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

Author(s): James Chih-Hsin Yang, M.D., Ph.D.¹; Shun Lu, M.D., Ph.D.²; Hidetoshi Hayashi, M.D., Ph.D.³; Enriqueta Felip, M.D., Ph.D.⁴; Alexander I. Spira, M.D., Ph.D.⁵; Nicolas Girard, M.D., Ph.D.^6,7; Yu Jung Kim, M.D., Ph.D.⁸; Se-Hoon Lee, M.D., Ph.D.⁹; Yurii Ostapenko, M.D., Ph.D.¹⁰; Pongwut Danchaivijitr, M.D.¹¹; Baogang Liu, M.D.¹²; Adlinda Alip, M.D.¹³; Ernesto Korbenfeld, M.D.¹⁴; Josiane Mourão Dias, M.D.¹⁵; Benjamin Besse, M.D., Ph.D.¹⁶; Antonio Passaro, M.D., Ph.D.¹⁷; Ki-Hyeong Lee, M.D.¹⁸; Hailin Xiong, M.D.¹⁹; Soon-Hin How, M.D.²⁰; Ying Cheng, M.D.²¹; Gee-Chen Chang, M.D., Ph.D.²²; Hiroshige Yoshioka, M.D., Ph.D.²³; Michael Thomas, M.D.^24,25,26; Danny Nguyen, M.D.²⁷; Sai-Hong Ignatius Ou, M.D., Ph.D.²⁸; Sanjay Mukhedkar, M.D.²⁹; Kumar Prabhash, M.D., D.M.³⁰; Manolo D’Arcangelo, M.D.³¹; Jorge Alatorre-Alexander, M.D.³²; Juan Carlos Vázquez Limón, M.D.³³; Sara Alves, M.D.³⁴; Daniil Stroyakovskiy, M.D.³⁵; Marina Peregudova, M.D., Ph.D.³⁶; Mehmet Ali Nahit Şendur, M.D., Ph.D.³⁷; Ozan Yazici, M.D.³⁸; Raffaele Califano, M.D.³⁹; Vanesa Gutiérrez Calderón, M.D.⁴⁰; Filippo de Marinis, M.D.¹⁷; Sang-We Kim, M.D., Ph.D.⁴¹; Shirish M. Gadgeel, M.D., Ph.D.⁴²; Scott Owen, M.D.⁴³; John Xie, Ph.D.⁴⁴; Tao Sun, Ph.D.⁴⁴; Jaydeep Mehta, Ph.D.⁴⁵; Raja Venkatasubramanian, Ph.D.⁴⁶; Mariah Ennis, M.S.⁴⁵; Elizabeth Fennema, M.A.⁴⁷; Mahesh Daksh, Ph.D.⁴⁴; Amy Roshak, B.S.⁴⁵; Julie Man, M.S.⁴⁴; Roland E. Knoblauch, M.D., Ph.D.⁴⁵; Joshua M. Bauml, M.D.⁴⁵; Mahadi Baig, M.D.⁴⁴; Sujay Shah, M.D.⁴⁵; Seema Sethi, D.O.⁴⁵; Byoung Chul Cho, M.D., Ph.D.⁴⁸; the MARIPOSA Investigators*;

Source: DOI: 10.1056/NEJMoa2503001

Dr. Anjan Patel's Thoughts

The phase 3 MARIPOSA trial compared amivantamab–lazertinib (Ami-Laz) to osimertinib (Osi) in untreated EGFR-mutated advanced non-small cell lung cancer (NSCLC), showing a significant overall survival (OS) benefit for Ami-Laz (3-yr OS was 60% vs 51%). Median OS was not reached for Ami-Laz vs 36.7 months for Osi, with a projected >12-month median OS advantage. Ami-Laz also improved time to symptomatic progression (43.6 vs 29.3 months) and showed durable intracranial control, though grade ≥3 adverse events (AEs) were higher (80% vs 52%), notably skin, venous thromboembolism (VTE), and infusion reactions. In short, Ami-Laz is emerging as a new standard for first-line EGFRm NSCLC, but we’ll need to be proactive about managing its toxicity profile in clinic and whether this is superior or equivalent to Osi + chemo is currently unclear.

BACKGROUND

Previous results from this phase 3 trial showed that progression-free survival among participants with previously untreated EGFR (epidermal growth factor receptor)–mutated advanced non–small-cell lung cancer (NSCLC) was significantly improved with amivantamab–lazertinib as compared with osimertinib. Results of the protocol-specified final overall survival analysis in this trial have not been reported.

METHODS

We randomly assigned, in a 2:2:1 ratio, participants with previously untreated EGFR-mutated (exon 19 deletion or L858R substitution), locally advanced or metastatic NSCLC to receive amivantamab–lazertinib, osimertinib, or lazertinib. Overall survival (assessed in an analysis of the time from randomization to death from any cause) in the amivantamab–lazertinib group as compared with the osimertinib group was a key secondary end point. Additional end points included safety.

RESULTS

A total of 429 participants each were assigned to receive amivantamab–lazertinib or osimertinib. Over a median follow-up of 37.8 months, amivantamab–lazertinib led to significantly longer overall survival than osimertinib (hazard ratio for death, 0.75; 95% confidence interval, 0.61 to 0.92; P=0.005); 3-year overall survival was 60% and 51%, respectively. the clinical cutoff date, 38% of participants in the amivantamab–lazertinib group and 28% in the osimertinib group were still receiving the assigned treatment. Adverse events of grade 3 or higher were more common with amivantamab–lazertinib (in 80% of participants) than with osimertinib (in 52%), particularly skin-related events, venous thromboembolism, and infusion-related events; these findings were consistent with the established safety profile of each treatment. No new safety signals were observed with additional follow-up.

CONCLUSIONS

Amivantamab–lazertinib led to significantly longer overall survival among participants with previously untreated EGFR-mutated advanced NSCLC than osimertinib but was associated with an increased risk of adverse events of grade 3 or higher. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.)

Author Affiliations

¹National Taiwan University Cancer Center, National Taiwan University Hospital, Taipei, Taiwan; ²Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; ³Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan; ⁴Medical Oncology Service, Vall d’Hebron Institute of Oncology, Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona; ⁵Virginia Cancer Specialists, Fairfax; ⁶Institut Curie, Paris; ⁷Paris-Saclay University, Université de Versailles Saint-Quentin-en-Yvelines, Versailles, France; ⁸Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea; ⁹Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; ¹⁰National Cancer Institute, Kyiv, Ukraine; ¹¹Division of Medical Oncology, Department of Medicine, Siriraj Hospital Faculty of Medicine, Mahidol University Bangkok Noi Campus, Bangkok, Thailand; ¹²Harbin Medical University Cancer Hospital, Harbin, China; ¹³Clinical Oncology Department, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; ¹⁴British Hospital of Buenos Aires, Central British Hospital, Buenos Aires; ¹⁵Department of Medical Oncology, Barretos Cancer Hospital, São Paulo; ¹⁶Paris-Saclay University, Gustave Roussy, Villejuif, France; ¹⁷Division of Thoracic Oncology, European Institute of Oncology IRCCS, Milan; ¹⁸Medical Department, Chungbuk National University Hospital, Cheongju, South Korea; ¹⁹Department of Medical Oncology, Huizhou Municipal Central Hospital of Guangdong Province, Huizhou, China; ²⁰Department of Internal Medicine, Division of Respiratory Medicine, International Islamic University Malaysia Medical Specialist Center, Pahang, Malaysia; ²¹Jilin Cancer Hospital, Changchun, China; ²²School of Medicine and Institute of Medicine, Chung Shan Medical University and Division of Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; ²³Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata, Japan; ²⁴Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital, Heidelberg, Germany; ²⁵National Center for Tumor Diseases Heidelberg, a partnership between the German Cancer Research Center and Heidelberg University Hospital, Heidelberg, Germany; ²⁶Translational Lung Research Center Heidelberg, German Center for Lung Research, Heidelberg, Germany; ²⁷City of Hope National Medical Center, Duarte, CA; ²⁸University of California, Irvine School of Medicine, Orange; ²⁹St. John of God Murdoch Hospital, Murdoch, WA, Australia; ³⁰Department of Medical Oncology, Division of Adult Solid Tumor Oncology, Tata Memorial Hospital, Mumbai, India; ³¹Local Health Unit Authority of Romagna, Ravenna Hospital and Department of Onco-Hematology, Santa Maria delle Croci Hospital of Ravenna, Emilia-Romagna, Italy; ³²Health Pharma Professional Research, Mexico City; ³³Oncología Médica, Antiguo Hospital Civil de Guadalajara “Fray Antonio Alcalde” and Universidad de Guadalajara, Guadalajara, Mexico; ³⁴Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal; ³⁵Moscow City Oncology Hospital No. 62, Moscow; ³⁶Medical Center in Kolomenskoe, Moscow; ³⁷Department of Medical Oncology, Ankara Bilkent City Hospital and Ankara Yıldırım Beyazıt University, Ankara, Turkey; ³⁸Department of Medical Oncology, Gazi University Faculty of Medicine, Ankara, Turkey; ³⁹Department of Medical Oncology, Christie NHS Foundation Trust and Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom; ⁴⁰Medical Oncology Department, Hospital Regional Universitario de Málaga, Málaga, Spain; ⁴¹Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; ⁴²Division of Hematology-Oncology, Henry Ford Cancer Institute, Henry Ford Health, Detroit; ⁴³Department of Medical Oncology, McGill University Health Centre, Montreal; ⁴⁴Johnson & Johnson, Raritan, NJ; ⁴⁵Johnson & Johnson, Spring House, PA; ⁴⁶Johnson & Johnson, Titusville, NJ; ⁴⁷Johnson & Johnson, San Diego, CA; ⁴⁸Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea

Amivantamab Plus Lazertinib in Atypical EGFR-Mutated Advanced Non–Small Cell Lung Cancer: Results From CHRYSALIS-2

The CHRYSALIS-2, the cohort C analysis of patients with atypical EGFR mutations showed meaningful and durable activity. Atypical mutations can be difficult to deal with as a clinician, and having concrete data on these (S768I, L861Q and G719ZX) mutations gives assurance that this doublet is active. Overall response rate (ORR) was 52% and median progression-free survival (PFS) was 11.1 months in refractory patients and 19.5 months in the treatment-naive population.

Survival with Osimertinib plus Chemotherapy in EGFR-Mutated Advanced NSCLC

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.

Updated Overall Survival Analysis From the Phase II PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic Non–Small Cell Lung Cancer

This update demonstrated that encorafenib plus binimetinib was associated with the longest median overall survival (mOS) reported to date among targeted therapies in patients with treatment-naïve BRAF V600E–mutant metastatic NSCLC (mNSCLC). Median OS was 47.6 months in treatment-naïve patients. By the way check the authors there 😊.

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.