Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial

Powles, Thomas; Özgüroǧlu, Mustafa; Matsubara, Nobuaki; Gergely, Lajos; Fradet, Yves; Oudard, Stéphane; Vulsteke, Christof; Barrera, Rafael; Fléchon, Aude; Gündüz, Şeyda; Loriot, Yohann; Rodríguez‐Vida, Alejo; Mamtani, Ronac; Nam, Kijoeng; Imai, K.; Moreno, Blanca Homet; Alva, Ajjai; Cascallar, D.; Varela, Mirta; Lazzaro, Mauricio Fernandez; Kaen, Diego; Gatica, Gabriela; Flores, David; Falco, Agustín; Molina, Matias; Aelst, F Van; Sautois, Brieuc; Machiels, Jean‐Pascal; Schallier, Denis; Brust, Leandro; Rapatoni, Liane; Azevedo, Sérgio Jobim; Marinho, Gisele Souza Parmezzani; Soares, João Paulo Holanda; Dzik, Carlos; Silva, Jamile Almeida; Fay, André P.; Gingerich, Joel Roger; Ferrario, Cristiano; Potvin, Kylea; Vanhuyse, Marie; Abdelsalam, Mahmoud; Cheng, Susanna; Caglevic, Christian; Reyes, Felipe; Leal, José Luis; Francisco, Francisco; Ibáñez, Carolina; Joly, Florence; Laguerre, Brigitte; Ladoire, Sylvain; Topart, Delphine; Huillard, Olivier; Gross‐Goupil, Marine; Culine, Stéphane; Gravis, Gwénaëlle; Reichardt, Peter; Retz, Margitta; Herden, Jan; Pfister, David G.; Ohlman, Carsten; Stöeckle, Michael; Wirth, Manfred P.; Lorch, Anja; Niegisch, Guenter; Goebell, Peter J.; Boegemann, Martin; Merseburger, Axel S.; Gakis, Georgios; Bedke, Jens; Neisius, Andreas; Hoefner, Thomas; Telekes, András; Kósa, Judit; Révész, János; Bodoky, G.; Csőszi, Tibor; Csejtei, András; Ruzsa, Ágnes; Kolonics, Zsuzsanna; Erfán, József; McDermott, Ray; Bambury, Richard; Sella, Avishay; Frank, Stephen Jay; Kejzman, Daniel; Goldman, Olesya; Rosenbaum, Eli; Peer, Avivit; Berger, Raanan; Rouvinov, Keren; Sarid, David; Fukasawa, Satoshi; Arai, Gaku; Yamaguchi, Akito; Yokomizo, Akira; Takayama, Tadateru; Kinoshita, Hidefumi; Kikuchi, Eiji; Mizuno, Ryuichi; Fujii, Yasuhisa; Sassa, Naoto; Matsukawa, Yoshihisa; Fujimoto, Kiyohide; Tanikawa, Toshiki; Tomita, Yoshihiko; Nishimura, Kazuo; Tsujihata, Masao; Oyama, Masafumi; Masumori, Naoya; Kanayama, Hiro‐omi; Takano, Toshimi; Miura, Yuji; Miyazaki, Jun; Joraku, Akira; Kimura, Tomokazu; Yamamoto, Yoshiaki; Kobayashi, Kazuki; Wit, Ronald de; Aarts, Maureen J.B.; Gerritsen, Winald R.; Los, Maartje; Beerepoot, Laurens V.; Измайлов, А. А.; Gorelov, S.; Alekseev, Boris; Semenov, Andrey; Kostorov, V.; Алексеев, С. М.; Zyryаnov, A. V.; Oschepkov, Vasiliy Nikolaevich; Шидин, В.А.; Vladimirov, Vladimir; Gafanov, Rustem; Karlov, Petr; Anderson, David; Shepherd, Lucinda; Cohen, G.; Rapoport, B.; Ruff, Paul; Lee, Nari; Bae, Woo Kyun; Lee, Hyo Jin; Herranz, Urbano Anido; Grande, Enrique; Gordoa, Teresa Alonso; Padró, Josep Gumà; Gauna, D. Castellano; Arranz, José Ángel; Langa, J. Muñoz; Sarrió, Regina Gironés; Pino, Á. Montesa; Fita, María José Juan; Su, Yu‐Li; Lin, Yung‐Chang; Su, Wen-Pin; Shen, Ying‐Chun; Chang, Yen‐Hwa; Huang, Yi-Hsiu; Sriuranpong, Virote; Chansriwong, Phichai; Srimuninnimit, Vichien; Danchaivijitr, Pongwut; Abalı, Hüseyin; Yavuz, Sinan; Özyılkan, Özgür; Şendur, Mehmet Ali Nahit; Ekenel, Meltem; Arslan, Çağatay; Özdoğan, Mustafa; Birtle, Alison; Huddart, Robert; Santis, Maria De; Zarkar, Anjali; Evans, Linda; Hussain, Syed A.; DiSimone, Christopher; Muina, Antonio F; Schlegel, Peter J; Jhangiani, Haresh S.; Harrison, M.; Slater, Dennis; Wright, David; Percent, Ivor; Lin, Jianqing; Hwang, Clara; Gupta, Sumati; Bajaj, Madhuri; Galamaga, Robert; Eklund, John; Wallace, James A.; Shtivelband, Mikhail; Suh, Jason; Burhani, Nafisa; Eadens, Matthew; Gunturu, Krishna S.; Burgess, Earle F; Wong, John; Chaudhry, Arvind; Veldhuizen, Peter J. Van; Graff, Stephanie L.; Thomas, Christian A.; Schnadig, Ian D.; Carneiro, Benedito A.; Hussain, Maha; Morgans, Alicia K.; Fitzharris, John T; Oliff, Ira; Vuky, Jacqueline; Hauke, Ralph J.; Baron, Ari David; Joshi, Monika; Bolemon, Britt Haley; Jiang, Peter; Mega, Anthony; Markus, M.; Pfanzelter, Nicklas; Lawler, W; Cobb, Patrick; Courtright, Jay; Jain, Sharad; Doshi, Gurjyot K.; Gunuganti, Vijay; Sartor, Oliver; Cole, Scott Wesley; Babiker, Hani; Uchio, Edward; Drakaki, Alexandra; Mannuel, Heather D; Guancial, Elizabeth A.; Fung, Chunkit; Charles, Anthony; Amato, Robert J.; Arriaga, Yull; Bowman, I. Alex; Ades, Steven; Dreicer, Robert; Yu, Evan Y.; Quinn, David I.; Fleming, Mark T.

doi:10.1016/s1470-2045(21)00152-2

Cited by 376 publications

(330 citation statements)

References 17 publications

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“…With regard to PFS, the IMvigor130 trial showed the advantage of combined chemoimmunotherapy (atezolizumab) over chemotherapy alone (8.2 months vs. 6.3 months; HR, 0.82; 95% CI, 0.70-0.96; p = 0.007), while no statistically significant benefit on OS was seen at the interim analysis after a median follow-up of 11.8 months [64]. Similarly, the final analysis of the KEYNOTE-361 study suggests that the addition of pembrolizumab to first-line platinum-based chemotherapy does not yield survival benefits in patients with advanced UC [61].…”

Section: Icis With Chemotherapymentioning

confidence: 98%

“…The phase III KEYNOTE-361 trial is a randomized study comparing (1:1:1) pembrolizumab +/− chemotherapy (cisplatin or carboplatin plus gemcitabine) in 1010 patients with treatment-naïve unresectable or metastatic BC [61]. The median PFS and median OS were 8.3 and 17 months, respectively, for the combination therapy vs. 7.1 and 14.3 months for chemotherapy alone.…”

Section: Advanced or Metastatic Bladder Cancer 41 First-line Therapymentioning

confidence: 99%

See 1 more Smart Citation

Immune Checkpoint Inhibitors in Urothelial Bladder Cancer: State of the Art and Future Perspectives

Roviello

Catalano

Santi

et al. 2021

Cancers

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Bladder cancer (BC) is the most common malignancy of the genitourinary tract, with high morbidity and mortality rates. Until recently, the treatment of locally advanced or metastatic urothelial BC was based on the use of chemotherapy alone. Since 2016, five immune checkpoint inhibitors (ICIs) have been approved by the Food and Drug Administration (FDA) in different settings, i.e., first-line, maintenance and second-line treatment, while several trials are still ongoing in the perioperative context. Lately, pembrolizumab, a programmed death-1 (PD-1) inhibitor, has been approved for Bacillus Calmette–Guérin (BCG)-unresponsive high-risk non-muscle invasive bladder cancer (NMIBC), using immunotherapy at an early stage of the disease. This review investigates the current state and future perspectives of immunotherapy in BC, focusing on the rationale and results of combining immunotherapy with other therapeutic strategies.

show abstract

Section: Icis With Chemotherapymentioning

confidence: 98%

Section: Advanced or Metastatic Bladder Cancer 41 First-line Therapymentioning

confidence: 99%

Immune Checkpoint Inhibitors in Urothelial Bladder Cancer: State of the Art and Future Perspectives

Roviello

Catalano

Santi

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…However, unfortunately, atezolizumab in monotherapy failed to improve overall survival compared to chemotherapy in pretreated metastatic UC [70]. In the same manner, the addition of pembrolizumab to first-line platinum-based chemotherapy was not associated with a survival benefit compared to chemotherapy alone (Table 2) [69].…”

Section: Immune Checkpoint Inhibitors In the Metastatic Settingmentioning

confidence: 98%

Efficacy of Immune Checkpoint Inhibitors in Upper Tract Urothelial Carcinomas: Current Knowledge and Future Directions

Thouvenin

Chanzá

Alhalabi

et al. 2021

Cancers

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Upper tract urothelial carcinoma (UTUC) represents a rare and aggressive malignancy arising from the renal pelvis or ureter. It can develop sporadically or have a hereditary origin, such as Lynch syndrome, caused by DNA mismatch repair deficiency, leading to microsatellite instability phenotype. According to molecular characterization studies, UTUC presents different mutational profiles as compared to urinary bladder urothelial carcinomas. In particular, it has been reported that UTUC harbored a higher level of FGFR3 alterations associated with a T-cell depleted immune microenvironment. The therapeutic landscape in urothelial carcinoma is rapidly evolving, with immune checkpoint inhibitors forming part of the standard of care. A greater understanding of the molecular alterations and immune microenvironment leads to the development of new treatment combinations and targeted therapy. This review summarizes the available evidence concerning the use of immune checkpoint inhibitors and the biological rationale underlying their use in high-grade UTUC.

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“…Pembrolizumab blocks PD-1, and in 2017 received accelerated FDA approval for patients with advanced/ metastatic UC who are ineligible for cisplatin-containing chemotherapy. In 2018, the FDA modified this indication so that pembrolizumab could be used only in cisplatin-ineligible patients and high PDL1 expression with CPS (Combined Positive Score) >10, or in patients who are unfit for any platinum therapy, regardless of their PD-L1 expression as the KEYNOTE-361 trial showed decreased survival in patients with PD-L1-low status in the pembrolizumab monotherapy arm (49,50). It also received regular FDA approval for advanced/ metastatic UC progression during/after first-line platinum chemotherapy or within 12 months of receiving adjuvant/ neoadjuvant platinum chemotherapy (51).…”

Section: Therapeutic Agents For Advanced or Metastatic Urothelial Carcinoma Immunotherapymentioning

confidence: 99%

Elucidation of Novel Molecular Targets for Therapeutic Strategies in Urothelial Carcinoma: A Literature Review

2021

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Urothelial carcinoma therapy is a rapidly evolving and expanding field. Traditional cytotoxic chemotherapy regimens have not produced optimal long-term outcomes, and many urothelial cancer patients have comorbidities that disqualify them as chemotherapy candidates. In recent years, a plethora of novel therapeutic agents that target diverse molecular pathways has emerged as alternative treatment modalities for not only metastatic urothelial carcinoma, but also for muscle-invasive bladder cancer and non-muscle invasive bladder cancer in adjuvant and definitive settings. This review paper aims to discuss the various categories of therapeutic agents for these different types of urothelial cancer, discussing immunotherapy, antibody-drug conjugates, kinase inhibitors, CAR-T cell therapy, peptide vaccination, and other drugs targeting pathways such as angiogenesis, DNA synthesis, mTOR/PI3K/AKT, and EGFR/HER-2.

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Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial

Cited by 376 publications

References 17 publications

Immune Checkpoint Inhibitors in Urothelial Bladder Cancer: State of the Art and Future Perspectives

Immune Checkpoint Inhibitors in Urothelial Bladder Cancer: State of the Art and Future Perspectives

Efficacy of Immune Checkpoint Inhibitors in Upper Tract Urothelial Carcinomas: Current Knowledge and Future Directions

Elucidation of Novel Molecular Targets for Therapeutic Strategies in Urothelial Carcinoma: A Literature Review

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