Efficacy and Safety of Rovalpituzumab Tesirine in Third-Line and Beyond Patients with DLL3-Expressing, Relapsed/Refractory Small-Cell Lung Cancer: Results From the Phase II TRINITY Study

Morgensztern, Daniel; Besse, Benjamin; Greillier, L.; Santana-Dávila, Rafael; Ready, Neal; Hann, Christine L.; Glisson, Bonnie S.; Farago, Anna F.; Dowlati, Afshin; Rudin, Charles M.; Moulec, Sylvestre Le; Lally, Satwant; Yalamanchili, Sreeni; Wolf, Juergen; Govindan, Ramaswamy; Carbone, David P.

doi:10.1158/1078-0432.ccr-19-1133

Cited by 223 publications

(187 citation statements)

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“…A primary criterion for efficient drug delivery is to choose an exclusively or overexpressed target for the cancer cells. Figures 6I and S6 show the expression of two receptors of clinical ADCs in the SCLC cell lines: DLL3 (used for SCLCs as rovalpituzumab tesirine [Rova-T]; Morgensztern et al, 2019 ; Rudin et al, 2017 ) and the carcinoembryonic antigen CEACAMC5 (used in other clinical indications as labetuzumab govitecan; Das, 2017 ). DLL3 expression is highly correlated with ASCL1 expression (p = 0.62), suggesting that targeting DLL3 could be selective toward SCLC-A tumors.…”

Section: Resultsmentioning

confidence: 99%

“…Second, we highlight potential surface markers that could be targeted on the basis of the NAPY subgroups. For example, SCLC-Y cells express neither the therapeutically relevant surface epitopes DLL3 or CEACAM5 ( Das, 2017 ; Morgensztern et al, 2019 ; Rudin et al, 2017 ), which tend to be specific for the SCLC-A (and N). However, SCLC-Y express CD151 and EPHA2 ( Figure 6K ) and might respond to the YAP1 and NOTCH inhibitors in clinical development ( Crawford et al, 2018 ; Leonetti et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

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SCLC-CellMiner: A Resource for Small Cell Lung Cancer Cell Line Genomics and Pharmacology Based on Genomic Signatures

et al. 2020

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SUMMARY CellMiner-SCLC ( https://discover.nci.nih.gov/SclcCellMinerCDB/ ) integrates drug sensitivity and genomic data, including high-resolution methylome and transcriptome from 118 patient-derived small cell lung cancer (SCLC) cell lines, providing a resource for research into this “recalcitrant cancer.” We demonstrate the reproducibility and stability of data from multiple sources and validate the SCLC consensus nomenclature on the basis of expression of master transcription factors NEUROD1, ASCL1, POU2F3, and YAP1. Our analyses reveal transcription networks linking SCLC subtypes with MYC and its paralogs and the NOTCH and HIPPO pathways. SCLC subsets express specific surface markers, providing potential opportunities for antibody-based targeted therapies. YAP1-driven SCLCs are notable for differential expression of the NOTCH pathway, epithelial-mesenchymal transition (EMT), and antigen-presenting machinery (APM) genes and sensitivity to mTOR and AKT inhibitors. These analyses provide insights into SCLC biology and a framework for future investigations into subtype-specific SCLC vulnerabilities.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SCLC-CellMiner: A Resource for Small Cell Lung Cancer Cell Line Genomics and Pharmacology Based on Genomic Signatures

et al. 2020

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“…After this trial, phase 2 clinical trial assessed safety and efficacy of Rova-T for patients with DLL3 expression-positive SCLC in the third-line and beyond setting (TRINITY), and the results demonstrated modest clinical activity with associated toxicities. 27 The anti-DLL3/CD3 Bispecific T cell engager (BiTE) antibody (AMG 757) and a chimeric antigen receptor T cell therapy targeting DLL3 (AMG119) have been clinically evaluated in phase 1 clinical trials for the treatment of relapsed/refractory SCLC. 28 There is increasing evidence that surgical resection alone is insufficient for treating LCNEC, 3 and several researchers have reported that adjuvant platinum-based chemotherapy for patients with LCNEC dramatically improved the surgical outcomes.…”

Section: Discussionmentioning

confidence: 99%

DLL3 expression is a predictive marker of sensitivity to adjuvant chemotherapy for pulmonary LCNEC

et al. 2020

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Background The mammalian Notch family ligands delta‐like 3 (DLL3) is reported to be a potential therapeutic target for large cell neuroendocrine carcinomas (LCNEC). The effect of DLL3 expression on LCNEC prognosis has not yet been elucidated. Methods We reviewed the medical records of 70 LCNEC patients undergoing surgical resection between 2001 and 2015 using a prospectively maintained database. We performed immunohistochemistry for DLL3 and investigated the correlation between the sensitivity of LCNEC to platinum‐based adjuvant chemotherapy. Results DLL3 expression was positive in 26 (37.1%) LCNEC patients. A total of 23 patients (32.9%) received platinum‐based adjuvant chemotherapy. Among patients with DLL3 expression‐positive tumors, no difference was found in the five‐year overall survival (OS) or recurrence‐free survival (RFS) between patients with and without adjuvant chemotherapy (surgery + chemotherapy vs. surgery alone, five‐year OS: 58.3% vs. 35.7% P = 0.36, five‐year RFS: 41.7% vs. 35.7% P = 0.74). In contrast, among patients with DLL3‐negative tumors, significantly greater five‐year OS and RFS rates were observed for patients with adjuvant chemotherapy than for those without it (surgery + chemotherapy vs. surgery alone: five‐year OS: 90.0% vs. 26.9% P<0.01, five‐year RFS: 80.0% vs. 21.7% P < 0.01). A multivariate analysis for the RFS revealed that adjuvant chemotherapy was a significant independent prognostic factor among patients with DLL3‐negative tumors (hazard ratio [HR]: 0.05, 95% confidence interval [CI]: 0.01–0.41, P < 0.01), although it was not a factor among patients with DLL3‐positive tumors (HR: 0.73, 95% CI: 0.23–2.27, P = 0.58). Conclusions Our results revealed that DLL3 is a predictive marker of sensitivity to platinum‐based adjuvant chemotherapy for LCNEC. Key points Significant findings of the study DLL3 was a predictive marker of sensitivity to platinum‐based adjuvant chemotherapy for LCNEC. Among patients with DLL3 expression‐negative LCNEC, platinum‐based adjuvant chemotherapy significantly improved the OS and RFS, although it did not do so among patients with DLL3 expression‐positive LCNEC. What this study adds Our results suggest that DLL3 expression‐positive LCNEC may be better treated with other types of adjuvant chemotherapy, such as the anti‐DLL3 therapies if these effects are confirmed by ongoing clinical research.

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“…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.…”

Section: Rovalpituzumab Tesirine (Abbvie Inc)mentioning

confidence: 99%

Antibodies to watch in 2020

Kaplon

Muralidharan²,

Schneider

et al. 2019

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296

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This 2020 installment of the annual 'Antibodies to Watch' series documents the antibody therapeutics approved in 2019 and in regulatory review in the United States or European Union, as well as those in late-stage clinical studies, as of November 2019*. At this time, a total of 5 novel antibody therapeutics (romosozumab, risankizumab, polatuzumab vedotin, brolucizumab, and crizanlizumab) had been granted a first approval in either the US or EU, and marketing applications for 13 novel antibody therapeutics (eptinezumab, teprotumumab, enfortumab vedotin, isatuximab, [fam-]trastuzumab deruxtecan, inebilizumab, leronlimab, sacituzumab govitecan, satralizumab, narsoplimab, tafasitamab, REGNEB3 and naxituximab) were undergoing review in these regions, which represent the major markets for antibody therapeutics. Also as of November 2019, 79 novel antibodies were undergoing evaluation in late-stage clinical studies. Of the 79 antibodies, 39 were undergoing evaluation in late-stage studies for non-cancer indications, with 2 of these (ublituximab, pamrevlumab) also in late-stage studies for cancer indications. Companies developing 7 (tanezumab, aducanumab, evinacumab, etrolizumab, sutimlimab, anifrolumab, and teplizumab) of the 39 drugs have indicated that they may submit a marketing application in either the US or EU in 2020. Of the 79 antibodies in late-stage studies, 40 were undergoing evaluation as treatments for cancer, and potentially 9 of these (belantamab mafodotin, oportuzumab monatox, margetuximab, dostarlimab, spartalizumab, 131I-omburtamab, loncastuximab tesirine, balstilimab, and zalifrelimab) may enter regulatory review in late 2019 or in 2020. Overall, the biopharmaceutical industry's clinical pipeline of antibody therapeutics is robust, and should provide a continuous supply of innovative products for patients in the future. *Note on key updates through December 18, 2019: 1) the US Food and Drug Administration granted accelerated approval to enfortumab vedotin-ejfv (Padcev) on December 18, 2019, bringing the total number of novel antibody therapeutics granted a first approval in either the US or EU during 2019 to 6; 2) the European Commission approved romosozumab on December 9, 2019; 3) the European Medicines Agency issued a positive opinion for brolucizumab; 4) Sesen Bio initiated a rolling biologics license application (BLA) on December 6, 2019; 5) GlaxoSmithKline submitted a BLA for belantamab mafodotin; and 6) the status of the Phase 3 study (NCT04128696) of GSK3359609, a humanized IgG4 anti-ICOS antibody, in patients with head and neck squamous cell carcinoma was updated to recruiting from not yet recruiting. ARTICLE HISTORY

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Efficacy and Safety of Rovalpituzumab Tesirine in Third-Line and Beyond Patients with DLL3-Expressing, Relapsed/Refractory Small-Cell Lung Cancer: Results From the Phase II TRINITY Study

Cited by 223 publications

References 33 publications

SCLC-CellMiner: A Resource for Small Cell Lung Cancer Cell Line Genomics and Pharmacology Based on Genomic Signatures

SCLC-CellMiner: A Resource for Small Cell Lung Cancer Cell Line Genomics and Pharmacology Based on Genomic Signatures

DLL3 expression is a predictive marker of sensitivity to adjuvant chemotherapy for pulmonary LCNEC

Antibodies to watch in 2020

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