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

Author(s): Jianxing He, MD, PhD¹; Masahiro Tsuboi, MD²; Walter Weder, MD³; Ke-Neng Chen, MD, PhD⁴; Maximilian J. Hochmair, MD^5,6; Jin-Yuan Shih, MD, PhD⁷; Sung Yong Lee, MD, PhD⁸; Kang-Yun Lee, MD, PhD⁹; Nguyen Viet Nhung, MD, PhD¹⁰; Somcharoen Saeteng, MD¹¹; Lunxu Liu, MD, PhD¹²; Ligang Xing, MD, PhD¹³; Nguyen Hoang Gia, MD¹⁴; Shuji Murakami, MD¹⁵; Yongtao Han, MD¹⁶; María Paz Saavedra, MD¹⁷; Seong Hoon Yoon, MD¹⁸; Carlos H.A. Teixeira, MD¹⁹; Carles Escriu, PhD, MBBS^20,21; Alex Martinez-Marti, MD²²; Collin M. Blakely, MD, PhD^23,24; Yasushi Yatabe, MD, PhD²⁵; Sanja Dacic, MD, PhD²⁶; Yuri Rukazenkov, MD, PhD²⁷; Xiangning Huang, PhD²⁸; Anupriya Dayal, MD²⁹; Jamie E. Chaft, MD^30,31; for the NeoADAURA Investigators;

Source: doi.org/10.1200/JCO-25-00883

Dr. Anjan Patel's Thoughts

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.

PURPOSE

Adjuvant osimertinib is the standard of care for patients with resected epidermal growth factor receptor (EGFR)–mutated non–small cell lung cancer (NSCLC). Neoadjuvant treatment could improve surgical and long-term outcomes.

METHODS

In this randomized, controlled, phase III study, patients with resectable, EGFR-mutated, stage II-IIIB NSCLC were randomly assigned (1:1:1) to receive neoadjuvant osimertinib (80 mg orally once daily for ≥9 weeks) plus platinum-based chemotherapy (once every 3 weeks for three cycles), osimertinib monotherapy (for ≥9 weeks), or placebo plus platinum-based chemotherapy (control), followed by surgical resection. Adjuvant osimertinib was offered to eligible patients after completion of surgery. The primary end point was major pathologic response (MPR) by blinded central pathology review. Event-free survival (EFS) was a secondary end point.

RESULTS

Overall, 358 patients were randomly assigned to receive osimertinib plus chemotherapy (121 patients), osimertinib monotherapy (117 patients), or placebo plus chemotherapy (120 patients). Osimertinib plus chemotherapy (MPR rate 26%) and osimertinib monotherapy (25%) demonstrated statistically significant improvement in the MPR rate versus placebo plus chemotherapy (2%), with corresponding odds ratios of 19.82 (95.002% CI, 4.60 to 85.33; P < .0001) and 19.28 (99.9% CI, 1.71 to 217.39; P < .0001), respectively. With 15% data maturity, the EFS rates 12 months were 93%, 95%, and 83% with osimertinib plus chemotherapy, osimertinib monotherapy, and placebo plus chemotherapy, respectively. In the neoadjuvant period, grade ≥3 adverse events of any cause occurred in 36%, 13%, and 33% of patients with osimertinib plus chemotherapy, osimertinib monotherapy, and placebo plus chemotherapy, respectively. No new safety concerns were identified.

CONCLUSION

Neoadjuvant osimertinib with or without chemotherapy demonstrated statistically significant improvement in the MPR rate over chemotherapy alone in patients with resectable, EGFR-mutated, stage II-IIIB NSCLC.

Author Affiliations

¹Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, China State Key Laboratory of Respiratory Disease & National Clinical Research Centre for Respiratory Disease, Guangzhou, China; ²Department of Thoracic Surgery and Oncology, National Cancer Center Hospital East, Kashiwa, Japan; ³Department of Thoracic Surgery, University of Zurich, Thoracic Surgery, Clinic Bethanien, Zurich, Switzerland; ⁴State Key Laboratory of Molecular Oncology, Beijing Key Laboratory of Carcinogenesis and Translational Research, The First Department of Thoracic Surgery, Peking University Cancer Hospital & Institute, Beijing, China; ⁵Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Vienna, Austria; ⁶Department of Respiratory and Critical Care Medicine, Klinik Floridsdorf, Vienna Healthcare Group, Vienna, Austria; ⁷Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; ⁸Division of Pulmonary Medicine, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea; ⁹Division of Pulmonary Medicine, Department of Internal Medicine, Shuang-Ho Hospital, Taipei Medical University, Taipei, Taiwan; ¹⁰Vietnam National Lung Hospital, Faculty of Medicine, UMP, VNU, Hanoi, Vietnam; ¹¹Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; ¹²Department of Thoracic Surgery, West China Hospital of Sichuan University, Chengdu, China; ¹³Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China; ¹⁴Department of Medical Oncology, Hanoi Oncology Hospital, Hanoi, Vietnam; ¹⁵Department of Thoracic Oncology, Kanagawa Cancer Canter, Yokohama, Japan; ¹⁶Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China; ¹⁷Orlandi Oncología, Santiago, Chile; ¹⁸Department of Internal Medicine, Pusan National University, School of Medicine, and Yangsan Hospital, Yangsan, Republic of Korea; ¹⁹Clinical Oncology Department, Hospital Alemão Oswaldo Cruz, São Paulo, Brazil; ²⁰Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom; ²¹Department of Medical Oncology, Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, United Kingdom; ²²Department of Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Barcelona, Spain; ²³Department of Medicine, University of California, San Francisco, CA; ²⁴Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA; ²⁵Department of Diagnostic Pathology, National Cancer Center, Tokyo, Japan; ²⁶Department of Pathology, Yale School of Medicine, New Haven, CT; ²⁷Late-stage Development, Oncology R&D, AstraZeneca, Cambridge, United Kingdom; ²⁸Biometrics, Late-stage Development, Oncology R&D, AstraZeneca, Cambridge, United Kingdom; ²⁹Late-stage Development, Oncology R&D, AstraZeneca, Gaithersburg, MD; ³⁰Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY; ³¹Department of Medicine, Weill Cornell Medical College, New York, NY

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.

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

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.

Adagrasib versus docetaxel in KRASG12C-mutated non-small-cell lung cancer (KRYSTAL-12): a randomised, open-label, phase 3 trial

Adagrasib demonstrated a median progression-free survival (PFS) of 5.5 months compared to 3.8 months with docetaxel in patients with KRAS G12C-mutated tumors. Treatment-related adverse events occurred in 47% of patients receiving Adagrasib and 46% in the docetaxel group. In my experience, Adagrasib is also more tolerable, making it a favorable option for this patient population.

Overall Survival with Neoadjuvant Nivolumab plus Chemotherapy in Lung Cancer

There was a 28% reduction in mortality. Patients who achieved a complete response (CR) or clearance of circulating tumor DNA (ctDNA) also experienced better outcomes.

Zongertinib in Previously Treated HER2-Mutant Non–Small-Cell Lung Cancer

Another option for HER-2 lung cancer patients. 71% had an objective response with a duration of 14.1 months and progression-free survival (PFS) of 12.4 months. Grade 3 adverse events were observed in 17% of patients. Some patients had been previously treated with HER-2 ADC therapy.