Mariano Provencio1, Roberto Serna-Blasco2, Fabio Franco2, Virgina Calvo2, Ana Royuela3, Milda Auglytė2, Alfredo Sánchez-Hernández4, María de Julián Campayo4, Carlos García-Girón5, Manuel Dómine6, Ana Blasco7, José M Sánchez8, Juana Oramas9, Joaquim Bosch-Barrera10, María Á Sala11, María Sereno12, Ana L Ortega13, Luis Chara14, Berta Hernández15, Airam Padilla16, Juan Coves17, Remedios Blanco18, José Balsalobre19, Xabier Mielgo20, Coralia Bueno21, Eloisa Jantus-Lewintre22, Miguel Á Molina-Vila23, Atocha Romero24. 1. Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain. Electronic address: mprovenciop@gmail.com. 2. Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain. 3. Biostatistics Unit, Hospital Universitario Puerta de Hierro- Majadahonda, CIBERESP, Majadahonda, Madrid, Spain. 4. Medical Oncology, Hospital Provincial Centre de Castelló, Castellón de La Plana, Castellón, Spain. 5. Medical Oncology, Hospital Universitario de Burgos, Burgos, Burgos, Spain. 6. Medical Oncology, Fundación Jiménez Díaz, Madrid, Madrid, Spain. 7. Medical Oncology, Hospital General Universitario Valencia, Valencia, Valencia, Spain. 8. Medical Oncology, Hospital de La Princesa, Madrid, Madrid, Spain. 9. Medical Oncology, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain. 10. Medical Oncology, Hospital ICO Girona, Girona, Girona, Spain. 11. Medical Oncology, Hospital Basurto, Bilbao, Vizcaya, Spain. 12. Medical Oncology, Hospital Universitario Infanta Sofía, San Sebastián de Los Reyes, Madrid, Spain. 13. Medical Oncology, Consorcio Hospitalario de Jaén, Jaén, Jaén, Spain. 14. Medical Oncology, Hospital Universitario de Guadalajara, Guadalajara, Guadalajara, Spain. 15. Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain. 16. Medical Oncology, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Santa Cruz de Tenerife, Spain. 17. Medical Oncology, Hospital Son Llàtzer, Palma, Islas Baleares, Spain. 18. Medical Oncology, Consorci Sanitari Terrassa, Terrassa, Barcelona, Spain. 19. Medical Oncology, Hospital General Universitario Santa Lucia, Cartagena, Murcia, Spain. 20. Medical Oncology, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain. 21. Medical Oncology, Hospital Universitario Infanta Cristina, Parla, Madrid, Spain. 22. Mixed Unit TRIAL, Príncipe Felipe Research Center & General University Hospital of Valencia Research Foundation, Valencia, Spain. 23. Laboratory of Oncology/Pangaea Oncology, Quirón-Dexeus University Hospital, Barcelona, Spain. 24. Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain. Electronic address: aromero@idiphim.org.
Abstract
BACKGROUND: Survival data support the use of first-line osimertinib as the standard of care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC). However, it remains unclear whether upfront osimertinib is superior to sequential first- or second-generation tyrosine kinase inhibitors (TKIs) followed by osimertinib for all patients. It is impossible to predict which patients are at high risk of progression, and this constitutes a major limitation of the sequential TKI approach. PATIENTS AND METHODS: A total of 830 plasma samples from 228 patients with stage IV, EGFR-positive NSCLC who were treated with first-line TKIs were analysed by digital polymerase chain reaction (dPCR). RESULTS: The circulating tumour DNA (ctDNA) levels helped to identify patients with significantly improved survival rate, regardless of the treatment. Patients treated with first- or second-generation TKIs (N = 189) with EGFR mutations in plasma at a mutant allele frequency (MAF) <7% before treatment initiation (low-risk patients) or who were ctDNA negative after 3 or 6 months of treatment and with an MAF <7% at diagnosis (high responders) had two-thirds lower risk of death than patients in the opposite situation (adjusted hazard ratio [HR] = 0.38; 95% confidence interval [CI]: 0.23-0.64 and HR = 0.22; 95% CI: 0.12-0.42, respectively). The median overall survival (OS) for low-risk patients and high responders treated with first- or second-generation TKIs was 34.2 months and not reached, respectively, regardless of second-line treatment. There were no significant difference in OS between low-risk or high-responder patients treated upfront with osimertinib (N = 39) and those treated under a sequential approach with osimertinib (N = 60). Median OS was not reached in both cases. CONCLUSIONS: Pre-treatment ctDNA levels identify low-risk patients, who may benefit from sequential TKI treatment. Information regarding EGFR mutation clearance can help to improve patient selection.
BACKGROUND: Survival data support the use of first-line osimertinib as the standard of care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC). However, it remains unclear whether upfront osimertinib is superior to sequential first- or second-generation tyrosine kinase inhibitors (TKIs) followed by osimertinib for all patients. It is impossible to predict which patients are at high risk of progression, and this constitutes a major limitation of the sequential TKI approach. PATIENTS AND METHODS: A total of 830 plasma samples from 228 patients with stage IV, EGFR-positive NSCLC who were treated with first-line TKIs were analysed by digital polymerase chain reaction (dPCR). RESULTS: The circulating tumour DNA (ctDNA) levels helped to identify patients with significantly improved survival rate, regardless of the treatment. Patients treated with first- or second-generation TKIs (N = 189) with EGFR mutations in plasma at a mutant allele frequency (MAF) <7% before treatment initiation (low-risk patients) or who were ctDNA negative after 3 or 6 months of treatment and with an MAF <7% at diagnosis (high responders) had two-thirds lower risk of death than patients in the opposite situation (adjusted hazard ratio [HR] = 0.38; 95% confidence interval [CI]: 0.23-0.64 and HR = 0.22; 95% CI: 0.12-0.42, respectively). The median overall survival (OS) for low-risk patients and high responders treated with first- or second-generation TKIs was 34.2 months and not reached, respectively, regardless of second-line treatment. There were no significant difference in OS between low-risk or high-responder patients treated upfront with osimertinib (N = 39) and those treated under a sequential approach with osimertinib (N = 60). Median OS was not reached in both cases. CONCLUSIONS: Pre-treatment ctDNA levels identify low-risk patients, who may benefit from sequential TKI treatment. Information regarding EGFR mutation clearance can help to improve patient selection.
Authors: Mariano Provencio; Roberto Serna-Blasco; Ernest Nadal; Amelia Insa; M Rosario García-Campelo; Joaquín Casal Rubio; Manuel Dómine; Margarita Majem; Delvys Rodríguez-Abreu; Alex Martínez-Martí; Javier De Castro Carpeño; Manuel Cobo; Guillermo López Vivanco; Edel Del Barco; Reyes Bernabé Caro; Nuria Viñolas; Isidoro Barneto Aranda; Santiago Viteri; Eva Pereira; Ana Royuela; Virginia Calvo; Javier Martín-López; Francisco García-García; Marta Casarrubios; Fernando Franco; Estela Sánchez-Herrero; Bartomeu Massuti; Alberto Cruz-Bermúdez; Atocha Romero Journal: J Clin Oncol Date: 2022-05-16 Impact factor: 50.717