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

Autores organización

• 

  Andres Felipe Cardona Mendoza

  Autor

Autores

• Arrieta O
• Barrón F
• Ramírez-Tirado LA
• Zatarain-Barrón ZL
• Díaz-García D
• Yamamoto Ramos M
• Mota-Vega B
• Carmona A
• Peralta Álvarez MP
• Bautista Y
• Aldaco F
• Gerson R
• Rolfo C
• Rosell R

Unidades de investigación

• Grupo de Inmunología celular y molecular Universidad El Bosque (InmuBo)

  Investigador

  Maria Consuelo Romero Sanchez

Resumen

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. © 2020 American Medical Association. All rights reserved.

Keywords

• Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Docetaxel; Female; Humans; Immune Checkpoint Inhibitors; Lung Neoplasms; Male; Middle Aged; Programmed Cell Death 1 Receptor; Treatment Outcome; anaplastic lymphoma kinase; docetaxel; epidermal growth factor receptor; pembrolizumab; programmed death 1 ligand 1; antineoplastic agent; docetaxel; monoclonal antibody; PDCD1 protein, human; pembrolizumab; programmed death 1 receptor; adult; ALK gene; alopecia; anemia; anorexia; arthralgia; Article; cancer chemotherapy; cancer growth; constipation; controlled study; diarrhea; drug efficacy; drug safety; dysgeusia; edema; EGFR gene; fatigue; female; gene mutation; genetic variability; hand foot syndrome; headache; hepatitis; histology; human; human tissue; hypercalcemia; hyperthyroidism; hyponatremia; hypothyroidism; lacrimal duct occlusion; lymphocytopenia; maintenance chemotherapy; major clin