Effectiveness and prognostic factors of first-line crizotinib treatment in patients with ROS1-rearranged non-small cell lung cancer: A multicenter retrospective study

Zheng, Jing; Cao, He; Li, Yuping; Rao, Chuangzhou; Zhang, Te; Luo, Jiayou; Lv, Dongqing; Zhu, Yueyong; Zhou, Jianya; Zhou, Jianying

doi:10.1016/j.lungcan.2020.07.016

Cited by 10 publications

(20 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many patients with ALK, ROS1, or RET fusion benefiting from matched targeted therapy will develop acquired resistance within 1 year, and a small fraction of patients were found to have progressive disease (PD) as their best response owing to intrinsic resistance. [5][6][7] High-throughput next-generation sequencing (NGS) is ideal for uncovering diverse genetic events in NSCLC. 8 Target-capture DNA NGS is capable of pinpointing breakpoints to specific base positions in the genome, and thus can identify variable fusion variants.…”

Section: Introductionmentioning

confidence: 99%

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

Guo

Liu

et al. 2021

Journal of Thoracic Oncology

View full text Add to dashboard Cite

Introduction: Variable genomic breakpoints have been identified through the application of target-capture DNA next-generation sequencing (NGS) for ALK, ROS1, and RET fusion detection in NSCLC. We investigated whether ALK, ROS1, and RET genomic breakpoint location can predict matched targeted therapy efficacy.Methods: NSCLCs were analyzed by DNA NGS, targetspecific RNA NGS, whole-transcriptome sequencing, and immunohistochemistry.Results: In total, 3787 NSCLC samples were analyzed. DNA NGS detected ALK, ROS1, and RET fusions in 241, 59, and 76 cases, respectively. These fusions were divided into canonical (single EML4-ALK, CD74/EZR/TPM3/SDC4-ROS1, and KIF5B/CCDC6-RET fusions), noncanonical (single non-EML4-ALK, non-CD74/EZR/TPM3/SDC4-ROS1, and non-KIF5B/CCDC6-RET fusions), and primary/reciprocal (both primary and reciprocal rearrangements were detected) subtypes on the basis of genomic breakpoint position, and noncanonical and primary/reciprocal subtypes were defined as uncommon fusions. Further RNA sequencing and immunohistochemistry revealed that six of 47 (12.8%) uncommon fusions were actually nonproductive rearrangements that generated no aberrant transcripts or proteins. Moreover, genomic breakpoints of canonical ALK and RET, but not ROS1, fusions always predicted breakpoints at the transcript level, whereas 85.4% (35 of 41) of uncommon fusions actually produced canonical fusion transcripts. Patients with uncommon ALK fusion (n ¼ 31) who received first-line crizotinib exhibited shorter median progressionfree survival than those with canonical ALK fusion (n ¼ 53, 8.4 mo versus 12.0 mo, p ¼ 0.004). However, no difference in progression-free survival was observed when only ALK RNA or protein-positive cases were analyzed (p ¼ 0.185).Conclusions: Uncommon ALK, ROS1, and RET genomic breakpoint is an unreliable predictor of matched targeted therapy efficacy. Functional validation by RNA or protein assay may add value for the accurate detection and interpretation of rare fusions.

show abstract

Section: Introductionmentioning

confidence: 99%

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

Guo

Liu

et al. 2021

Journal of Thoracic Oncology

View full text Add to dashboard Cite

show abstract

“…Given the prominent efficacy of crizotinib in ROS1-rearranged NSCLC patients, with the median PFS ranging from 15.9 to 19.3 months in different clinical studies (17,18), the relatively shorter PFS in our case prompted us to explore potential negative factors influencing crizotinib efficacy. NSCLC patients with CD74-ROS1 fusion, concomitant mutations, or >2 metastatic organs have been confirmed to have a relatively inferior response to crizotinib treatment in previous studies (8)(9)(10)(11). In this case, the patient was initially diagnosed as stage IIIA lung adenocarcinoma.…”

Section: Discussionmentioning

confidence: 69%

“…NSCLC patients with CD74-ROS1 fusion, concomitant mutations, or >2 metastatic organs have been confirmed to have a relatively inferior response to crizotinib treatment in previous studies ( 8 – 11 ). In this case, the patient was initially diagnosed as stage IIIA lung adenocarcinoma.…”

Section: Discussionmentioning

confidence: 82%

“…The result suggested that patients with exclusive ROS1 fusion had a longer PFS than those with concomitant mutations (15.5 vs. 8.5 months, p = 0.0213) ( 10 ). In addition, the clinical characteristics related to crizotinib efficacy in patients with ROS1 -rearranged NSCLC were analyzed, and >2 baseline metastatic organ involvement was identified as the only independent prognostic factor of PFS (hazard ratio, 4.762; 95% confidence interval, 1.515–14.961; p = 0.008) ( 11 ). The report of worse clinical outcomes in ALK -rearranged NSCLC patients whose tumors harbor nonreciprocal/reciprocal ALK translocation, which leads to another gene fused to ALK gene, reminded us to explore whether complex ROS1 fusions influence the response of patients to crizotinib.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Case Report: Detection of Double ROS1 Translocations, SDC4-ROS1 and ROS1-GK, in a Lung Adenocarcinoma Patient and Response to Crizotinib

Chen

Hong

et al. 2021

Front. Med.

View full text Add to dashboard Cite

ROS1 rearrangement, identified in ~2% of non-small cell lung cancer (NSCLC), has defined a distinctive molecular subtype. Patients with ROS1 fusion have been shown to be highly sensitive to treatment with crizotinib. However, the efficacy of crizotinib in NSCLC patients with double ROS1 fusions remains to be elucidated. Here, we report a 40-year-old male diagnosed with stage IIIA lung adenocarcinoma. Two ROS1 fusions [SDC4-ROS1 (EX2:EX32) and ROS1-GK (EX31:EX13)] were detected simultaneously in tumor tissue of this patient by next-generation sequencing. Crizotinib was administered, and the patient showed a partial response in lung lesions. Nevertheless, a brain lesion was found at 8 months after treatment. The slightly short duration of response may be related to the presence of ROS1-GK rearrangement. This case proved that patients with SDC4-ROS1 and ROS1-GK fusions may be sensitive to crizotinib, but short progression-free survival of this case showed that the presence of ROS1-GK rearrangement may affect the efficacy of crizotinib. A large-scale investigation on the efficacy of ROS1 inhibitors in patients with complex ROS1 fusions should be conducted in the future.

show abstract

“…Factors associated with a poor prognosis were the presence of brain metastases, more than two metastatic sites and a TP53 mutation [41,46,81,82]. The presence of a CD74-ROS-1 fusion was associated with a more favorable prognosis in some studies [41] but had no impact according to others [36,83,84]. Despite crizotinib's notable benefit in the management of ROS-1-positive NSCLCs, its poor brain penetration makes the central nervous system the primary site of progression under crizotinib (47% of patients).…”

Section: Crizotinibmentioning

confidence: 99%

ROS-1 Fusions in Non-Small-Cell Lung Cancer: Evidence to Date

et al. 2022

View full text Add to dashboard Cite

The ROS-1 gene plays a major role in the oncogenesis of numerous tumors. ROS-1 rearrangement is found in 0.9–2.6% of non-small-cell lung cancers (NSCLCs), mostly lung adenocarcinomas, with a significantly higher rate of women, non-smokers, and a tendency to a younger age. It has been demonstrated that ROS-1 is a true oncogenic driver, and tyrosine kinase inhibitors (TKIs) targeting ROS-1 can block tumor growth and provide clinical benefit for the patient. Since 2016, crizotinib has been the first-line reference therapy, with two-thirds of the patients’ tumors responding and progression-free survival lasting ~20 months. More recently developed are ROS-1-targeting TKIs that are active against resistance mechanisms appearing under crizotinib and have better brain penetration. This review summarizes current knowledge on ROS-1 rearrangement in NSCLCs, including the mechanisms responsible for ROS-1 oncogenicity, epidemiology of ROS-1-positive tumors, methods for detecting rearrangement, phenotypic, histological, and molecular characteristics, and their therapeutic management. Much of this work is devoted to resistance mechanisms and the development of promising new molecules.

show abstract

Effectiveness and prognostic factors of first-line crizotinib treatment in patients with ROS1-rearranged non-small cell lung cancer: A multicenter retrospective study

Cited by 10 publications

References 31 publications

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

Case Report: Detection of Double ROS1 Translocations, SDC4-ROS1 and ROS1-GK, in a Lung Adenocarcinoma Patient and Response to Crizotinib

ROS-1 Fusions in Non-Small-Cell Lung Cancer: Evidence to Date

Contact Info

Product

Resources

About