Impact of tumor-intrinsic molecular features on survival and acquired tyrosine kinase inhibitor resistance in ALK-positive NSCLC Journal Article
| Authors: | Nakazawa, M.; Harada, G.; Ghanem, P.; Bubie, A.; Kiedrowski, L. A.; Murray, J. C.; Marrone, K. A.; Scott, S. C.; Houseknecht, S.; Falcon, C. J.; Evans, P.; Feliciano, J.; Hann, C. L.; Ettinger, D. S.; Smith, K. N.; Anagnostou, V.; Forde, P. M.; Brahmer, J. R.; Levy, B.; Drilon, A.; Lam, V. K. |
| Article Title: | Impact of tumor-intrinsic molecular features on survival and acquired tyrosine kinase inhibitor resistance in ALK-positive NSCLC |
| Abstract: | While tyrosine kinase inhibitors (TKI) have shown remarkable efficacy in anaplastic lymphoma kinase (ALK) fusion-positive advanced non-small cell lung cancer (NSCLC), clinical outcomes vary and acquired resistance remains a significant challenge. We conducted a retrospective study of patients with ALK-positive NSCLC who had clinico-genomic data independently collected from two academic institutions (n = 309). This was paired with a large-scale genomic cohort of patients with ALK-positive NSCLC who underwent liquid biopsies (n = 1,118). Somatic co-mutations in TP53 and loss-of-function alterations in CDKN2A/B were most commonly identified (24.1% and 22.5%, respectively in the clinical cohort), each of which was independently associated with inferior overall survival (HR: 2.58; 95% confidence interval, CI: 1.62-4.09 and HR: 1.93; 95% CI: 1.17-3.17, respectively). Tumors harboring EML4-ALK variant 3 (v3) were not associated with specific co-alterations but were more likely to develop ALK resistance mutations, particularly G1202R and I1171N (OR: 4.11; P < 0.001 and OR: 2.94; P = 0.026, respectively), and had inferior progression-free survival on first-line TKI (HR: 1.52; 95% CI: 1.03-2.25). Non-v3 tumors were associated with L1196M resistance mutation (OR: 4.63; P < 0.001). EML4-ALK v3 and somatic co-alterations in TP53 and CDKN2A/B are associated with inferior clinical outcomes. v3 status is also associated with specific patterns of clinically important ALK resistance mutations. These tumor-intrinsic features may inform rational selection and optimization of first-line and consolidative therapy. SIGNIFICANCE: In a large-scale, contemporary cohort of patients with advanced ALK-positive NSCLC, we evaluated molecular characteristics and their impact on acquired resistance mutations and clinical outcomes. Our findings that certain ALK variants and co-mutations are associated with differential survival and specific TKI-relevant resistance patterns highlight potential molecular underpinnings of the heterogenous response to ALK TKIs and nominate biomarkers that may inform patient selection for first-line and consolidative therapies. © 2024 The Authors; Published by the American Association for Cancer Research. |
| Keywords: | retrospective studies; genetics; protein kinase inhibitor; carcinoma, non-small-cell lung; lung neoplasms; protein tyrosine kinase; retrospective study; tyrosine kinase inhibitors; protein tyrosine kinase inhibitor; protein kinase inhibitors; lung tumor; receptor protein-tyrosine kinases; non small cell lung cancer; humans; human |
| Journal Title: | Cancer Research Communications |
| Volume: | 4 |
| Issue: | 3 |
| ISSN: | 2767-9764 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-03-01 |
| Start Page: | 786 |
| End Page: | 795 |
| Language: | English |
| DOI: | 10.1158/2767-9764.Crc-24-0065 |
| PUBMED: | 38407352 |
| PROVIDER: | scopus |
| PMCID: | PMC10939006 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work