Neoadjuvant Osimertinib for the Treatment of Stage I-IIIA Epidermal Growth Factor Receptor–Mutated Non–Small Cell Lung Cancer: A Phase II Multicenter Study

Author(s): Collin M. Blakely, MD, PhD^1,2; Anatoly Urisman, MD, PhD^2,3; Matthew A. Gubens, MD, MS^1,2; Claire K. Mulvey, MD^1,2; Greg M. Allen, MD, PhD^1,2; Stephen C. Shiboski, PhD⁴; Julia K. Rotow, MD⁵; Turja Chakrabarti, MD, MS^1,2; D. Lucas Kerr, BS^1,2; Jacqueline V. Aredo, MD, MS¹; Bianca Bacaltos, MS²; Megan Gee, BS²; Lisa Tan, BS²; Kirk D. Jones, MD³; W. Patrick Devine, MD, PhD^3,6; Robert C. Doebele, MD, PhD⁷; Dara L. Aisner, MD, PhD⁸; Tejas Patil, MD⁷; Erin L. Schenk, MD, PhD⁷; Trever G. Bivona, MD, PhD⁹; Jonathan W. Riess, MD, MS¹⁰; Melissa Coleman, MD^2,11; Johannes R. Kratz, MD^2,11; David M. Jablons, MD^2,11

Source: https://doi.org/10.1200/JCO.24.00071

Dr. Anjan Patel's Thoughts

Neoadjuvant Osimertinib did not have a significant impact on major pathologic response and there were no ypCR’s after a median of ~8 weeks of therapy. I do think this shows a measurable response, enough such that I would consider Osi in a patient with “borderline resectable” disease.

PURPOSE

To assess the safety and efficacy of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib as neoadjuvant therapy in patients with surgically resectable stage I-IIIA EGFR-mutated non–small cell lung cancer (NSCLC).

PATIENTS AND METHODS

This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (American Joint Committee on Cancer [AJCC] V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (ClinicalTrials.gov identifier: NCT03433469). Patients received osimertinib 80 mg orally once daily for up to two 28-day cycles before surgical resection. The primary end point was major pathological response (MPR) rate. Secondary safety and efficacy end points were also assessed. Exploratory end points included pretreatment and post-treatment tumor mutation profiling.

RESULTS

A total of 27 patients were enrolled and treated with neoadjuvant osimertinib for a median 56 days before surgical resection. Twenty-four (89%) patients underwent subsequent surgery; three (11%) patients were converted to definitive chemoradiotherapy. The MPR rate was 14.8% (95% CI, 4.2 to 33.7). No pathological complete responses were observed. The ORR was 52%, and the median DFS was 40.9 months. One treatment-related serious adverse event (AE) occurred (3.7%). No patients were unable to undergo surgical resection or had surgery delayed because of an AE. The most common co-occurring tumor genomic alterations were in TP53 (42%) and RBM10 (21%).

CONCLUSION

Treatment with neoadjuvant osimertinib in surgically resectable (stage IA-IIIA, AJCC V7) EGFR-mutated NSCLC did not meet its primary end point for MPR rate. However, neoadjuvant osimertinib did not lead to unanticipated AEs, surgical delays, nor result in a significant unresectability rate.

Author Affiliations

¹Department of Medicine, University of California, San Francisco, San Francisco, CA; ²Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA; ³Department of Pathology, University of California, San Francisco, San Francisco, CA; ⁴Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA; ⁵Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA; ⁶Institute for Human Genetics, University of California, San Francisco, San Francisco, CA; ⁷Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO; ⁸Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO; ⁹Chan Zuckerberg Biohub, San Francisco, CA; ¹⁰Department of Medicine, University of California Davis, Sacramento, CA; ¹¹Department of Surgery, University of California, San Francisco, San Francisco, CA

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.