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

Incidence and Severity of Interstitial Lung Disease Associated With Antibody-Drug Conjugates in NSCLC and SCLC: A Meta-Analysis (IASLC-WCLC 2025) - "In NSCLC, the highest pooled incidence of any-grade ILD was seen with patritumab deruxtecan (23%) and trastuzumab deruxtecan (22%), followed by datopotamab deruxtecan (9%), telisotuzumab vedotin (7%), and sacituzumab govitecan (1%)...Treatment discontinuation due to ILD in NSCLC was highest with telisotuzumab vedotin combined with erlotinib (36%), followed by trastuzumab deruxtecan (9%) and patritumab deruxtecan (7%)...In SCLC, any-grade ILD incidence was 8% with rovalpituzumab tesirine, with no reported grade ≥3 ILD events...HER2/HER3-targeted, deruxtecan-containing ADCs demonstrated the highest ILD rates, while other ADCs such as sacituzumab govitecan had minimal reported toxicity. These findings highlight the need for agent-specific ILD monitoring and support the consideration of ADC design, including target and payload, when evaluating pulmonary safety and guiding clinical decision-making."

Retrospective data • Interstitial Lung Disease • Lung Cancer • Non Small Cell Lung Cancer • Pulmonary Disease • Respiratory Diseases • Small Cell Lung Cancer • Solid Tumor • ERBB3 • HER-2

DLL3-directed immune redirection in small-cell lung cancer: a lineage-defined vulnerability that doubles as an escape route. (PubMed, Front Immunol) - "Delta-like ligand 3 (DLL3) is the first tumor cell surface antigen in small cell lung cancer (SCLC) to support an approved T-cell-redirecting therapy with demonstrated survival benefit, namely the DLL3×CD3 bispecific T-cell engager tarlatamab...The failure of rovalpituzumab tesirine does not establish that DLL3 is intrinsically unsuitable for payload delivery; rather, it highlights the construct-specific challenge of achieving a sufficient therapeutic index with a PBD-based antibody-drug conjugate...The lineage-defined vulnerability that the therapy exploits can thus double as the route of escape. We propose that next-generation strategies should be organized by the axis they are designed to preserve, and that the operative clinical question should shift from baseline DLL3 positivity toward the durability of antigen availability and effector function."

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

Decoding Small Cell Lung Cancer: Molecular Subtypes, Surface Antigens, and the Target-Modality Problem. (PubMed, Cancers (Basel)) - "Second, the development of delta-like ligand 3 (DLL3)-directed therapies provides a natural experiment: the same validated surface antigen failed as an antibody-drug conjugate (rovalpituzumab tesirine, three negative randomized trials) yet succeeded as a bispecific T-cell engager (tarlatamab, which received FDA accelerated approval in 2024 and subsequent traditional FDA approval in 2025 following positive confirmatory phase 3 data). In this review, we integrate the current first-line standard of care-chemoimmunotherapy with atezolizumab- or durvalumab-based regimens followed by maintenance intensification with lurbinectedin-atezolizumab (IMforte)-with the molecular framework of subtypes and biomarkers, and we use DLL3 as a case study to propose that delivery modality is an important determinant of therapeutic success in SCLC and should be considered alongside target biology and tumor heterogeneity...The emerging B7-H3 and SEZ6 programs-including ifinatamab deruxtecan and..."

IO biomarker • Journal • Review • CNS Disorders • Lung Cancer • Oncology • Psychiatry • Small Cell Lung Cancer • Solid Tumor • ASCL1 • CD276 • DLL3 • NEUROD1 • POU2F3 • RB1 • SEZ6 • TP53

Prevalence of Antibody Drug Conjugated-Induced Nausea and Vomiting (ADCINV) in Patients with Cancer (MASCC-ISOO 2026) - "Higher emetogenic ADCs include trastuzumab deruxtecan, sacituzumab govitecan, bretuximab vedotin, and patritumab deruxtecan. Lower emetogenic agents include disitimab vedotin, telisotuzumab vedotin, and rovalpituzumab tesirine. Conclusions This is the first study to report prevalence of ADCINV across ADCs. It is a prevalent adverse effect akin to chemotherapy-induced nausea and vomiting, that should be viewed as clinically relevant and further investigated to help develop optimal strategies related to antiemetics."

ADC • Clinical • Chemotherapy-Induced Nausea and Vomiting • Oncology

Characterizing the prevalence of antibody-drug conjugated–induced nausea and vomiting (ADCINV) in patients with cancer. (ASCO 2026) - "Higher nausea rates were observed with patritumab deruxtecan (59%), trastuzumab deruxtecan (55%), sacituzumab govitecan (51%), and brentuximab vedotin (47%), while lower rates were seen with disitamab vedotin (28%), telisotuzumab vedotin (22%), rovalpituzumab tesirine (19%), and belantamab mafodotin (6%). ADCINV is prevalent adverse effect, affecting every one in three patients with no standard prophylactic regimen to date. Severe nausea and vomiting rates remain relatively low. Younger patients, females and specific ADCs may be at higher risk."

ADC • Clinical • Oncology

Prevalence of antibody drug conjugated-induced nausea and vomiting (ADCINV) in patients with cancer. (PubMed, Support Care Cancer) - "This is the first study to report prevalence of ADCINV across ADCs. It is a prevalent adverse effect akin to chemotherapy-induced nausea and vomiting that should be viewed as clinically relevant and further investigated to help develop optimal strategies related to antiemetics."

Journal • Review • Chemotherapy-Induced Nausea and Vomiting • Oncology

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."

ADC • Bispecific • Preclinical • Brain Cancer • CNS Tumor • Endocrine Cancer • Glioblastoma • Lung Cancer • Neuroendocrine Carcinoma • 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."

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

A novel nomogram based on DLL3 and PD-L1 for predicting the prognosis of patients with small cell lung cancer. (PubMed, BMC Cancer) - "The prognostic model developed in this study offers predictive value in estimating 12-month survival probability for SCLC patients, aiding clinicians in making more informed treatment decisions."

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

Bispecific antibody-drug conjugates targeting DLL3×B7-H3 and DLL3×SEZ6 demonstrate potent anti-tumor activity in preclinical models of small-cell lung cancer (SITC 2025) - "Despite the approval of tarlatamab and ongoing development of DLL3- or B7-H3-targeted ADCs, tumor relapse and heterogeneity in target expression continue to pose challenges...We used in vitro internalization activity, in vivo anti-tumor efficacy in SCLC CDX or PDX models, and developability screening as primary selection criteria.Results The DLL3×B7-H3 bsAb showed stronger internalization in double positive cell lines than the parental monovalent arms and outperformed the naked antibodies of DS-7300 and rovalpituzumab (Rova)...The DLL3×SEZ6 bsADC demonstrated comparable efficacy to benchmark with same payload and showed more potent anti-tumor efficacy than parental monovalent ADCs in SCLC CDX models.DLL3×B7-H3 and DLL3×SEZ6 bsAbs exhibited excellent stability under stress conditions, suggesting them as promising candidates for CMC development.Conclusions DLL3×B7-H3 and DLL3×SEZ6 bsADCs represent two novel and complementary strategies for..."

Preclinical • Endocrine Cancer • Lung Cancer • Neuroendocrine Carcinoma • Oncology • Small Cell Lung Cancer • Solid Tumor • CD276 • DLL3 • SEZ6 • TOP1

Impact of DLL3 isoforms on DLL3-targeting antibody therapies (ESMO 2025) - "Background DLL3 can now be targeted in small cell lung cancer (SCLC) with the approval of the bispecific T cell engager tarlatamab (Tarla). Previous efforts to target DLL3 with the antibody drug conjugate rovalpituzumab tesirine (Rova-T) were not successful...The effects of isoforms on epitope retention and target affinity are underappreciated and may contribute to failure of antibody-based therapies. Legal entity responsible for the study The authors."

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

DLL3 expression in small round cell tumors: a potential therapeutic target for SMARCA4-deficient tumors (ECP 2025) - "Rova-T demonstrated dose-dependent efficacy against both H661 (IC50=0.07686 μM) and H82 (IC50=0.1061 μM), with BEAS-2B showing similar sensitivity (IC50=0.09885 μM)... DLL3 is expressed in a subset of SRTs, with significantly higher rates in SMARCA4-dUT. The association between DLL3 and synaptophysin suggests neuroendocrine differentiation. These findings identify DLL3 as a potential therapeutic target for SMARCA4-dUTs, warranting further investigation the absence of survival differences in our clinical cohort."

Ewing Sarcoma • Lung Cancer • Neuroblastoma • NUT Midline Carcinoma • Oncology • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Small Cell Lung Cancer • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma • DLL3 • SMARCA4 • SMARCB1 • SYP

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."

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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