Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial

Petrylak, Daniel P.; Wit, Ronald de; N., Kim; Drakaki, Alexandra; Sternberg, Cora N.; Nishiyama, Hiroyuki; Castellano, Daniel; Hussain, Syed A.; Fléchon, Aude; Bamias, Aristotelis; Yu, Evan Y.; Heijden, Michiel S. van der; Matsubara, Nobuaki; Alekseev, B. Ya.; Necchi, Andrea; Gergely, Lajos; Ou, Yen Chuan; Çoşkun, Hasan Şenol; Su, Wen; Bedke, Jens; Gakis, Georgios; Percent, Ivor; Lee, Jae‐Lyun; Tucci, Marco; Semenov, Andrey; Laestadius, Fredrik; Peer, Avivit; Tortora, Giampaolo; Safina, Sufia; Muro, Xavier García del; Rodríguez‐Vida, Alejo; Çiçin, İrfan; Harputluoğlu, Hakan; Tagawa, Scott T.; Vaishampayan, Ulka N.; Aragon‐Ching, Jeanny B.; Hamid, Oday; Liepa, Astra M.; Wijayawardana, Sameera R.; Russo, Francesca; Walgren, Richard A.; Zimmermann, Annamaria H.; Hozak, Rebecca R.; Bell‐McGuinn, Katherine M.; Powles, Thomas; Wong, Suet Lai Shirley; Tan, Thean Hsiang; Hovey, Elizabeth; Clay, Timothy Dudley; Ng, Siobhan; Rutten, Annemie; Machiels, Jean Pascal; Dumez, Herlinde; Cheng, Susanna; Ferrario, Cristiano; Sengeloev, Lisa; Jensen, Niels Viggo; Thibault, Constance; Laguerre, Brigitte; Joly, Florence; Culine, Stéphane; Becht, Catherine; Niegisch, Günter; Stöckle, Michael; Grimm, Marc‐Oliver; Schwentner, Christina A.; Schultze-Seemann, Wolfgang; Kalofonos, H. P.; Mavroudis, Dimitriοs; Papandreou, Christos N.; Karavasilis, Vasilis; Révész, János; Rosenbaum, Eli; Leibowitz-Amit, Raya; Kejzman, Daniel; Sarid, David; Scagliotti, Giorgio Vittorio; Bracarda, Sergio; Massari, Francesco; Osawa, Takahiro; Minamino, Naoto; Shinohara, Nobuo; Fukuta, Fumimasa; Οhyama, Chikara; Obara, Wataru; Yamashita, Shinichi; Tomita, Yoshihiko; Kawai, Koji; Fukasawa, Satoshi; Oyama, Masafumi; Yonese, Junji; Nagata, Masayoshi; Uemura, Mamoru; Nishimura, Kazuo; Kawakita, Mutsushi; Tsunemori, Hiroyuki; Hashine, Katsuyoshi; Inokuchi, Junichi; Yokomizo, Akira; Nagamori, Satoshi; Lee, Hyo Jin; Park, Se Hoon; Rha, Sun Young; Kim, Yu Jung; Lee, Yun Gyoo; Cortés, Leticia Vazquez; Flores, Claudia Lorena Urzua; Blaisse, Reinoud J B; Erdkamp, F.; Aarts, Maureen J.B.; Wójcik-Tomaszewska, Joanna; Tomczak, Piotr; Sikora-Kupis, Bożena; Schenker, Michael; Herzal, Alina Amalia; Udrea, Anghel Adrian; Karlov, Petr; Фомкин, Р Н; Borau, P. Gajate; Grande, Enrique; Mignorance, Juan Ignacio Delgado; Su, Yu-Li; Li, Jian Ri; Lin, Chien Liang; Lin, Chia Chi; Yeh, Su Peng; Erman, Mustafa; Ürün, Yüksel; Golovko, Yuriy; Bondarenko, Igor; Sinielnikov, Ivan; Crabb, Simon J.; Syndikus, Isabel; Huddart, Robert; Sundar, Santhanam; Chowdhury, Simon; Sarwar, Naveed; Flaig, Thomas W.; Pan, Chong Xian; Schwarz, James K.; Cultrera, Jennifer L.; Ács, Péter; Hainsworth, John D.; Herms, Benjamin; Lawler, W; Lowe, T. E.

doi:10.1016/s1470-2045(19)30668-0

Cited by 71 publications

(63 citation statements)

References 35 publications

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“…Bevacizumab failed to improve OS relative to placebo in a phase III study, and caused grade ≥3 AEs in 83.4% of patients [ 94 ]. In the RANGE phase III trial, ramucirumab did not significantly improve OS in patients who had previously been treated with platinum-containing chemotherapy and/or ICI therapy [ 95 ]. The mAb trastuzumab that targets HER2 has also been extensively evaluated in the clinic against bladder cancer.…”

Section: Futurementioning

confidence: 99%

Targeted Molecular Therapeutics for Bladder Cancer—A New Option beyond the Mixed Fortunes of Immune Checkpoint Inhibitors?

Bednova

Leyton

2020

IJMS

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The fact that there are now five immune checkpoint inhibitor (ICI) monoclonal antibodies approved since 2016 that target programmed cell death protein 1 or programmed death ligand-1 for the treatment of metastatic and refractory bladder cancer is an outstanding achievement. Although patients can display pronounced responses that extend survival when treated with ICIs, the main benefit of these drugs compared to traditional chemotherapy is that they are better tolerated and result in reduced adverse events (AEs). Unfortunately, response rates to ICI treatment are relatively low and, these drugs are expensive and have a high economic burden. As a result, their clinical efficacy/cost-value relationship is debated. Long sought after targeted molecular therapeutics have now emerged and are boasting impressive response rates in heavily pre-treated, including ICI treated, patients with metastatic bladder cancer. The antibody-drug conjugates (ADCs) enfortumab vedotin (EV) and sacituzumab govitecan (SG) have demonstrated the ability to provide objective response rates (ORRs) of 44% and 31% in patients with bladder tumor cells that express Nectin-4 and Trop-2, respectively. As a result, EV was approved by the U.S. Food and Drug Administration for the treatment of patients with advanced or metastatic bladder cancer who have previously received ICI and platinum-containing chemotherapy. SG has been granted fast track designation. The small molecule Erdafitinib was recently approved for the treatment of patients with advanced or metastatic bladder cancer with genetic alterations in fibroblast growth factor receptors that have previously been treated with a platinum-containing chemotherapy. Erdafitinib achieved an ORR of 40% in patients including a proportion who had previously received ICI therapy. In addition, these targeted drugs are sufficiently tolerated or AEs can be appropriately managed. Hence, the early performance in clinical effectiveness of these targeted drugs are substantially increased relative to ICIs. In this article, the most up to date follow-ups on treatment efficacy and AEs of the ICIs and targeted therapeutics are described. In addition, drug price and cost-effectiveness are described. For best overall value taking into account clinical effectiveness, price and cost-effectiveness, results favor avelumab and atezolizumab for ICIs. Although therapeutically promising, it is too early to determine if the described targeted therapeutics provide the best overall value as cost-effectiveness analyses have yet to be performed and long-term follow-ups are needed. Nonetheless, with the arrival of targeted molecular therapeutics and their increased effectiveness relative to ICIs, creates a potential novel paradigm based on ‘targeting’ for affecting clinical practice for metastatic bladder cancer treatment.

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Section: Futurementioning

confidence: 99%

Targeted Molecular Therapeutics for Bladder Cancer—A New Option beyond the Mixed Fortunes of Immune Checkpoint Inhibitors?

Bednova

Leyton

2020

IJMS

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“…These are still early days in the development of transcription therapy. Nevertheless, a handful of compounds are in clinical development and have made it to clinical trials (see selected examples in Table 1) [142][143][144][145]. The best example of TF-targeted drugs that entered clinical trials are the aforementioned p53-MDM2 PPI inhibitors, based on the nutlin scaffold or other chemical backbones.…”

Section: Clinical Trials For Transcription Therapymentioning

confidence: 99%

Biophysical Techniques for Target Validation and Drug Discovery in Transcription-Targeted Therapy

Moustaqil

Gambin

Sierecki

2020

IJMS

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In the post-genome era, pathologies become associated with specific gene expression profiles and defined molecular lesions can be identified. The traditional therapeutic strategy is to block the identified aberrant biochemical activity. However, an attractive alternative could aim at antagonizing key transcriptional events underlying the pathogenesis, thereby blocking the consequences of a disorder, irrespective of the original biochemical nature. This approach, called transcription therapy, is now rendered possible by major advances in biophysical technologies. In the last two decades, techniques have evolved to become key components of drug discovery platforms, within pharmaceutical companies as well as academic laboratories. This review outlines the current biophysical strategies for transcription manipulation and provides examples of successful applications. It also provides insights into the future development of biophysical methods in drug discovery and personalized medicine.

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“…Despite approvals of various targeted therapies for platinum-refractory advanced UC, most patients have limited treatment options as they experience disease progression. Ramucirumab plus docetaxel has shown higher response rate and improved progression-free survival (PFS) compared to placebo plus docetaxel in the platinum-refractory population [ 2 , 3 ]. In the refractory setting, quality of life (QoL) is an important factor in the treatment decision-making process for patients with cancer where symptom palliation is the primary goal of therapy [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…Patients treated in the ramucirumab arm also had a numerically higher objective response rate (24.50%, 95% CI [18.80, 30.30] vs 14.0%, 95% CI [9.40, 18.60]) [ 2 ]. Although not statistically significant, overall survival (OS) at the final analysis favored the ramucirumab arm (HR = 0.887; 95% CI [0.724, 1.086]; p = 0.25) [ 3 ]. The most frequent adverse events (AEs) of any grade reported for both the ramucirumab and placebo arms were fatigue (39.1% vs 36.2%), alopecia (23.6% vs 30.6%), diarrhea (23.6% vs 16.6%), decreased appetite (22.1% vs 17.0%), nausea (22.1% vs 14.0%), and stomatitis (23.2% vs 9.0%).…”

Section: Introductionmentioning

confidence: 99%

“…Of these AEs, only fatigue had an incidence of ≥ 5% for grade 3/4 (7.0% vs 6.0%). On-study, treatment-related deaths were relatively rare (8 [3.0%] and 5 [2.0%], respectively) [ 3 ]. Overall, the proportion of patients with AEs receiving ramucirumab plus docetaxel was similar to the proportion of patients with AEs in the placebo plus docetaxel arm.…”

Section: Introductionmentioning

confidence: 99%

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Health-related quality of life in the randomized phase 3 study of ramucirumab plus docetaxel versus placebo plus docetaxel in platinum-refractory advanced urothelial carcinoma (RANGE)

et al. 2020

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Background To evaluate patient-reported outcomes with ramucirumab plus docetaxel, a regimen which improved progression-free survival in platinum-refractory advanced urothelial carcinoma (aUC). Methods RANGE—a randomized, double-blinded, phase 3 trial in patients with platinum-refractory aUC. Ramucirumab (10 mg/kg) plus docetaxel (75 mg/m2) or placebo plus docetaxel were administered every 21 days until disease progression or unacceptable toxicity. Patients received maximum 10 cycles of docetaxel. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and EuroQoL five-dimensions (EQ-5D-5L) were administered at baseline, start of each cycle, and 30-day follow-up visit. A ≥ 10-point change in QLQ-C30 scores was considered meaningful. Rates of improved/stable scores were compared between treatment arms using Fisher’s exact test. Time to deterioration (TtD) was estimated and compared using Kaplan–Meier estimation and log-rank test. Results Of the 530 patients, ~ 97% patients in each arm provided baseline QLQ-C30 data. On-treatment compliance was ≥ 88% for first 8 cycles. Mean baseline QLQ-C30 scores were similar between arms, with global quality of life (QoL), fatigue, pain, and insomnia having greatest impairment. Postbaseline rates of improved/stable QLQ-C30 scores were similar between treatment arms except for greater improvement in pain score with ramucirumab. TtD of QLQ-C30 scales favored ramucirumab arm. Baseline EQ-5D-5L index and visual analogue scale scores were similar between arms, followed by relatively stable on-treatment scores. EQ-5D-5L scores worsened at post-discontinuation follow-up visit. Conclusions Ramucirumab plus docetaxel did not negatively impact QoL compared with docetaxel alone in platinum-refractory aUC. Improved TtD and tumor associated rates of pain favored ramucirumab treatment. Clinical trail registration NCT02426125. https://clinicaltrials.gov/ct2/show/NCT02426125. Date of registration: April 24th 2015

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Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial

Cited by 71 publications

References 35 publications

Targeted Molecular Therapeutics for Bladder Cancer—A New Option beyond the Mixed Fortunes of Immune Checkpoint Inhibitors?

Targeted Molecular Therapeutics for Bladder Cancer—A New Option beyond the Mixed Fortunes of Immune Checkpoint Inhibitors?

Biophysical Techniques for Target Validation and Drug Discovery in Transcription-Targeted Therapy

Health-related quality of life in the randomized phase 3 study of ramucirumab plus docetaxel versus placebo plus docetaxel in platinum-refractory advanced urothelial carcinoma (RANGE)

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