Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer

By T. Mok, Yi-long Wu, M. Ahn, M. Garassino, H. R. Kim, S. Ramalingam, F. Shepherd, Yong He, H. Akamatsu, W. Theelen and 7 more. New England Journal of Medicine, 2016

2,861 citations recorded by the source corpus.

BACKGROUND Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) that is selective for both EGFR‐TKI sensitizing and T790M resistance mutations in patients with non–small‐cell lung cancer. The efficacy of osimertinib as compared with platinum‐based therapy plus pemetrexed in such patients is unknown. METHODS In this randomized, international, open‐label, phase 3 trial, we assigned 419 patients with T790M‐positive advanced non–small‐cell lung cancer, who had disease progression after first‐line EGFR‐TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body‐surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first‐line EGFR‐TKI therapy. The primary end point was investigator‐assessed progression‐free survival. RESULTS The median duration of progression‐free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression‐free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%). CONCLUSIONS Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M‐positive advanced non–small‐cell lung cancer (including those with CNS metastases) in whom disease had progressed during first‐line EGFR‐TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981.)

Subfields: Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/bd8840946a65bec6d407a96092eda55497e49a58

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In Pulmonary and Respiratory Medicine

1. Jin-Yuan Shih
2. Shang-Gin Wu

Citations in the corpus

• Acquired Resistance to Immune Checkpoint Inhibitors (2020, background): “For example, in EGFR-mutant lung cancer, an archetype for molecularly targeted therapy, knowledge of resistance to first-generation tyrosine kinase inhibitors (TKIs) identified a secondary EGFR point mutation which, in turn, led to the development of the third-generation EGFR-T790M targeted TKI osim”
• Management of acquired resistance to EGFR TKI–targeted therapy in advanced non-small cell lung cancer (2018, positive): “Skin rash FDA approved Dacomitinib EGFR del19, L858R, HER2, HER4 Diarrhea, skin rash/acne Phase III Neratinib EGFR G719X, HER2, HER4 Diarrhea, dyspnea, N/V Phase II 3rd-generation Irreversible; Osimertinib EGFR mutations and T790M Diarrhea, skin rash FDA approved covalent Rociletinib EGFR T790M muta”
• Molecular profiling for precision cancer therapies (2020, background): “the incorporation of new treatment options in patients with EGFR-mutant NSCLC (such as osimertinib) [34, 35] and BRAF-mutant NSCLC [36, 37] and melanoma (such as the dabrafenib and trametinib combination) [38], which have led to a significant improvement in survival in these patient populations and ”
• Osimertinib in Untreated EGFR‐Mutated Advanced Non–Small‐Cell Lung Cancer (2018, neutral): “J Clin Oncol 2017; 35(15): Suppl: 9005.”
• Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. (2016, background): “A single randomized phase III trial explored the efficacy of osimertinib compared with a platinum doublet (pemetrexed with either cisplatin or carboplatin) in patients whose cancer progressed on a first-line EGFR-TKI and who had an EGFR T790M mutation detected.(13) In this study, enrolled patients w”