Rova-T (rovalpituzumab tesirine)

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.

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.

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.

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.

Delta-like canonical Notch ligand 3 is a protein frequently overexpressed in SCLC and is therefore being explored as a potentially promising therapeutic target in high-grade neuroendocrine lung cancer. In this article, we critically review the activity and efficacy of old DLL3 inhibitors antibody-drug conjugate (ADC) and their failures through new compounds and their possible applications in clinical practice, with a focus on new molecular classification of SCLC.

Strong membranous staining was necessary, but not sufficient, for anti-tumor activity. Rova-T has activity in a subset of neuroblastoma preclinical models, but heterogeneous expression in these models and the near absence of expression seen in human tumors suggests that any DLL3-targeting clinical trial should be only performed with a robust companion diagnostic to evaluate DLL3 expression for patient selection.

The immunotoxins had the right structure and can be produced in a prokaryotic host. The recombinant immunotoxins against DLL3 can be promising therapeutic agents for SCLC cancer.

ADC agents including trastuzumab emtansine, trastuzumab deruxtecan, sacituzumab govitecan, enfortumab vedotin, and rovalpituzumab tesirine were highly studied. Further clinical trials of ADCs and designs of the next generation of ADCs are the current focuses of the field. Acquired resistance of ADCs and biomarkers for ADC therapy efficacy monitoring are future concerns.

P1, N=182, Completed, AbbVie | Active, not recruiting --> Completed

"Third-line therapies included rovalpituzumab tesirine (n=1), checkpoint kinase 1 inhibitor (n=1), irinotecan (n=1), or paclitaxel (n=4). In patients with relapsed SCLC, early clearance of ctDNA predicts an improvement in PFS and OS, and an early increase in peak VAF suggests chemoresistance. Larger cohorts are needed to validate this finding, and we are currently compiling additional patients and samples for a larger analysis."

Antibody-drug conjugates (ADCs) are rapidly establishing their place and have shown promising preliminary data in lung cancer with impressive response rates and survival outcomes in previously treated patients.There are several ADCs currently in clinical trials for NSCLC and small cell lung cancer (SCLC). These ADCs often have different targets which include HER2, HER3, TROP2, CEACAM5, and MET in NSCLC and DLL3 in SCLC.Here we review the safety, and efficacy of newer ADCs in lung cancer including ado-trastuzumab emtansine, trastuzumab deruxetecan, patritomab deruxetecan, datopotamab deruxetecan, sacituzumab govitecan, SAR408701, Telisotuzumab vedotin, rovalpituzumab tesirine, lorvotuzumab mertansine, and sacituzumab govitecan.  Several novel methods are underway to improve the safety and efficacy of ADCs which include increasing the drug to antibody ratio (DAR), the potency of the payload, using more innovative payloads and replacing the antibody.

Small cell lung cancer (SCLC) is frequently found disseminated at first presentation and holds a poor prognosis due to emerging resistance to first-line platinum-based and second-line topotecan chemotherapy. Chemosensitivity of the cell lines is not correlated with DLL3 protein expression possibly due to toxicity of the free payload in tissue culture. The clinical trials and experimental results demonstrate that refractoriness to ROVA-T is linked to a low initial tumor expression of DLL3, loss of DLL3 expression, higher chemoresistance to ROVA-T and the putative formation of resistant spheroids by the SCLC cells.

Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate directed against Delta-like protein 3 (DLL3), is under development for patients with small cell lung cancer (SCLC). Unlike in chemonaive samples, a high DLL3 expression in chemorelapsed samples indicated a trend for a more favorable prognosis. Our results highlight the importance to investigate DLL3 in latest chemorelapsed SCLC tumor tissue.

Lower Rova-T doses may be associated with lower incidence of some Rova-T-related AESI. Rova-T 0.2 mg/kg + CE (Cohort 3) was tolerable; however, there was no clear efficacy benefit of adding Rova-T to CE.

However, the development of ROVA-T was suspended because of shorter overall survival compared to topotecan, the second-line standard treatment. Thus, several studies on the mechanism and function of DLL3 in several malignancies are underway to find a new strategy for targeting DLL3. In this review, we discuss the roles of DLL3 in various malignancies and the future perspectives of DLL3-related research, especially as a therapeutic target.

A DLL3-targeted antibody-drug conjugate, rovalpituzumab tesirine (Rova-T) has recently been developed for treatment of SCLC...The patients with ASCL1 and DLL3 high expression may represent a distinct subgroup of SCLC benefit from targeted therapy. Therefore, ASCL1 and DLL3 could be potential biomarkers served for selection of related patients.

Responses were confirmed in 15/145 patients (10%) treated at 0.3 mg/kg, including 9/69 patients (13%) with NEC/NET. Rova-T at 0.3 mg/kg q6w had manageable toxicity, with antitumor activity observed in patients with NEC/NET, melanoma, MTC, and glioblastoma.

Combination therapy with budigalimab and Rova-T had promising efficacy and appeared to be tolerated in patients with SCLC. Although Rova-T development has been discontinued, development of budigalimab combined with other anticancer agents is ongoing.

P1, N=182, Active, not recruiting, AbbVie | Trial completion date: Mar 2021 --> May 2022 | Trial primary completion date: Mar 2021 --> May 2022

Due to the lack of survival benefit in the Rova-T arm, the study did not meet its primary endpoint and was terminated early. As a result, CRAC assessment of PFS was not performed. The frequency of Grade ≥3 and drug-related toxicities were higher with Rova-T vs placebo. Rova-T was associated with unique toxicities such as pleural and pericardial effusions, photosensitivity reaction, and peripheral edema, which should be carefully considered in the ES SCLC population.

Despite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab ± ipilimumab was not well tolerated at the dose levels and administration schedules evaluated.

Compared with topotecan, which is the current standard second-line chemotherapy, Rova-T showed an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. Significant unmet therapeutic need remains in this population.

Confirmed partial responses were observed in 24% of patients. Based on the evaluation of ECG data collected in this study from patients treated with Rova-T at 0.3 mg/kg i.v. administered every 6 weeks, a QTcF effect of clinical concern can be excluded.

Therefore, we investigated the potential effect of combining Rova-T and CBL in SCLC to eradicate TICs more effectively. Our preclinical studies report a novel and highly translatable therapeutic strategy of dual targeting TICs using Rova-T in combination with CBL to potentially increase survival of SCLC patients.

Despite frequent DLL3 expression in NEC, a potential therapeutic benefit of DLL3-targeted drugs remains uncertain given the recent failure of the Rova-T therapeutic trial in small cell lung carcinomas. Small cohorts of NEC enriched in PIK3CA/PTEN/AKT and programmed cell death protein 1/PD-L1 alterations indicate therapeutic roles for their respective inhibitors.

Lurbinectedin, which targets active transcription, has shown activity in platinum-sensitive and platinum-resistant SCLC as monotherapy and in combination with doxorubicin. Aurora A kinase (AAK) inhibitors showed initial activity when given with paclitaxel but in randomized studies, failed to improve outcomes over paclitaxel plus placebo...Delta-like protein 3 (DLL3) is an appealing therapeutic target given its selective expression on SCLC cells, but after initial exciting results, the antibody-drug conjugate (ADC) Rovalpituzumab tesirine (Rova-T) did not have a favorable efficacy to toxicity profile in randomized trials...Targeting angiogenesis has yielded modest improvements in the past but newer agents such as anlotinib are renewing interest. While the current therapeutic landscape beyond chemo-immunotherapy remains the same as it was decades ago, drug development for SCLC is rapidly moving forward and promises to deliver the needed novel agents in the very near future.

Mice previously treated with Rova-T + anti-PD1 withstood tumor re-challenge, demonstrating sustained anti-tumor immunity. Collectively our pre-clinical data support clinical combination of sub-efficacious Rova-T with anti-PD1 to extend the benefit of immune checkpoint inhibitors to more SCLC patients.

Small‑molecule γ‑secretase inhibitors (AL101, MRK‑560, nirogacestat and others) and antibody‑based biologics targeting Notch ligands or receptors [ABT‑165, AMG 119, rovalpituzumab tesirine (Rova‑T) and others] have been developed as investigational drugs...Phase III clinical trials of Rova‑T for patients with small‑cell lung cancer and a phase III clinical trial of nirogacestat for patients with desmoid tumors are ongoing. Integration of human intelligence, cognitive computing and explainable artificial intelligence is necessary to construct a Notch‑related knowledge‑base and optimize Notch‑targeted therapy for patients with cancer.

Although a recent phase 2 trial with lurbinectidin has shown promising activity, topotecan continues to be the only approved drug in the Western World for second line therapy, but its activity in platin resistant disease is rather limited and participation in clinical trials with novel agents may be the preferred option for many of these patients...Similarly, the anti-body drug conjugate Rovalpituzumab Tesirin (Rova-T) which targets the NOTCH pathway by binding to the delta like-ligand 3 (DLL3) also failed to improve outcomes as maintenance therapy or as second line treatment in phase III trials...Whether PCI or prophylactic thoracic irradiation improve outcomes of patients with metastatic disease remains controversial. Finally, major improvements of the dismal prognosis of patients with metastatic SCLC will only be possible with a better understanding of the tumor biology and the identification of predictive markers.

P1, N=221, Recruiting, AbbVie | Trial primary completion date: Sep 2021 --> Dec 2021

Delta-like protein 3 (DLL3) is being developed as a predictive biomarker to identify patients for treatment with DLL3-targeting agents. Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. We found that DLL3 overexpression is very common in MCC by immunohistochemistry and significantly associated with Merkel cell polyomavirus expression. Despite the lack of prognostic significance in this cohort, DLL3 expression may have predictive relevance for DLL3-targeting therapies in MCC. The high levels of DLL3 expression in a subset of MCC may potentially be used to select patients to receive DLL3-targeting therapies.

Rova-T was tolerable in patients with advanced solid tumors at 0.3 mg/kg q6wk for 2 cycles. Antitumor activity was observed in patients with NEC, MM, MTC, SCC, and GBM. Research Funding: Abbvie, Inc

DLL3 is selectively and homogeneously expressed in IDH mutant gliomas and can be targeted with Rova-T in patient-derived IDH mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens.

Background: Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target expressed in more than 80% of patients with small-cell lung cancer (Rudin et al., Lancet Oncol 2017)... We optimized an RNAish assay to evaluate DLL3 expression – a therapeutic target - in CRPC. A signficant number of cases – especially CRPC-NE – overexpress DLL3. Future studies will establish the potential application of this assay as a potential predictive biomarker for CRPC patients who are candidates for DLL3 targeted therapy.

A number of agents thought to be very promising, including the antibody drug conjugate Rova-T, and PARP inhibitors have yielded negative results...We will discuss promising new agents such as lurbinectedin, and EZH2 inhibitors and DNA damage response modifiers.A number of molecular vulnerabilities of SCLC have been identified...These new insights will be discussed in this presentation. The most significant advancements in the last year shown in Figure 1 below will be described