Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC

Author(s): Byoung C. Cho, M.D., Ph.D. https://orcid.org/0000-0002-5562-270X, Shun Lu, M.D., Ph.D., Enriqueta Felip, M.D., Ph.D., Alexander I. Spira, M.D., Ph.D., Nicolas Girard, M.D., Ph.D., Jong-Seok Lee, M.D., Ph.D., Se-Hoon Lee, M.D., Ph.D., Yurii Ostapenko, M.D., Ph.D., Pongwut Danchaivijitr, M.D., Baogang Liu, M.D., Adlinda Alip, M.D., Ernesto Korbenfeld, M.D., Josiane Mourão Dias, M.D., Benjamin Besse, M.D., Ph.D., Ki-Hyeong Lee, M.D., Hailin Xiong, M.D., Soon-Hin How, M.D., Ying Cheng, M.D., Gee-Chen Chang, M.D., Ph.D., Hiroshige Yoshioka, M.D., Ph.D., James C.-H. Yang, M.D., Ph.D., Michael Thomas, M.D., Danny Nguyen, M.D., Sai-Hong I. Ou, M.D., Ph.D., Sanjay Mukhedkar, M.D., Kumar Prabhash, M.D., D.M., Manolo D’Arcangelo, M.D., Jorge Alatorre-Alexander, M.D., Juan C. Vázquez Limón, M.D., Sara Alves, M.D., Daniil Stroyakovskiy, M.D., Marina Peregudova, M.D., Ph.D., Mehmet A.N. Şendur, M.D., Ph.D., Ozan Yazici, M.D., Raffaele Califano, M.D., Vanesa Gutiérrez Calderón, M.D., Filippo de Marinis, M.D., Antonio Passaro, M.D., Ph.D. https://orcid.org/0000-0002-7575-3870, Sang-We Kim, M.D., Ph.D., Shirish M. Gadgeel, M.D., Ph.D., John Xie, Ph.D., Tao Sun, Ph.D., Melissa Martinez, M.S., Mariah Ennis, M.S., Elizabeth Fennema, M.A., Mahesh Daksh, Ph.D., Dawn Millington, M.S., Isabelle Leconte, Ph.D., Ryota Iwasawa, Ph.D., Patricia Lorenzini, M.S., Mahadi Baig, M.D., Sujay Shah, M.D., Joshua M. Bauml, M.D., S. Martin Shreeve, M.D., Ph.D., Seema Sethi, D.O., Roland E. Knoblauch, M.D., Ph.D., and Hidetoshi Hayashi, M.D., Ph.D. https://orcid.org/0000-0001-8787-5587, for the MARIPOSA Investigators*

Source: DOI: 10.1056/NEJMoa2403614

Dr. Maen Hussein's Thoughts

Another possible option for first line NSCLC EGFR mutated (non-exon 20) is Osimertinib (osi). Osi and chemotherapy had less brain metastases. And with Amivantamab and Lazertinib (EGFR inhibitor), the combination had better PFS and OS (HR0.8). Higher toxicity though with 10% discontinuation vs 3% for Osimertinib. This is interim analysis, toxicity was EGFR related mostly.

BACKGROUND

Amivantamab plus lazertinib (amivantamab–lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)–mutated advanced non–small-cell lung cancer (NSCLC).

METHODS

In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR-mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab–lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab–lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review.

RESULTS

Overall, 1074 patients underwent randomization (429 to amivantamab–lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab–lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab–lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab–lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab–lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR-related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab–lazertinib and 3% with osimertinib.

CONCLUSIONS

Amivantamab–lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR-mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.)

Author Affiliations

From the Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine (B.C.C.), Samsung Medical Center, Sungkyunkwan University School of Medicine (S.-H.L.), and the Lung Cancer Center, Asan Medical Center Cancer Institute (S.-W.K.), Seoul, the Department of Hematology–Oncology, Seoul National University Bundang Hospital, Seongnam (J.-S.L.), and the Medical Department, Chungbuk National University Hospital, Cheongju (K.-H.L.) — all in South Korea; the Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai (S.L.), Harbin Medical University Cancer Hospital, Harbin (B.L.), the Department of Medical Oncology, Huizhou Municipal Central Hospital of Guangdong Province, Huizhou (H.X.), and Jilin Cancer Hospital, Changchun (Y.C.) — all in China; the Medical Oncology Service, Vall d’Hebron Barcelona Hospital Campus–Vall d’Hebron University Hospital, Barcelona (E. Felip), and the Medical Oncology Department, Hospital Regional Universitario de Málaga y Virgen de la Victoria, Institute of Biomedical Research of Malaga, Malaga (V.G.C.) — both in Spain; Virginia Cancer Specialists, Fairfax (A.I.S.); Institut Curie, Institut du Thorax Curie-Montsouris, Paris (N.G.), and Paris-Saclay University, Université de Versailles Saint-Quentin-en-Yvelines, Versailles (N.G.), and Paris-Saclay University and Institut Gustave Roussy, Villejuif (B.B.) — all in France; the National Cancer Institute, Kyiv, Ukraine (Y.O.); the Division of Medical Oncology, Department of Medicine, Siriraj Hospital Faculty of Medicine, Mahidol University Bangkok Noi Campus, Bangkok, Thailand (P.D.); the Clinical Oncology Unit, Faculty of Medicine, University of Malaya, Kuala Lumpur (A.A.), and the Department of Internal Medicine, Division of Respiratory Medicine, International Islamic University Malaysia Medical Specialist Center, Pahang (S.-H.H.) — both in Malaysia; British Hospital of Buenos Aires, Central British Hospital, Buenos Aires (E.K.); the Department of Medical Oncology, Barretos Cancer Hospital, São Paulo (J.M.D.); the School of Medicine and Institute of Medicine, Chung Shan Medical University, and the Division of Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung (G.-C.C.), and the Department of Medical Oncology, National Taiwan University Cancer Center, Taipei (J.C.-H.Y.) — both in Taiwan; the Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata (H.Y.), and the Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka (H.H.) — both in Japan; the Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital, and the National Center for Tumor Diseases Heidelberg, German Center for Lung Research, Heidelberg, Germany (M.T.); City of Hope National Medical Center, Duarte (D.N.), Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Orange (S.-H.I.O.), and Janssen Research and Development, San Diego (E. Fennema, D.M., S.M.S.) — all in California; St. John of God Murdoch Hospital, Murdoch, WA, Australia (S.M.); the Department of Medical Oncology, Division of Adult Solid Tumor, Tata Memorial Center and Homi Bhabha National Institute, Mumbai, India (K.P.); the Local Health Unit Authority of Romagna, Ravenna Hospital and Department of Onco-Hematology, Santa Maria delle Croci Hospital of Ravenna, Ravenna (M. D’Arcangelo), and the Division of Thoracic Oncology, European Institute of Oncology IRCCS, Milan (F.M., A.P.) — both in Italy; Health Pharma Professional Research, Mexico City (J.A.-A.), Oncología Médica, Antiguo Hospital Civil de Guadalajara “Fray Antonio Alcalde,” Guadalajara, and Universidad de Guadalajara, Guadalajara (J.C.V.L.) — all in Mexico; Instituto Português de Oncologia do Porto, Porto, Portugal (S.A.); Moscow City Oncology Hospital No. 62 (D.S.) and the Medical Center in Kolomenskoe (M.P.) — both in Moscow; the Department of Medical Oncology, Ankara Bilkent City Hospital and Ankara Yıldırım Beyazıt University (M.A.N.Ş.), and the Department of Medical Oncology, Gazi University Faculty of Medicine (O.Y.) — both in Ankara, Turkey; the Department of Medical Oncology, Christie NHS Foundation Trust and Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom (R.C.); the Division of Hematology–Oncology, Henry Ford Cancer Institute, Henry Ford Health, Detroit (S.M.G.); Janssen Research and Development, Raritan, NJ (J.X., T.S., M.M., M. Daksh, M.B.); Janssen Research and Development, Spring House, PA (M.E., R.I., P.L., S. Shah, J.M.B., S. Sethi, R.E.K.); and Johnson and Johnson Clinical Innovation, Campus Basel, Allschwil, Switzerland (I.L.).

Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non–Small Cell Lung Cancer: The Phase III PACIFIC-2 Study

PACIFIC-2 was a phase III trial testing durva given concurrently with cCRT (and continued as consolidation) versus placebo + cCRT in unresectable stage III NSCLC, and it did not meet its primary endpoint. The overall response rate (ORR) was essentially identical (60.7% vs 60.6%), and pneumonitis rates were similar (any grade 28.8% vs 28.7%; grade ≥3: 4.6% vs 5.6%), but adverse events (AEs) leading to discontinuation and fatal AEs were higher with durva (25.6% vs 12.0%; 13.7% vs 10.2%), especially early on. Starting IO up front with cCRT didn’t improve outcomes and added early toxicity—consolidation durva after cCRT is still the way to go.

Sevabertinib in Advanced HER2-Mutant Non–Small-Cell Lung Cancer

Sevabertinib shows strong efficacy in HER2-mutant NSCLC, with an overall response rate (ORR) of 64% and median progression-free survival (PFS) of 8.3 months in previously treated, HER2-TKI–naive patients, and an overall response rate (ORR) of 71% with a duration of response (DOR) of 11.0 months in first-line therapy. Activity is highest in TKD mutations, especially Y772_A775dupYVMA, and intracranial responses are seen. Safety is manageable: diarrhea is common but mostly low grade, with grade ≥3 in 5–23% and rare discontinuations. Notably, interstitial lung disease (ILD) was not observed. These data position sevabertinib as a viable oral TKI alongside ADCs for HER2-mutant NSCLC, particularly for TKD/YVMA disease.

Overall Survival with Amivantamab–Lazertinib in EGFR-Mutated Advanced NSCLC

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.

Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small Cell Lung Cancer

The phase III NeoADAURA trial evaluated neoadjuvant osimertinib (OSI) with or without platinum-based chemotherapy (CT) versus CT alone in resectable, EGFR-mutated stage II-IIIB non-small cell lung cancer (NSCLC). Both OSI+CT and OSI monotherapy significantly improved major pathologic response (MPR: 26% and 25% vs 2%), and 12-month event-free survival (EFS) rates were higher with OSI-containing regimens (OSI+CT 93%, OSI 95%, CT 83%). Nodal downstaging was also more frequent with OSI arms (53% vs 21%). Neoadjuvant OSI—with or without CT—looks like a real step forward for our EGFR-mutant NSCLC patients, especially given the robust pathologic responses and high rates of surgical completion.

Phase III Study of Mediastinal Lymph Node Dissection for Ground Glass Opacity–Dominant Lung Adenocarcinoma

This large, well-done study compared systematic mediastinal lymph node dissection (LND) versus no LND in patients with GGO-dominant invasive lung adenocarcinoma (CTR ≤0.5, ≤3 cm, cT1N0M0). Interim analysis of 302 patients showed no lymph node metastases in either arm, with both groups achieving 3-year disease-free survival (DFS) and overall survival (OS) of 100% at the time of analysis. The no LND arm had significantly shorter surgery duration (74 vs 109 min), less blood loss (44 vs 82 mL), shorter hospital stays (3.9 vs 4.5 days), and fewer grade ≥2 complications (3.3% vs 9.3%). Based on these findings, the trial was terminated early for nonmaleficence, and the authors recommend omitting systematic mediastinal LND in this population. In short, for carefully selected GGO-dominant lung adenocarcinoma, skipping mediastinal LND appears safe and spares patients’ unnecessary morbidity—this could be a real practice-changer for our early-stage, node-negative cases.