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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Rovalpituzumab tesirine (Rova-T), another example of an ADC utilizing a PBD dimer as a payload, was developed by StemCentrx which was later acquired by AbbVie. Rova-T was based on an anti-DLL3 antibody targeted to small-cell lung cancer, conjugated to a less-hydrophobic PBD dimer analog known as teserine. This ADC reached Phase III clinical trials but progression was also halted due to an overall lack of efficacy.
Antibodies to watch in 2020
Published in mAbs, 2020
Hélène Kaplon, Mrinalini Muralidharan, Zita Schneider, Janice M. Reichert
Rovalpituzumab tesirine is an ADC composed of a humanized IgG1 antibody targeting delta-like ligand (DLL3) conjugated to the cytotoxic pyrrolobenzodiazepine dimer D6.5 via a protease-cleavable linker. DLL3 is over-expressed in small cell lung cancer cells, and clinical development of this ADC was focused on small cell lung cancer. Study results, however, showed modest clinical activity. In the Phase 2 TRINITY study (NCT02674568), the ORR was 12.4%, 14.3%, and 13.2% in all, DLL3-high, and DLL3-positive patients, respectively; DLL3-positive and DLL3-high were defined as ≥25% and ≥75% of tumor cells positive for DLL3, respectively. Median OS was 5.6 months in all patients.104 On August 29, 2019 AbbVie announced that the Phase 3 MERU study (NCT03033511), which was evaluating rovalpituzumab tesirine as a first-line maintenance therapy for advanced small cell lung cancer, demonstrated no survival benefit at a preplanned interim analysis for patients receiving the drug as compared with placebo. The MERU trial is being closed, and the research and development program for rovalpituzumab tesirine has been terminated.105
Current and future therapeutic approaches for the treatment of small cell lung cancer
Published in Expert Review of Anticancer Therapy, 2018
Antonio Rossi, Rebecca Tay, Jaseela Chiramel, Arsela Prelaj, Raffaele Califano
Rovalpituzumab tesirine (Rova-T) is a first-in-class antibody-drug conjugate directed against DLL3. It comprises of a DLL3-targeting IgG1 monoclonal antibody tethered to a DNA cross-linking toxin. In a phase I study, Rova-T demonstrated antitumor activity and manageable safety in a cohort of 84 SCLC and LCNEC patients, including 74 patients with recurrent SCLC [93]. The most frequent grade ≥3 adverse events were thrombocytopenia (11%), pleural effusion (8%), and increased lipase. The maximum tolerated dose was 0.4 mg/kg, every 3 weeks with a recommended dose of 0.3 mg/kg, every 6 weeks. The ORR was 18% for the cohort of 60 assessable patients. Of the 26 patients with high DLL3 expression (>50% of tumor cells), confirmed ORR was 38%.
Targeting cancer with antibody-drug conjugates: Promises and challenges
Published in mAbs, 2021
Alexis Q. Dean, Shen Luo, Julianne D. Twomey, Baolin Zhang
Despite the growing number of ADC approvals, challenges remain in the development of ADCs that demonstrate both superior safety and efficacy in the clinic. One unexpected challenge many developers face during clinical evaluation is the inability to demonstrate benefits over the control arm, such as occurred with MM-302. MM-302 was an anti-HER2 mAb conjugated to liposomal doxorubicin.85 The phase II HERMIONE trial (NCT02213744) was designed to determine the benefit of MM-302 treatment with trastuzumab compared to standard care chemotherapy as either gemcitabine, capecitabine, or vinorelbine in HER2-positive locally advanced mBC.86 However, the study was terminated due to lack of benefit over comparator treatments. Another ADC to report similar circumstances was AbbVie’s rovalpituzumab tesirine (Rova-T), which targeted cancer-stem cell-associated delta-like protein 3 (DLL3).87 Rova-T consisted of an IgG1 anti-DLL3 mAb conjugated to two PBD dimers via a valine-citrulline dipeptide linker. The ADC was intended to treat small cell lung cancer, which is known to overexpress DLL3 in 80% of small cell lung cancer patients with no expression on normal tissues.87 Encouraging results in the phase I trial reported 18% ORR in assessable patients and a 38% ORR in patients with high DLL3 expression (NCT01901653), but safety and efficacy concerns were raised due to the results of the phase II trial TRINITY (NCT02674568) in which the primary endpoint was not achieved and high toxicity rates were reported. The most frequent event among patients was pleural effusion, which is considered to be a toxicity associated with PBD dimers.88,89 Ultimately, the results of the phase III trials, TAHOE (NCT03061812) and MERU (NCT03033511), in which a lack of survival benefit over the control arm was observed, led to the complete discontinuation of the development of Rova-T by AbbVie.90