Survival with Osimertinib plus Chemotherapy in EGFR-Mutated Advanced NSCLC

Author(s): Pasi A. Jänne, M.D., Ph.D.¹; David Planchard, M.D., Ph.D.^2,3; Kunihiko Kobayashi, M.D., Ph.D.⁴; James Chih-Hsin Yang, M.D., Ph.D.^5,6; Ying Liu, M.D.⁷; Natalia Valdiviezo, M.D.⁸; Tae Min Kim, M.D., Ph.D.⁹; Liyan Jiang, M.D., Ph.D.¹⁰; Hiroshi Kagamu, M.D., Ph.D.⁴; Noriko Yanagitani, M.D., Ph.D.¹¹; Jialei Wang, M.D.¹²; Bivas Biswas, M.D., D.M.¹³; Artem Poltoratskiy, M.D., Ph.D.¹⁴; Yeni Neron, M.D.¹⁵; Carlos Rojas, M.D.¹⁶; Leona Koubkova, M.D.¹⁷; Carles Escriu, M.D., Ph.D.¹⁸; Doreen A. Ezeife, M.D.¹⁹; Helen Mann, M.Sc.²⁰; Elena Armenteros-Monterroso, Ph.D.²¹; Yuri Rukazenkov, M.D., Ph.D.²²; Chee Khoon Lee, M.B., B.S., Ph.D.²³; the FLAURA2 Investigators*;

Source: DOI: 10.1056/NEJMoa2510308

Dr. Anjan Patel's Thoughts

The final overall survival (OS) analysis from the FLAURA2 confirms the well-published findings that Osi + chemo improves survival over Osi monotherapy. OS difference was about 10 months at 47 vs 37 months, with a predictable toxicity tradeoff.

BACKGROUND

The primary analysis of this trial showed that first-line treatment with osimertinib plus chemotherapy with a platinum-based agent and pemetrexed led to significantly longer progression-free survival than osimertinib monotherapy among patients with epidermal growth factor receptor (EGFR)–mutated advanced non–small-cell lung cancer (NSCLC). Results from the planned final analysis of overall survival are needed.

METHODS

In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced NSCLC who had not previously received treatment for advanced disease to receive either osimertinib (80 mg once daily) plus chemotherapy with pemetrexed (500 mg per square meter of body-surface area) and a platinum-based agent (cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or osimertinib monotherapy (80 mg once daily). The key secondary end point was overall survival. Research Summary Osimertinib plus Chemotherapy in EGFR-Mutated NSCLC

RESULTS

A total of 557 patients were randomly assigned to the osimertinib plus platinum–pemetrexed group (279 patients) or the osimertinib monotherapy group (278 patients). The median overall survival was 47.5 months in the osimertinib plus platinum–pemetrexed group and 37.6 months in the osimertinib monotherapy group (hazard ratio for death, 0.77; 95% confidence interval, 0.61 to 0.96; P=0.02). Grade 3 or higher adverse events of any cause were reported in 70% of the patients in the osimertinib plus platinum–pemetrexed group and in 34% of the patients in the osimertinib monotherapy group; adverse events leading to the discontinuation of osimertinib were reported in 12% and 7%, respectively.

CONCLUSIONS

Among patients with EGFR-mutated advanced NSCLC, first-line treatment with osimertinib plus platinum–pemetrexed led to significantly longer overall survival than osimertinib monotherapy and was associated with an increased risk of reversible adverse events of grade 3 or higher. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.)

Author Affiliations

¹Department of Medical Oncology, Lowe Center for Thoracic Oncology, Dana–Farber Cancer Institute, Boston; ²Department of Medical Oncology, Institut Gustave Roussy, Thoracic Unit, Villejuif, France; ³Faculty of Medicine, Université Paris-Saclay, Paris; ⁴Department of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka, Japan; ⁵Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; ⁶Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan; ⁷Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, China; ⁸Department of Oncology, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; ⁹Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea; ¹⁰Department of Respiratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai; ¹¹Department of Thoracic Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo; ¹²Department of Thoracic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai; ¹³Department of Medical Oncology, Tata Medical Center, Kolkata, India; ¹⁴Petrov Research Institute of Oncology, St. Petersburg, Russia; ¹⁵Oncology Research Center, Florianopolis, Brazil; ¹⁶Medical Oncology Department, Bradford Hill Clinical Research Center, Santiago, Chile; ¹⁷Department of Pulmonology, Motol University Hospital, Prague, Czech Republic; ¹⁸Department of Medical Oncology, Clatterbridge Cancer Centre National Health Service Foundation Trust, Liverpool, United Kingdom; ¹⁹Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; ²⁰Oncology Biometrics, AstraZeneca, Cambridge, United Kingdom; ²¹Oncology Research and Development, AstraZeneca, Barcelona; ²²Oncology Research and Development, AstraZeneca, Cambridge, United Kingdom; ²³Department of Medical Oncology, Cancer Care Centre, St. George Hospital, Kogarah, NSW, Australia

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The combination therapy demonstrated improved overall survival (a 25% reduction in mortality) but was associated with increased toxicity, including skin rash and venous thromboembolic events (VTEs). Single-agent osimertinib may lose its role as monotherapy for EGFR-mutated NSCLC, as the FLAURA2 trial showed that combining osimertinib with chemotherapy yielded better outcomes than osimertinib alone.