • Small Cell Lung Cancer

Ph1/2 study of Rova-T in combination with nivolumab (Nivo) ipilimumab (Ipi) for patients (pts) with 2L+ extensive-stage (ED) SCLC. (ASCO 2019) - P1/2; "Despite activity in 2L+ ED-SCLC, Rova-T with Nivo/Ipi is not appropriate due to DLTs. Rova-T/Nivo demonstrated some durable responses; however, the safety data suggest that optimization of dose and schedule is warranted. NCT03026166.*G5 (all in C1): pneumonitis (2), acute kidney injury (1), malignant neoplasm progression (1)."

Clinical • Combination therapy • IO biomarker • PD(L)-1 Biomarker • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer

Rovalpituzumab tesirine enhances the anti-tumor efficacy of PD-1 blockade in a murine model of small cell lung cancer with endogenous Dll3 expression (AACR 2019) - P1, P1/2; "In contrast, a single cycle of cisplatin + etoposide (C/E) standard of care chemotherapy alone showed some tumor burden reduction, but no additive activity was seen for combination C/E + anti-PD1 mAb. Mice treated with a single efficacious dose of Rova-T alone or Rova-T + anti-PD1 showed durable tumor suppression (>50 days) and did not develop tumors when re-injected with 1 million tumor cells on the opposite flank, indicating that treatment conferred immunologic memory and sustained anti-tumor immunity. Together, these data provide pre-clinical rationale for the ongoing combination SCLC clinical trials of Rova-T and Nivolumab (NCT03026166) and Rova-T and ABBV-181 (NCT03000257)."

IO biomarker • PD(L)-1 Biomarker • Tumor mutational burden • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer

Rovalpituzumab Tesirine vs Topotecan in Patients with Advanced Small Cell Lung Cancer Following 1st Line Chemotherapy (WCLC 2017) - P3; "...Arm A regimen: 0.3 mg/kg Rova-T intravenous (IV) on Day 1 + 8 mg dexamethasone orally, twice daily on Day -1, 1 and 2 of a 42-day cycle; administered for 2 cycles with up to 2 additional cycles permitted...Pt eligibility: ≥ 18 years; confirmed, advanced/metastatic SCLC with first disease progression following frontline standard therapy; DLL3-high tumor expression; ECOG 0-1; no prior exposure to a pyrrolobenzodiazepine-based drug or topotecan, irinotecan, or other topoisomerase I inhibitor...Section not applicable"

Clinical • Quality Measures • Neuroendocrine Tumor • Small Cell Lung Cancer

Future Directions (IASLC-WCLC 2018) - P1/2, P1b, P2, P3; "...To date, two ADCs have entered clinical practice, brentuximab vedotin for hematological malignancies and trastuzumab emtansine in advanced breast cancer overexpressing human epidermal growth factor receptor 2 (HER2) [1]...In fact, the two ADCs currently underway in most advanced phases of clinical trials are rovalpituzumab tesirine for SCLC and anetumab emtansine for unresectable mesothelioma; however, with suboptimal early results [2;3]...Notably, a phase I/II trial of anetumab plus atezolizumab in advanced NSCLC patients has already been planned [9]...Long and winding is the path for the ADC entry in NSCLC clinical practice. However, the rapidly evolving landscape in tumor sequencing and proteomics along with the clinical research experiences, may pave the way to find the most appropriate setting for ADCs in terms of manageable side effects and NSCLC patients’ selection. "

HER2 Breast Cancer • Leukemia • Mesothelioma • Non Small Cell Lung Cancer • Small Cell Lung Cancer

A phase 3 trial of rovalpituzumab tesirine vs topotecan in patients with advanced small cell lung cancer following frontline platinum-based chemotherapy (ESMO 2017) - P3; "...Arm A regimen: 0.3 mg/kg Rova-T intravenous (IV) on Day 1 + 8 mg dexamethasone orally, twice daily on Day -1, 1 and 2 of a 42-day cycle; administered for 2 cycles with up to 2 additional cycles permitted...Pt eligibility: ≥ 18 years; confirmed, advanced/metastatic SCLC with first disease progression following frontline standard therapy; DLL3-high tumor expression; ECOG 0-1; no prior exposure to a pyrrolobenzodiazepine-based drug or topotecan, irinotecan, or other topoisomerase I inhibitor. Primary objectives: to determine if Rova-T improves objective response rate and overall survival vs topotecan. Secondary objectives: to assess if Rova-T improves progression-free survival vs topotecan; to compare duration of objective response between arms; and to assess effect on patient-reported outcomes."

Clinical • P3 data • Neuroendocrine Tumor • Small Cell Lung Cancer

An open-label study on safety and tolerability of rovalpituzumab tesirine in Japanese patients with advanced, recurrent small cell lung cancer (ESMO 2017) - P1; "Pts will receive Rova-T 0.2, 0.3, or 0.4 mg/kg intravenously on Day 1 of each 6-week cycle x 2 doses and dexamethasone 8 mg orally twice daily on Day -1, Day 1, and Day 2 of each 6-week cycle. 1. Rudin et al., Lancet Oncol, 2016."

Clinical • Neuroendocrine Tumor • Small Cell Lung Cancer