Crizotinib vs platinum‐based chemotherapy as first‐line treatment for advanced non‐small cell lung cancer with different <i>ROS1</i> fusion variants

Xu, Haiyan; Zhang, Quan; Liang, Li; Li, Junling; Liu, Zhefeng; Li, Weihua; Yang, Lu; Gao, Yang; Xu, Fei; Jin, Ying; Zhang, Shucai; Wang, Yan

doi:10.1002/cam4.2984

Cited by 23 publications

(15 citation statements)

References 30 publications

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“…Our study has provided real-world clinical evidence on the efficacy of crizotinib in the first-line setting as reported in numerous clinical trials and other studies [ 8 , 13 , 14 , 21 – 23 ]. The clinical outcomes we have observed from the 168 crizotinib-treated patients were consistent with another study that reported the better ORR, DCR, and PFS with first-line crizotinib as compared to chemotherapy for ROS1 -rearranged NSCLC (ORR 80.0% vs 40.8%; DCR 90.0% vs. 71.4%; PFS 9.8 months vs 6.0 months) [ 21 , 24 ]. Moreover, our results that demonstrated better survival outcomes with first-line crizotinib for patients with non- CD74 ROS1 fusions than those who harbor CD74-ROS1 fusions (21.0 months vs 17.0 months) were consistent with a prior report that demonstrated a PFS of 17.6 months and 12.6 months, respectively [ 12 ].…”

Section: Discussionsupporting

confidence: 88%

“…Moreover, our results that demonstrated better survival outcomes with first-line crizotinib for patients with non- CD74 ROS1 fusions than those who harbor CD74-ROS1 fusions (21.0 months vs 17.0 months) were consistent with a prior report that demonstrated a PFS of 17.6 months and 12.6 months, respectively [ 12 ]. Meanwhile, another study reported an opposite trend of longer PFS with crizotinib for patients with CD74-ROS1 than non- CD74-ROS1 (20.1 months vs. 12.0 months) [ 24 ], while no difference in PFS with chemotherapy was observed between CD74-ROS1 and non- CD74-ROS1 (8.6 months vs. 4.3 months) [ 24 ]. Since some of the ROS1 fusion partners are not as common as CD74 , survival outcome data for patients with these fusion partners remains limited.…”

Section: Discussionmentioning

confidence: 99%

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Clinical and molecular factors that impact the efficacy of first-line crizotinib in ROS1-rearranged non-small-cell lung cancer: a large multicenter retrospective study

Zhang

et al. 2021

BMC Med

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Background ROS1-rearranged lung cancers benefit from first-line crizotinib therapy; however, clinical and molecular factors that could affect crizotinib efficacy in ROS1-rearranged lung cancers are not yet well-elucidated. Our retrospective study aimed to compare the efficacy of chemotherapy and crizotinib in the first-line treatment of ROS1-rearranged advanced lung cancer and evaluate various clinical and molecular factors that might impact crizotinib efficacy in real-world practice. Methods Treatment responses, survival outcomes, and patterns of disease progression were analyzed for 235 patients with locally advanced to advanced disease who received first-line chemotherapy (n = 67) or crizotinib (n = 168). Results The overall response rate was 85.7% (144/168) for first-line crizotinib and 41.8% (28/67) for chemotherapy. Patients treated with first-line crizotinib (n = 168) had significantly longer median progression-free survival (PFS) than chemotherapy (n = 67) (18.0 months vs. 7.0 months, p < 0.001). Patients harboring single CD74-ROS1 (n = 90) had significantly shorter median PFS with crizotinib than those harboring non-CD74 ROS1 fusions (n = 69) (17.0 months vs. 21.0 months; p = 0.008). Patients with baseline brain metastasis (n = 45) had a significantly shorter PFS on first-line crizotinib than those without brain metastasis (n = 123) (16.0 months vs. 22.0 months; p = 0.03). At progression, intracranial-only progression (n = 40), with or without baseline CNS metastasis, was associated with longer median PFS than those with extracranial-only progression (n = 64) (19.0 months vs. 13.0 months, p < 0.001). TP53 mutations were the most common concomitant mutation, detected in 13.1% (7/54) of patients with CD74-ROS1 fusions, and 18.8% (6/32) with non-CD74 ROS1 fusions. Patients with concomitant TP53 mutations (n=13) had significantly shorter PFS than those who had wild-type TP53 (n = 81) (6.5 months vs. 21.0 months; p < 0.001). PFS was significantly shorter for the patients who harbored concomitant driver mutations (n = 9) (11.0 months vs 24.0 months; p = 0.0167) or concomitant tumor suppressor genes (i.e., TP53, RB1, or PTEN) (n = 25) (9.5 months vs 24.0 months; p < 0.001) as compared to patients without concomitant mutations (n = 58). Conclusion Our results demonstrate that baseline brain metastatic status and various molecular factors could contribute to distinct clinical outcomes from first-line crizotinib therapy of patients with ROS1-rearranged lung cancer. Clinical trials registration CORE, NCT03646994

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Clinical and molecular factors that impact the efficacy of first-line crizotinib in ROS1-rearranged non-small-cell lung cancer: a large multicenter retrospective study

Zhang

et al. 2021

BMC Med

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“…The treatment of patients with ROS1 gene rearrangement is classical chemotherapy and/or targeted therapy, and the commonly used targeted drug is crizotinib. Scheffler’s study showed that 64.2% of patients with ROS1 gene rearrangement responded to chemotherapy, and the average overall survival (OS) of patients who received chemotherapy and crizotinib was estimated at 5.3 years ( 64 ), The results are somewhat consistent with the recently reported efficacy of crizotinib in the treatment of advanced NSCLC ( 65 , 66 ), recent studies have shown a change in the choice of treatment for patients with advanced ROS1 rearrangement in NSCLC. Patients with first-line selection of platinum-pemetrexed and crizotinib had different objective remission rates (85.1% vs. 86.7%) and progression-free survival (8.6 vs. 18.4 months), and there was no significant difference in OS (less than vs. 28.4 months) between the two groups ( 66 ).…”

Section: Discussionsupporting

confidence: 63%

Clinical characteristics of patients with ROS1 gene rearrangement in non-small cell lung cancer: a meta-analysis

Bi¹,

Ding²,

Yin³

et al. 2020

Transl Cancer Res TCR

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Background ROS1 gene rearrangement has been reported in several types of cancers, including non-small cell lung cancer (NSCLC). It is reported that tyrosine kinase inhibitors are effective in the treatment of ROS1- rearranged NSCLC. Therefore, the identification of ROS1 rearrangement can be used as potential therapeutic target in lung cancer. Epidemiological data indicates that ROS1 gene rearrangement occurs in approximately 1–2% of NSCLC patients. The small sample sizes of the existing associated studies only represent the characteristics of patients in specific regions or countries, and there is still no latest statistical analysis on ROS1 gene rearrangement anywhere in the world. Methods We conducted a systematic search of the PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), CBM, CNKI, Wanfang, and VIP databases to identify studies on ROS1 gene rearrangement in NSCLC patients from January 1, 2015 to October 27, 2019. We conducted a meta-analysis to investigate the relationship between ROS1 gene rearrangement and clinical characteristics of NSCLC patients. The four clinical features are as follows: gender, smoking status, pathological type, and lung cancer stage. Results Thirty-nine studies constituting of 25,055 NSCLC patients were eligible for inclusion in this meta-analysis. A prominently higher rate of ROS1 gene rearrangement was observed in female NSCLC patients (OR =1.94, 95% CI: 1.62–2.32%, P<0.05), patients with no smoking history (OR =2.82, 95% CI: 2.24–3.55%, P<0.05), patients with adenocarcinoma (OR =1.55, 95% CI: 1.14–2.11%, P<0.05), and patients with stage III–IV disease (OR =1.50, 95% CI: 1.15–1.94%, P<0.05). Our meta-analysis also showed that the prevalence of ROS1 rearrangement in adenocarcinoma was 2.49% (95% CI: 1.92–3.11%), while it was lower in non-adenocarcinoma patients (1.37%). Conclusions ROS1 gene rearrangement was more predominant in female patients, patients without smoking history, patients with adenocarcinoma and patients with advanced-stage disease (stages III to IV).

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“…Several studies have focused on exploring the efficacy of TKIs among ALK, ROS1, and RET fusions with different partners and breakpoints. 10,35,36 We have previously found that patients with CD74-ROS1 fusion identified by DNA NGS who received first-line crizotinib have a longer PFS than patients with non-CD74-ROS1 fusion, 13 whereas Li et al 37 have observed diametrically opposite results. Moreover, at least 21 EML4-ALK variants have been described on the basis of breakpoint location, and these variants may be associated with clinical responses to TKIs.…”

Section: Discussionmentioning

confidence: 98%

“…9,10 By applying DNA NGS, we have previously revealed that certain molecular biomarkers, such as EML4-ALK variants and concurrent TP53 mutations in ALK-rearranged cases and types of fusion partners in ROS1-rearranged cases, are associated with the efficacy of crizotinib. [11][12][13] In addition, we have found that some uncommon fusion variants of ALK, ROS1, and RET can be identified by DNA NGS, including noncanonical fusions harboring fusion partners that are rare or never reported (e.g., single non-EML4-ALK) and primary/reciprocal fusions harboring concurrent primary and reciprocal rearrangements. [14][15][16] Nevertheless, it remains unclear whether these special rearrangements can unequivocally produce the corresponding in-frame fusion transcripts, thus contributing to variable response to targeted therapy.…”

Section: Introductionmentioning

confidence: 96%

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

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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.

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Crizotinib vs platinum‐based chemotherapy as first‐line treatment for advanced non‐small cell lung cancer with different ROS1 fusion variants

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 23 publications

References 30 publications

Clinical and molecular factors that impact the efficacy of first-line crizotinib in ROS1-rearranged non-small-cell lung cancer: a large multicenter retrospective study

Clinical and molecular factors that impact the efficacy of first-line crizotinib in ROS1-rearranged non-small-cell lung cancer: a large multicenter retrospective study

Clinical characteristics of patients with ROS1 gene rearrangement in non-small cell lung cancer: a meta-analysis

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

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