Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial.
| Title: | Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. |
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| Authors: | Rizvi NA; Division of Hematology/Oncology, Columbia University Medical Center, New York, New York.; Cho BC; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.; Reinmuth N; Asklepios Lung Clinic, Munich-Gauting, Germany.; Lee KH; Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, South Korea.; Luft A; Department of Oncology No. 1 (Thoracic Surgery), Leningrad Regional Clinical Hospital, St Petersburg, Russia.; Ahn MJ; Department of Hematology and Oncology, Samsung Medical Center, Seoul, South Korea.; van den Heuvel MM; Nederlands Kanker Instituut-Antoni van Leeuwenhoekziekenhuis, Amsterdam, the Netherlands.; Cobo M; Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain.; Vicente D; Department of Medical Oncology, Hospital Universitario Virgen Macarena, Seville, Spain.; Smolin A; Department of Radiology, Burdenko Main Military Clinical Hospital, Moscow, Russia.; Moiseyenko V; Oncological Clinical Research Center, St Petersburg, Russia.; Antonia SJ; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.; Le Moulec S; Department of Medical Oncology, Institut Bergonié, Bordeaux, France.; Robinet G; Service de Pneumologie, Centre Hospitalier Régional Universitaire de Brest-Hôpital Morvan, Brest, France.; Natale R; Cedars-Sinai Comprehensive Cancer Center, Los Angeles, California.; Schneider J; Department of Hematology and Oncology, NYU Winthrop Hospital, Mineola, New York.; Shepherd FA; Princess Margaret Cancer Centre and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada.; Geater SL; Department of Internal Medicine, Prince of Songkla University, Songkhla, Thailand.; Garon EB; David Geffen School of Medicine, University of California/TRIO-US Network, Los Angeles.; Kim ES; Levine Cancer Institute, Atrium Health, Charlotte, North Carolina.; Goldberg SB; Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut.; Nakagawa K; Faculty of Medicine, Department of Medical Oncology, Kindai University, Osaka, Japan.; Raja R; AstraZeneca, Gaithersburg, Maryland.; Higgs BW; AstraZeneca, Gaithersburg, Maryland.; Boothman AM; AstraZeneca, Cambridge, United Kingdom.; Zhao L; AstraZeneca, Gaithersburg, Maryland.; Scheuring U; AstraZeneca, Cambridge, United Kingdom.; Stockman PK; AstraZeneca, Cambridge, United Kingdom.; Chand VK; AstraZeneca, Gaithersburg, Maryland.; Peters S; Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne University, Lausanne, Switzerland. |
| Corporate Authors: | MYSTIC Investigators |
| Source: | JAMA oncology [JAMA Oncol] 2020 May 01; Vol. 6 (5), pp. 661-674. |
| Publication Type: | Clinical Trial, Phase III; Journal Article; Randomized Controlled Trial |
| Language: | English |
| Journal Info: | Publisher: American Medical Association Country of Publication: United States NLM ID: 101652861 Publication Model: Print Cited Medium: Internet ISSN: 2374-2445 (Electronic) Linking ISSN: 23742437 NLM ISO Abbreviation: JAMA Oncol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Chicago, Il : American Medical Association, [2015]- |
| MeSH Terms: | Antibodies, Monoclonal/*therapeutic use ; Antibodies, Monoclonal, Humanized/*therapeutic use ; Antineoplastic Agents, Immunological/*therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Carcinoma, Non-Small-Cell Lung/*drug therapy ; Lung Neoplasms/*drug therapy; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal, Humanized/pharmacology ; Antineoplastic Agents, Immunological/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Carcinoma, Non-Small-Cell Lung/pathology ; Lung Neoplasms/pathology ; Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Neoplasm Metastasis |
| Abstract: | Importance: Checkpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic non-small cell lung cancer.; Objective: To compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer.; Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non-small cell lung cancer who had no sensitizing EGFR or ALK genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018.; Interventions: Patients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy.; Main Outcomes and Measures: The primary end points, assessed in patients with ≥25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory.; Results: Between July 21, 2015, and June 8, 2016, 1118 patients were randomized. Baseline demographic and disease characteristics were balanced between treatment groups. Among 488 patients with ≥25% of tumor cells expressing PD-L1, median OS was 16.3 months (95% CI, 12.2-20.8) with durvalumab vs 12.9 months (95% CI, 10.5-15.0) with chemotherapy (hazard ratio [HR], 0.76; 97.54% CI, 0.56-1.02; P = .04 [nonsignificant]). Median OS was 11.9 months (95% CI, 9.0-17.7) with durvalumab plus tremelimumab (HR vs chemotherapy, 0.85; 98.77% CI, 0.61-1.17; P = .20). Median PFS was 3.9 months (95% CI, 2.8-5.0) with durvalumab plus tremelimumab vs 5.4 months (95% CI, 4.6-5.8) with chemotherapy (HR, 1.05; 99.5% CI, 0.72-1.53; P = .71). Among 809 patients with evaluable bTMB, those with a bTMB ≥20 mutations per megabase showed improved OS for durvalumab plus tremelimumab vs chemotherapy (median OS, 21.9 months [95% CI, 11.4-32.8] vs 10.0 months [95% CI, 8.1-11.7]; HR, 0.49; 95% CI, 0.32-0.74). Treatment-related adverse events of grade 3 or higher occurred in 55 (14.9%) of 369 patients who received treatment with durvalumab, 85 (22.9%) of 371 patients who received treatment with durvalumab plus tremelimumab, and 119 (33.8%) of 352 patients who received treatment with chemotherapy. These adverse events led to death in 2 (0.5%), 6 (1.6%), and 3 (0.9%) patients, respectively.; Conclusions and Relevance: The phase 3 MYSTIC study did not meet its primary end points of improved OS with durvalumab vs chemotherapy or improved OS or PFS with durvalumab plus tremelimumab vs chemotherapy in patients with ≥25% of tumor cells expressing PD-L1. Exploratory analyses identified a bTMB threshold of ≥20 mutations per megabase for optimal OS benefit with durvalumab plus tremelimumab.; Trial Registration: ClinicalT rials.gov Identifier: NCT02453282. |
| Comments: | Comment in: JAMA Oncol. 2020 May 1;6(5):674-675. doi: 10.1001/jamaoncol.2020.0264.. (PMID: 32271363); Erratum in: JAMA Oncol. 2020 Nov 1;6(11):1815. doi: 10.1001/jamaoncol.2020.5538.. (PMID: 33001136) |
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| Grant Information: | UL1 TR001863 United States TR NCATS NIH HHS |
| Molecular Sequence: | ClinicalTrials.gov NCT02453282 |
| Substance Nomenclature: | 0 (Antibodies, Monoclonal); 0 (Antibodies, Monoclonal, Humanized); 0 (Antineoplastic Agents, Immunological); 28X28X9OKV (durvalumab); QEN1X95CIX (tremelimumab) |
| Entry Date(s): | Date Created: 20200410 Date Completed: 20210104 Latest Revision: 20211120 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC7146551 |
| DOI: | 10.1001/jamaoncol.2020.0237 |
| PMID: | 32271377 |
| Database: | MEDLINE |
Clinical Trial, Phase III; Journal Article; Randomized Controlled Trial