Efficacy and safety of pembrolizumab plus docetaxel vs docetaxel alone in patients with previously treated advanced non-small cell lung cancer: the PROLUNG Phase 2 randomized clinical trial
Importance: Because of socioeconomic factors, many patients with advanced non-small cell lung cancer (NSCLC) do not receive immunotherapy in the first-line setting. It is unknown if the combination of immunotherapy with chemotherapy can provide clinical benefits in immunotherapy-naive patients with...
- Autores:
-
Arrieta, Oscar
Barrón-Barrón, Feliciano
Ramírez Tirado, Laura Alejandra
Zatarain-Barrón, Zyanya Lucia
Cardona-Mendoza, Andrés Felipe
Díaz-García, Diego
Yamamoto-Ramos, Masao
Mota-Vega, Beatriz
Carmona, Amir
Peralta-Alvarez, Marco Polo
Bautista, Yolanda
Aldaco, Fernando
Gerson, Raquel
Rolfo, Christian
Rosell, Rafael Costa
- Tipo de recurso:
- Article of journal
- Fecha de publicación:
- 2020
- Institución:
- Universidad El Bosque
- Repositorio:
- Repositorio U. El Bosque
- Idioma:
- eng
- OAI Identifier:
- oai:repositorio.unbosque.edu.co:20.500.12495/2601
- Acceso en línea:
- http://hdl.handle.net/20.500.12495/2601
https://jamanetwork.com/journals/jama/fullarticle/10.1001/jamaoncol.2020.0409?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamaoncol.2020.0409
https://repositorio.unbosque.edu.co
- Palabra clave:
- Neoplasias pulmonares
Inmunoterapia
Docetaxel
Targeted and immune cancer therapy
Lung cancer
Oncology
- Rights
- openAccess
- License
- Acceso cerrado
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|
dc.title.spa.fl_str_mv |
Efficacy and safety of pembrolizumab plus docetaxel vs docetaxel alone in patients with previously treated advanced non-small cell lung cancer: the PROLUNG Phase 2 randomized clinical trial |
dc.title.translated.spa.fl_str_mv |
Efficacy and safety of pembrolizumab plus docetaxel vs docetaxel alone in patients with previously treated advanced non-small cell lung cancer: the PROLUNG Phase 2 randomized clinical trial |
title |
Efficacy and safety of pembrolizumab plus docetaxel vs docetaxel alone in patients with previously treated advanced non-small cell lung cancer: the PROLUNG Phase 2 randomized clinical trial |
spellingShingle |
Efficacy and safety of pembrolizumab plus docetaxel vs docetaxel alone in patients with previously treated advanced non-small cell lung cancer: the PROLUNG Phase 2 randomized clinical trial Neoplasias pulmonares Inmunoterapia Docetaxel Targeted and immune cancer therapy Lung cancer Oncology |
title_short |
Efficacy and safety of pembrolizumab plus docetaxel vs docetaxel alone in patients with previously treated advanced non-small cell lung cancer: the PROLUNG Phase 2 randomized clinical trial |
title_full |
Efficacy and safety of pembrolizumab plus docetaxel vs docetaxel alone in patients with previously treated advanced non-small cell lung cancer: the PROLUNG Phase 2 randomized clinical trial |
title_fullStr |
Efficacy and safety of pembrolizumab plus docetaxel vs docetaxel alone in patients with previously treated advanced non-small cell lung cancer: the PROLUNG Phase 2 randomized clinical trial |
title_full_unstemmed |
Efficacy and safety of pembrolizumab plus docetaxel vs docetaxel alone in patients with previously treated advanced non-small cell lung cancer: the PROLUNG Phase 2 randomized clinical trial |
title_sort |
Efficacy and safety of pembrolizumab plus docetaxel vs docetaxel alone in patients with previously treated advanced non-small cell lung cancer: the PROLUNG Phase 2 randomized clinical trial |
dc.creator.fl_str_mv |
Arrieta, Oscar Barrón-Barrón, Feliciano Ramírez Tirado, Laura Alejandra Zatarain-Barrón, Zyanya Lucia Cardona-Mendoza, Andrés Felipe Díaz-García, Diego Yamamoto-Ramos, Masao Mota-Vega, Beatriz Carmona, Amir Peralta-Alvarez, Marco Polo Bautista, Yolanda Aldaco, Fernando Gerson, Raquel Rolfo, Christian Rosell, Rafael Costa |
dc.contributor.author.none.fl_str_mv |
Arrieta, Oscar Barrón-Barrón, Feliciano Ramírez Tirado, Laura Alejandra Zatarain-Barrón, Zyanya Lucia Cardona-Mendoza, Andrés Felipe Díaz-García, Diego Yamamoto-Ramos, Masao Mota-Vega, Beatriz Carmona, Amir Peralta-Alvarez, Marco Polo Bautista, Yolanda Aldaco, Fernando Gerson, Raquel Rolfo, Christian Rosell, Rafael Costa |
dc.contributor.orcid.none.fl_str_mv |
Cardona-Mendoza, Andrés Felipe [0000-0002-6697-5471] |
dc.subject.decs.spa.fl_str_mv |
Neoplasias pulmonares Inmunoterapia Docetaxel |
topic |
Neoplasias pulmonares Inmunoterapia Docetaxel Targeted and immune cancer therapy Lung cancer Oncology |
dc.subject.keywords.spa.fl_str_mv |
Targeted and immune cancer therapy Lung cancer Oncology |
description |
Importance: Because of socioeconomic factors, many patients with advanced non-small cell lung cancer (NSCLC) do not receive immunotherapy in the first-line setting. It is unknown if the combination of immunotherapy with chemotherapy can provide clinical benefits in immunotherapy-naive patients with disease progression after treatment with platinum-based chemotherapy. Objective: To evaluate the safety and efficacy of the combination of pembrolizumab plus docetaxel in patients with previously treated advanced NSCLC following platinum-based chemotherapy regardless of EGFR variants or programmed cell death ligand 1 status. Design, Setting, and Participants: The Pembrolizumab Plus Docetaxel for Advanced Non-Small Cell Lung Cancer (PROLUNG) trial randomized 78 patients with histologically confirmed advanced NSCLC in a 1:1 ratio to receive either pembrolizumab plus docetaxel or docetaxel alone from December 2016 through May 2019. Interventions: The experimental arm received docetaxel on day 1 (75 mg/m2) plus pembrolizumab on day 8 (200 mg) every 3 weeks for up to 6 cycles followed by pembrolizumab maintenance until progression or unacceptable toxic effects. The control arm received docetaxel monotherapy. Main Outcomes and Measures: The primary end point was overall response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival, and safety. Results: Among 78 recruited patients, 32 (41%) were men, 34 (44%) were never smokers, and 25 (32%) had an EGFR/ALK alteration. Forty patients were allocated to receive pembrolizumab plus docetaxel, and 38 were allocated to receive docetaxel. A statistically significant difference in ORR, assessed by an independent reviewer, was found in patients receiving pembrolizumab plus docetaxel vs patients receiving docetaxel (42.5% vs 15.8%; odds ratio, 3.94; 95% CI, 1.34-11.54; P =.01). Patients without EGFR variations had a considerable difference in ORR of 35.7% vs 12.0% (P =.06), whereas patients with EGFR variations had an ORR of 58.3% vs 23.1% (P =.14). Overall, PFS was longer in patients who received pembrolizumab plus docetaxel (9.5 months; 95% CI, 4.2-not reached) than in patients who received docetaxel (3.9 months; 95% CI, 3.2-5.7) (hazard ratio, 0.24; 95% CI, 0.13-0.46; P <.001). For patients without variations, PFS was 9.5 months (95% CI, 3.9-not reached) vs 4.1 months (95% CI, 3.5-5.3) (P <.001), whereas in patients with EGFR variations, PFS was 6.8 months (95% CI, 6.2-not reached) vs 3.5 months (95% CI, 2.3-6.2) (P =.04). In terms of safety, 23% (9 of 40) vs 5% (2 of 38) of patients experienced grade 1 to 2 pneumonitis in the pembrolizumab plus docetaxel and docetaxel arms, respectively (P =.03), while 28% (11 of 40) vs 3% (1 of 38) experienced any-grade hypothyroidism (P =.002). No new safety signals were identified. Conclusions and Relevance: In this phase 2 study, the combination of pembrolizumab plus docetaxel was well tolerated and substantially improved ORR and PFS in patients with advanced NSCLC who had previous progression after platinum-based chemotherapy, including NSCLC with EGFR variations. Trial Registration: ClinicalTrials.gov Identifier: NCT02574598. |
publishDate |
2020 |
dc.date.accessioned.none.fl_str_mv |
2020-05-12T00:46:09Z |
dc.date.available.none.fl_str_mv |
2020-05-12T00:46:09Z |
dc.type.spa.fl_str_mv |
article |
dc.type.coar.fl_str_mv |
http://purl.org/coar/resource_type/c_2df8fbb1 |
dc.type.coarversion.fl_str_mv |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
dc.type.local.spa.fl_str_mv |
artículo |
dc.type.coar.none.fl_str_mv |
http://purl.org/coar/resource_type/c_6501 |
dc.type.driver.none.fl_str_mv |
info:eu-repo/semantics/article |
format |
http://purl.org/coar/resource_type/c_6501 |
dc.identifier.issn.none.fl_str_mv |
2374-2497 |
dc.identifier.uri.none.fl_str_mv |
http://hdl.handle.net/20.500.12495/2601 |
dc.identifier.doi.none.fl_str_mv |
https://jamanetwork.com/journals/jama/fullarticle/10.1001/jamaoncol.2020.0409?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamaoncol.2020.0409 |
dc.identifier.instname.spa.fl_str_mv |
instname:Universidad El Bosque |
dc.identifier.reponame.spa.fl_str_mv |
reponame:Repositorio Institucional Universidad El Bosque |
dc.identifier.repourl.none.fl_str_mv |
https://repositorio.unbosque.edu.co |
identifier_str_mv |
2374-2497 instname:Universidad El Bosque reponame:Repositorio Institucional Universidad El Bosque |
url |
http://hdl.handle.net/20.500.12495/2601 https://jamanetwork.com/journals/jama/fullarticle/10.1001/jamaoncol.2020.0409?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamaoncol.2020.0409 https://repositorio.unbosque.edu.co |
dc.language.iso.none.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartofseries.spa.fl_str_mv |
JAMA oncology, 2374-2497, 2020 |
dc.relation.uri.none.fl_str_mv |
https://jamanetwork.com/journals/jamaoncology/article-abstract/2763865?utm_campaign=articlePDF%26utm_medium%3darticlePDFlink%26utm_source%3darticlePDF%26utm_content%3djamaoncol.2020.0409 |
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Acceso cerrado |
dc.rights.accessrights.none.fl_str_mv |
http://purl.org/coar/access_right/c_abf2 info:eu-repo/semantics/openAccess Acceso abierto |
dc.rights.creativecommons.none.fl_str_mv |
2020 |
rights_invalid_str_mv |
Acceso cerrado http://purl.org/coar/access_right/c_abf2 Acceso abierto 2020 |
eu_rights_str_mv |
openAccess |
dc.format.mimetype.none.fl_str_mv |
application/pdf |
dc.publisher.spa.fl_str_mv |
American Medical Association |
dc.publisher.journal.spa.fl_str_mv |
JAMA oncology |
institution |
Universidad El Bosque |
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Arrieta, OscarBarrón-Barrón, FelicianoRamírez Tirado, Laura AlejandraZatarain-Barrón, Zyanya LuciaCardona-Mendoza, Andrés FelipeDíaz-García, DiegoYamamoto-Ramos, MasaoMota-Vega, BeatrizCarmona, AmirPeralta-Alvarez, Marco PoloBautista, YolandaAldaco, FernandoGerson, RaquelRolfo, ChristianRosell, Rafael CostaCardona-Mendoza, Andrés Felipe [0000-0002-6697-5471]2020-05-12T00:46:09Z2020-05-12T00:46:09Z2374-2497http://hdl.handle.net/20.500.12495/2601https://jamanetwork.com/journals/jama/fullarticle/10.1001/jamaoncol.2020.0409?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamaoncol.2020.0409instname:Universidad El Bosquereponame:Repositorio Institucional Universidad El Bosquehttps://repositorio.unbosque.edu.coapplication/pdfengAmerican Medical AssociationJAMA oncologyJAMA oncology, 2374-2497, 2020https://jamanetwork.com/journals/jamaoncology/article-abstract/2763865?utm_campaign=articlePDF%26utm_medium%3darticlePDFlink%26utm_source%3darticlePDF%26utm_content%3djamaoncol.2020.0409Efficacy and safety of pembrolizumab plus docetaxel vs docetaxel alone in patients with previously treated advanced non-small cell lung cancer: the PROLUNG Phase 2 randomized clinical trialEfficacy and safety of pembrolizumab plus docetaxel vs docetaxel alone in patients with previously treated advanced non-small cell lung cancer: the PROLUNG Phase 2 randomized clinical trialarticleartículohttp://purl.org/coar/resource_type/c_6501http://purl.org/coar/resource_type/c_2df8fbb1info:eu-repo/semantics/articlehttp://purl.org/coar/version/c_970fb48d4fbd8a85Neoplasias pulmonaresInmunoterapiaDocetaxelTargeted and immune cancer therapyLung cancerOncologyImportance: Because of socioeconomic factors, many patients with advanced non-small cell lung cancer (NSCLC) do not receive immunotherapy in the first-line setting. It is unknown if the combination of immunotherapy with chemotherapy can provide clinical benefits in immunotherapy-naive patients with disease progression after treatment with platinum-based chemotherapy. Objective: To evaluate the safety and efficacy of the combination of pembrolizumab plus docetaxel in patients with previously treated advanced NSCLC following platinum-based chemotherapy regardless of EGFR variants or programmed cell death ligand 1 status. Design, Setting, and Participants: The Pembrolizumab Plus Docetaxel for Advanced Non-Small Cell Lung Cancer (PROLUNG) trial randomized 78 patients with histologically confirmed advanced NSCLC in a 1:1 ratio to receive either pembrolizumab plus docetaxel or docetaxel alone from December 2016 through May 2019. Interventions: The experimental arm received docetaxel on day 1 (75 mg/m2) plus pembrolizumab on day 8 (200 mg) every 3 weeks for up to 6 cycles followed by pembrolizumab maintenance until progression or unacceptable toxic effects. The control arm received docetaxel monotherapy. Main Outcomes and Measures: The primary end point was overall response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival, and safety. Results: Among 78 recruited patients, 32 (41%) were men, 34 (44%) were never smokers, and 25 (32%) had an EGFR/ALK alteration. Forty patients were allocated to receive pembrolizumab plus docetaxel, and 38 were allocated to receive docetaxel. A statistically significant difference in ORR, assessed by an independent reviewer, was found in patients receiving pembrolizumab plus docetaxel vs patients receiving docetaxel (42.5% vs 15.8%; odds ratio, 3.94; 95% CI, 1.34-11.54; P =.01). Patients without EGFR variations had a considerable difference in ORR of 35.7% vs 12.0% (P =.06), whereas patients with EGFR variations had an ORR of 58.3% vs 23.1% (P =.14). Overall, PFS was longer in patients who received pembrolizumab plus docetaxel (9.5 months; 95% CI, 4.2-not reached) than in patients who received docetaxel (3.9 months; 95% CI, 3.2-5.7) (hazard ratio, 0.24; 95% CI, 0.13-0.46; P <.001). For patients without variations, PFS was 9.5 months (95% CI, 3.9-not reached) vs 4.1 months (95% CI, 3.5-5.3) (P <.001), whereas in patients with EGFR variations, PFS was 6.8 months (95% CI, 6.2-not reached) vs 3.5 months (95% CI, 2.3-6.2) (P =.04). In terms of safety, 23% (9 of 40) vs 5% (2 of 38) of patients experienced grade 1 to 2 pneumonitis in the pembrolizumab plus docetaxel and docetaxel arms, respectively (P =.03), while 28% (11 of 40) vs 3% (1 of 38) experienced any-grade hypothyroidism (P =.002). No new safety signals were identified. Conclusions and Relevance: In this phase 2 study, the combination of pembrolizumab plus docetaxel was well tolerated and substantially improved ORR and PFS in patients with advanced NSCLC who had previous progression after platinum-based chemotherapy, including NSCLC with EGFR variations. Trial Registration: ClinicalTrials.gov Identifier: NCT02574598.Acceso cerradohttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessAcceso abierto2020THUMBNAILOscar Arrieta, MD, MSc; Feliciano Barrón, MD, MSc; Laura Alejandra Ramírez-Tirado, MD, MSc; Zyanya Lucia Zatarain-Barrón, MD, MSc;Andrés F. Cardona, MD, MSc, PhD; Diego Díaz-García, MD; Masao Yamamoto Ramos_2020.pdf.jpgOscar Arrieta, MD, MSc; Feliciano Barrón, MD, MSc; Laura Alejandra Ramírez-Tirado, MD, MSc; Zyanya Lucia Zatarain-Barrón, MD, MSc;Andrés F. Cardona, MD, MSc, PhD; Diego Díaz-García, MD; Masao Yamamoto Ramos_2020.pdf.jpgimage/jpeg5775https://repositorio.unbosque.edu.co/bitstreams/3be310b2-d831-46e2-96c9-6558de89c21a/download7210a811635d1799e7c05fee5d259be7MD53ORIGINALOscar Arrieta, MD, MSc; Feliciano Barrón, MD, MSc; Laura Alejandra Ramírez-Tirado, MD, MSc; Zyanya Lucia Zatarain-Barrón, MD, MSc;Andrés F. Cardona, MD, MSc, PhD; Diego Díaz-García, MD; Masao Yamamoto Ramos_2020.pdfOscar Arrieta, MD, MSc; Feliciano Barrón, MD, MSc; Laura Alejandra Ramírez-Tirado, MD, MSc; Zyanya Lucia Zatarain-Barrón, MD, MSc;Andrés F. Cardona, MD, MSc, PhD; Diego Díaz-García, MD; Masao Yamamoto Ramos_2020.pdfapplication/pdf543611https://repositorio.unbosque.edu.co/bitstreams/50d72e03-0ebf-4889-a208-ce7816d001e7/download922a5ceb8eb7b14abd4a51107916b6e3MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-81748https://repositorio.unbosque.edu.co/bitstreams/e6f056d8-db01-4df4-9d2e-d87994f82890/download8a4605be74aa9ea9d79846c1fba20a33MD52TEXTOscar Arrieta, MD, MSc; Feliciano Barrón, MD, MSc; Laura Alejandra Ramírez-Tirado, MD, MSc; Zyanya Lucia Zatarain-Barrón, MD, MSc;Andrés F. Cardona, MD, MSc, PhD; Diego Díaz-García, MD; Masao Yamamoto Ramos_2020.pdf.txtOscar Arrieta, MD, MSc; Feliciano Barrón, MD, MSc; Laura Alejandra Ramírez-Tirado, MD, MSc; Zyanya Lucia Zatarain-Barrón, MD, MSc;Andrés F. Cardona, MD, MSc, PhD; Diego Díaz-García, MD; Masao Yamamoto Ramos_2020.pdf.txtExtracted texttext/plain58744https://repositorio.unbosque.edu.co/bitstreams/12397d09-c559-44a4-b6b2-5e2f2c9df658/download59ddc2543b2c39b20013369d940f6fb5MD5420.500.12495/2601oai:repositorio.unbosque.edu.co:20.500.12495/26012024-02-07 10:43:01.518restrictedhttps://repositorio.unbosque.edu.coRepositorio Institucional Universidad El Bosquebibliotecas@biteca.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 |