Thoracic Radiotherapy Improves the Survival in Patients With EGFR-Mutated Oligo-Organ Metastatic Non–Small Cell Lung Cancer Treated With Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors: A Multicenter, Randomized, Controlled, Phase III Trial

Author(s): Hongfu Sun, MD¹; Minghao Li, MD^1,2; Wei Huang, MD¹; Jian Zhang, MD³; Shihong Wei, MD⁴; Yongjing Yang, MD⁵; Zhongtang Wang, MD¹; Shucheng Ye, MD⁶; Heyi Gong, MD³; Yaowen Zhang, MD⁷; Jie Li, MD⁸; Haixia Song, MD⁴; Lifang Wang, MD³; Xiangming Chen, BS⁹; Haiqun Lin, MD¹⁰; Gaofeng Ding, MD¹¹; Hongwei Li, MS⁸; Anping Zheng, MD⁷; Xuezhen Ma, MD¹²; ShaoShui Chen, MD¹³; Liping Liu, MD¹⁴; Kaixian Zhang, MD¹⁵; Chengrui Fu, MD¹; Wenzhi Liu, MD¹⁶; Jing Wang, PhD⁸; Xiaqin Zhang, MS⁸; Tingting Liu, MS¹; Dan Han, MD¹; Qian Zhao, MD¹; Peipei Wu, MD¹⁴; Qianqian Yuan, MD¹⁵; LiJun Tian, MD¹³; Ping Zhang, MD⁸; Xueqin Wu, MD⁸; Fei Chen, MD⁸; Zicheng Zhang, MD¹⁶; Baosheng Li, MD¹.

Source: https://doi.org/10.1200/JCO.23.02075

Dr. Maen Hussein's Thoughts

Patients were treated with thoracic and extrathoracic radiation to oligometastatic sites and it seems to help with improving survival, something to consider especially with SBRT now. Do our radiation oncologists have additional input?

PURPOSE

This multicenter, randomized, phase III clinical trial (Northern Radiation Oncology Group of China-002) focused on patients with oligo-organ metastatic non–small cell lung cancer (NSCLC) who have epidermal growth factor receptor (EGFR) mutations. We aimed to investigate whether first-line concurrent thoracic radiotherapy (TRT) and EGFR-tyrosine kinase inhibitors (TKIs), compared with TKIs alone, could achieve better survival.

MATERIALS AND METHODS

The patients in the TKI plus TRT group received 60 Gy to primary lung tumor and positive regional lymph nodes. Radiotherapy for metastases to other sites was determined by clinicians. The primary end point was the progression-free survival (PFS). Secondary end points included overall survival (OS) and treatment-related adverse events (TRAEs). The first and second interim analyses were performed in March 2021 and March 2022.

RESULTS

Between April 14, 2016, and February 25, 2022, a total of 118 patients were enrolled. Compared with the TKI alone group, the TKI plus TRT group achieved significantly better PFS (hazard ratio [HR], 0.57; P = .004) and OS (HR, 0.62; P = .029). The median PFS was 10.6 months in the TKI alone group and 17.1 months in the TKI plus TRT group. The median OS was 26.2 months and 34.4 months in the TKI alone group and TKI plus TRT group, respectively. The TKI plus TRT group showed better local control but was associated with a higher incidence of severe TRAEs (11.9% v 5.1%).

CONCLUSION

For patients with EGFR-mutated oligo-organ metastatic NSCLC treated with first-line EGFR-TKIs, concurrent TRT improves the PFS and OS, and TRAEs are acceptable and tolerable.

Author Affiliations

¹Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, China; ²Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; ³Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China; ⁴Department of Radiation Oncology, Gansu Provincial Cancer Hospital, Lanzhou, China; ⁵Department of Radiation Oncology, Jilin Cancer Hospital, Changchun, China; ⁶Department of Radiation Oncology, Affiliated Hospital of Jining Medical University, Jining, China; ⁷Department of Radiation Oncology, Anyang Tumor Hospital, the Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Henan Medical Key Laboratory of Precise Prevention and Treatment of Esophageal Cancer, Anyang, China; ⁸Department of Radiation Oncology, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/ Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China; ⁹Department of Clinical Oncology, Taian City Central Hospital, Taian, China; ¹⁰Department of Oncology, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China; ¹¹Department of Radiation Oncology, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China; ¹²Department of Oncology, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Cancer Hospital, Qingdao, China; ¹³Department of Radiation Oncology, Binzhou Medical University Hospital, Binzhou, China; ¹⁴Department of Oncology, Jining No.1 People’s Hospital, Jining, China; ¹⁵Department of Radiation Oncology, Tengzhou Central People’s Hospital, Tengzhou, China; ¹⁶Department of Radiation Oncology, Shenzhen Traditional Chinese Medicine Hospital, the Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China.

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.