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

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.