Double-Blind, Placebo-Controlled, Randomized Phase III Trial Evaluating Pertuzumab Combined With Chemotherapy for Low Tumor Human Epidermal Growth Factor Receptor 3 mRNA–Expressing Platinum-Resistant Ovarian Cancer (PENELOPE)

Kurzeder, Christian; Bover, Isabel; Marmé, Frederik; Rau, Joern; Pautier, Patricia; Colombo, Nicoletta; Lorusso, Domenica; Ottevanger, Petronella B.; Bjurberg, Maria; Marth, Christian; Barretina-Ginesta, Pilar; Vergote, Ignace; Floquet, Anne; Campo, J. M. Del; Mahner, Sven; Bastiere-Truchot, Lydie; Martin, Nicolas; Oestergaard, Mikkel Z.; Kiermaier, Astrid; Schade‐Brittinger, Carmen; Polleis, Sandra; Bois, Andreas du; González-Martín, Antonio

doi:10.1200/jco.2015.66.0787

Cited by 61 publications

(49 citation statements)

References 15 publications

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“…Several HER2 inhibitors, either tyrosine kinase inhibitors or monoclonal antibodies, are already in clinical use and are invaluable drugs in the treatment of breast cancer. Regarding their clinical implications for EOC, several clinical trials using HER2 inhibitors have already been conducted with unsatisfying results (38,39), However, the latest phase III clinical trials (pertuzumab in platinum-resistant low human epidermal growth factor receptor 3 messenger ribonucleic acid epithelial ovarian cancer; PENELOPE) for EOC have shown favorable results for pertuzumab combined with gemcitabine and paclitaxel for platinum-resistant EOC with low HER3 mRNA levels (40). In accordance with these results, SKOV3 has the highest expression levels of HER2, and the fifth-lowest expression levels of HER3, among 52 EOC cell lines registered in the cancer cell line encyclopedia (41), which might have resulted in the identification of ERBB2 as the most potent drug target in our screen.…”

Section: Discussionmentioning

confidence: 99%

In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer

Kodama

Newberg

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Epithelial ovarian cancer (EOC) is a deadly cancer, and its prognosis has not been changed significantly during several decades. To seek new therapeutic targets for EOC, we performed an in vivo dropout screen in human tumor xenografts using a pooled shRNA library targeting thousands of druggable genes. Then, in follow-up studies, we performed a second screen using a genome-wide CRISPR/Cas9 library. These screens identified 10 high-confidence drug targets that included well-known oncogenes such as ERBB2 and RAF1, and novel oncogenes, notably KPNB1, which we investigated further. Genetic and pharmacological inhibition showed that KPNB1 exerts its antitumor effects through multiphase cell cycle arrest and apoptosis induction. Mechanistically, proteomic studies revealed that KPNB1 acts as a master regulator of cell cycle-related proteins, including p21, p27, and APC/ C. Clinically, EOC patients with higher expression levels of KPNB1 showed earlier recurrence and worse prognosis than those with lower expression levels of KPNB1. Interestingly, ivermectin, a Food and Drug Administration-approved antiparasitic drug, showed KPNB1-dependent antitumor effects on EOC, serving as an alternative therapeutic toward EOC patients through drug repositioning. Last, we found that the combination of ivermectin and paclitaxel produces a stronger antitumor effect on EOC both in vitro and in vivo than either drug alone. Our studies have thus identified a combinatorial therapy for EOC, in addition to a plethora of potential drug targets.ovarian cancer | KPNB1 | loss-of-function screen | CRISPR/Cas | RNAi

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Section: Discussionmentioning

confidence: 99%

In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer

Kodama

Newberg

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…ORR (RECIST and/or GCIG) was 3.3% and median PFS was 2.1 months (95% CI, 1.9–3.3 months) in the phase III AURELIA trial (most patients treated with the weekly regimen) [11, 12]. No responses (RECIST) and median PFS of 2.6 months (95% CI, 2.1–4.3 months) were found in the phase III PENELOPE trial ( n = 24 patients treated with topotecan 1.25 mg/m 2 days 1–5 q3wk) [13]. …”

Section: Discussionmentioning

confidence: 99%

Phase II randomized study of PM01183 versus topotecan in patients with platinum-resistant/refractory advanced ovarian cancer

et al. 2017

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Background PM01183 is a new compound that blocks active transcription, produces DNA breaks and apoptosis, and affects the inflammatory microenvironment. PM01183 showed strong antitumor activity in preclinical models of cisplatin-resistant epithelial ovarian cancer.Patients and methodsPatients with platinum-resistant/refractory ovarian cancer were included in a two-stage, controlled, randomized (in a second stage), multicenter, phase II study. Primary endpoint was overall response rate (ORR) by RECIST and/or GCIG criteria. The exploratory first stage (n = 22) confirmed the activity of PM01183 as a single agent at 7.0 mg flat dose every 3 weeks (q3wk). The second stage (n = 59) was randomized and controlled with topotecan on days 1–5 q3wk or weekly (every 4 weeks, q4wk).ResultsORR was 23% (95% CI, 13%–37%) for 52 PM01183-treated patients. Median duration of response was 4.6 months (95% CI, 2.5–6.9 months), and 23% (95% CI, 0%–51%) of responses lasted 6 months or more. Ten of the 12 confirmed responses were reported for 33 patients with platinum-resistant disease [ORR = 30% (95% CI, 16%–49%)]; for the 29 patients treated with topotecan in the second stage, no responses were found. Median PFS for all PM01183-treated patients was 4.0 months (95% CI, 2.7–5.6 months), and 5.0 months (95% CI, 2.7–6.9 months) for patients with platinum-resistant disease.Grade 3/4 neutropenia in 85% of patients; febrile neutropenia in 21% and fatigue (grade 3 in 35%) were the principal safety findings for PM01183.ConclusionPM01183 is an active drug in platinum-resistant/refractory ovarian cancer and warrants further development. The highest activity was observed in platinum-resistant disease. Its safety profile indicates the dose should be adjusted to body surface area (mg/m2).Trial codeEudraCT 2011-002172-16.

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“…This study suggested a role of P in treating T-resistant HER2/neu positive breast cancer [23]. In EOC patients, P has been the most extensively studied HER2/neu inhibitor in ovarian cancer, with over 600 patients enrolled in three large Phase II and one Phase III trials [24–27]. Makhija et al ., performed a randomized, placebo-controlled, Phase II trial of gemcitabine plus P in 130 women with platinum-resistant, recurrent ovarian carcinoma [25].…”

Section: Discussionmentioning

confidence: 99%

“…After investigators’ selection of the chemotherapy backbone (single-agent topotecan, weekly paclitaxel, or gemcitabine), 156 patients were randomly assigned to receive either placebo or P as an add-on. Although adding P to chemotherapy did not significantly improve PFS, subgroup analyses showed trends in PFS favoring P in the gemcitabine and paclitaxel cohorts [27]. …”

Section: Discussionmentioning

confidence: 99%

Superior in vitro and in vivo activity of trastuzumab-emtansine (T-DM1) in comparison to trastuzumab, pertuzumab and their combination in epithelial ovarian carcinoma with high HER2/neu expression

Menderes

Bonazzoli

Bellone

et al. 2017

Gynecologic Oncology

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Background Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. The objective of this study was to compare the anti-tumor activity of HER2/neu-targeting monoclonal antibodies, trastuzumab (T), pertuzumab (P), combination of trastuzumab and pertuzumab (T+P) and trastuzumab-emtansine (T-DM1) in EOC with high HER2/neu expression. Methods Primary EOC cell lines were established and cell blocks were analyzed for HER2/neu expression. Cytostatic, apoptotic and antibody-dependent cell-mediated cytotoxicity (ADCC) activities of T, P, T+P and T-DM1 were evaluated in vitro. The in vivo antitumor activity was tested in xenograft models with 3+ HER2/neu expression. Results High (3+) HER2/neu expression was detected in 40% of the primary EOC cell lines. T, P, T+P, and T-DM1 were similarly effective in inducing strong ADCC against primary EOC cell lines expressing 3+ HER2/neu. The combination of T and P was more cytostatic when compared with that of T or P used alone (p<0.0001 and p<0.0001, respectively). T-DM1 induced significantly more apoptosis when compared with T+P (p<0.0001). Finally, T-DM1 was significantly more effective in tumor growth inhibition in vivo in EOC xenografts overexpressing HER2/neu when compared to T alone, P alone and T+P (p=0.04). Conclusion In vitro and in vivo experiments with 3+ HER2/neu expressing EOC revealed limited anti-tumor activity of T or P. T-DM1 showed superior anti-tumor activity to T and P as single agents and as a combination. Our preclinical data support the design of clinical studies with T-DM1 for the treatment of chemotherapy-resistant EOC overexpressing HER2/neu.

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Double-Blind, Placebo-Controlled, Randomized Phase III Trial Evaluating Pertuzumab Combined With Chemotherapy for Low Tumor Human Epidermal Growth Factor Receptor 3 mRNA–Expressing Platinum-Resistant Ovarian Cancer (PENELOPE)

Abstract: Although the primary objective was not met, subgroup analyses showed trends in PFS favoring pertuzumab in the gemcitabine and paclitaxel cohorts, meriting further exploration of pertuzumab in ovarian cancer.

Cited by 61 publications

References 15 publications

In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer

In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer

Phase II randomized study of PM01183 versus topotecan in patients with platinum-resistant/refractory advanced ovarian cancer

Superior in vitro and in vivo activity of trastuzumab-emtansine (T-DM1) in comparison to trastuzumab, pertuzumab and their combination in epithelial ovarian carcinoma with high HER2/neu expression

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