Analysis of outcomes in resected early-stage NSCLC with rare targetable driver mutations

Nadia Ghazali; Jamie Feng; Katrina Hueniken; Khaleeq Khan; Karmugi Balaratnam; Thomas K Waddell; Kazuhiro Yasufuku; Andrew Pierre; Laura Donahoe; Elliot Wakeam; Marcelo Cypel; Jonathan Yeung; Shaf Keshavjee; Marc de Perrot; Natasha B Leighl; Geoffrey Liu; Penelope A Bradbury; Adrian Sacher; Lawson Eng; Tracy Stockley; Ming Sound Tsao; Frances A Shepherd

doi:10.1177/17588359241308466

Analysis of outcomes in resected early-stage NSCLC with rare targetable driver mutations

Ther Adv Med Oncol. 2024 Dec 23:16:17588359241308466. doi: 10.1177/17588359241308466. eCollection 2024.

Authors

Nadia Ghazali^{1

2}, Jamie Feng^{1

2}, Katrina Hueniken³, Khaleeq Khan⁴, Karmugi Balaratnam⁴, Thomas K Waddell^{5

2}, Kazuhiro Yasufuku^{5

2}, Andrew Pierre^{5

2}, Laura Donahoe^{5

2}, Elliot Wakeam^{5

2}, Marcelo Cypel^{5

2}, Jonathan Yeung^{5

2}, Shaf Keshavjee^{5

2}, Marc de Perrot^{5

2}, Natasha B Leighl^{1

2}, Geoffrey Liu^{1

2}, Penelope A Bradbury^{1

2}, Adrian Sacher^{1

2}, Lawson Eng^{1

2}, Tracy Stockley^{6

7}, Ming Sound Tsao^{8

2}, Frances A Shepherd^{8

2}

Affiliations

¹ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre (PMCC), University Health Network (UHN), Toronto, ON, Canada.
² University of Toronto, Toronto, ON, Canada.
³ Department of Biostatistics, PMCC, UHN, Toronto, ON, Canada.
⁴ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre (PMCC), University Health Network (UHN), Toronto ON, Canada.
⁵ Division of Thoracic Surgery, UHN, Toronto, ON, Canada.
⁶ Laboratory Medicine Program, UHN, Toronto, ON, Canada.
⁷ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
⁸ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre (PMCC), University Health Network (UHN), 700 University Avenue, 7-812, Toronto, ON M5G 2M9, Canada.

Abstract

Background: Given advancements in adjuvant treatments for non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK)-targeted therapies, it is important to consider postoperative targeted therapies for other early-stage oncogene-addicted NSCLC. Exploring baseline outcomes for early-stage NSCLC with these rare mutations is crucial.

Objectives: This study aims to assess relapse-free survival (RFS) and overall survival (OS) in patients with resected early-stage NSCLC with rare targetable driver mutations.

Methods: This retrospective single-center study identified stage I-III NSCLC patients with rare targetable mutations who underwent curative surgery. Tissue-based molecular profiling identified mutations in KRASG12C, EGFR Exon20, Erb-B2 receptor tyrosine kinase 2 (ERBB2), ALK, ROS1, B-Raf proto-oncogene (BRAF) V600E, mesenchymal-epithelial transition factor (MET) exon14 skipping, and rearranged during transfection (RET). Baseline patient and tumor characteristics, mutation subtype, and TP53 co-mutation were correlated with RFS and OS using Cox regression. The KRASG12C cohort was used as the reference for survival comparisons.

Results: Among 225 patients, mutations included the following: KRASG12C (n = 101, 45%), MET exon 14 skipping (n = 26, 12%), EGFR Exon 20 (n = 25, 11%), ERBB2 (n = 25, 11%), ALK fusion (n = 16, 7%), ROS1 fusion (n = 14, 6%), BRAF V600E mutation (n = 13, 6%), and RET fusion (n = 5, 2%). Five-year survival probabilities were 76% for stage I, 60% for stage II, and 58% for stage III. RFS was shorter across most mutation subgroups compared to KRASG12C, with ROS1 mutations showing significantly poorer RFS (HR 2.70, p = 0.019). By contrast, all mutation subgroups were associated with better OS than KRASG12C. The incidence of brain metastasis was highest in ERBB2 (22% at 5 years). TP53 co-mutation was associated with significantly worse OS (HR 2.35, p = 0.008).

Conclusion: While RFS was poorer for most mutations compared to KRASG12C, OS generally was better, suggesting a potential role for postoperative targeted therapies. These findings warrant further investigation through prospective studies and clinical trials to optimize adjuvant treatment strategies for patients with early-stage NSCLC harboring rare driver mutations.

Keywords: actionable genomic alteration; early-stage; non-small-cell lung cancer; rare driver mutation; surgery.

Plain language summary

Outcomes of patients with resected early-stage lung cancer with rare targetable driver mutations Early-stage non-small cell lung cancer (NSCLC) is often treated with surgery and sometimes chemotherapy after surgery. Recent advancement with discovery of mutations that drive cancer has led to improvement of outcomes in NSCLC with targeted therapies. Certain mutations in NSCLC are rare and how these mutations impact outcomes after surgery in early-stage NSCLC is less clear. Our study focused on patients with early-stage NSCLC who had surgery and specific rare mutations including EGFR Exon20 insertion, KRAS G12C, ALK, ROS1, BRAF, NTRK1/2/3, MET exon 14 skipping, RET, and ERBB2 mutations. We want to understand how presence of these mutations affects the chance of cancer returning (relapse-free survival) and overall survival after surgery. We found that most mutations had higher risk of cancer returning (relapse-free survival) compared to patients with KRAS mutation and ROS1 had highest risk of cancer returning in our study. However, for overall survival all mutations were linked to better overall survival than KRAS mutation. ERBB2 mutation had highest risk to develop brain metastasis when the cancer returns. Those with additional TP53 mutation, another genetic change had worse overall survival outcome. These results provide more evidence regarding the outcome of these patients with rare mutations in early-stage NSCLC. There might be a benefit of using targeted therapies early in the diagnosis of early-stage NSCLC. We hope our results help to inform potential studies in the future to show benefit of using targeted therapies after surgery in early-stage NSCLC.