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