Concomitant Genetic Alterations With Response to Treatment and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With <i>EGFR</i>-Mutant Advanced Non–Small Cell Lung Cancer

Hong, Shaodong; Gao, Fangfang; Fu, Sha; Wang, Yan; Fang, Wenfeng; Huang, Yan; Zhang, Li

doi:10.1001/jamaoncol.2018.0049

Cited by 151 publications

(173 citation statements)

References 6 publications

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“…However, when all genetic variations, including both SNVs and CNVs of HER2 bypass signaling pathway, PI3K/Akt/mTOR pathway, and TP53 were analyzed, it demonstrated that multiple (two or more) genetic variations were associated with significantly worse survival compared with one or none genetic variation. Similar results were observed with concomitant genetic alterations in EGFR-mutant advanced non-small cell lung cancer (22).…”

Section: Discussionsupporting

confidence: 83%

Safety, Efficacy, and Biomarker Analysis of Pyrotinib in Combination with Capecitabine in HER2-Positive Metastatic Breast Cancer Patients: A Phase I Clinical Trial

Guan

Chen

et al. 2019

Clinical Cancer Research

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Purpose: This phase I study assessed the safety, tolerability, MTD, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in combination with capecitabine in patients with HER2positive metastatic breast cancer (MBC).Patients and Methods: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1,000 mg/m 2 twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected on days 1 and 14. Next-generation sequencing was performed on circulating tumor DNA to probe for predictive biomarkers.Results: A total of 28 patients were enrolled, 22 patients were treated at the two top-level doses. Among 17 (60.7%) trastuzumab-pretreated patients, 11 received trastuzumab for metastatic disease and 6 received adjuvant trastuzumab. No dose-limited toxicity was observed. Grade 3 treatment-related adverse events (AE) occurred in 12 (42.9%) patients; anemia (14.3%) and diarrhea (10.7%) were the most common grade 3 AEs. The overall response rate (ORR) was 78.6% [95% confidence interval (CI): 59.0%-91.7%], and the clinical benefit rate was 85.7% (95% CI: 67.3%-96.0%). The median progression-free survival (PFS) was 22.1 months (95% CI: 9.0-26.2 months). ORR was 70.6% (12/17) in trastuzumabpretreated patients and 90.9% (10/11) in trastuzumab-na€ ve patients. Analysis of all genetic alterations in HER2-related signaling network in baseline blood samples suggested that multiple genetic alterations were significantly associated with poorer PFS compared with none or one genetic alteration (median, 16.8 vs. 29.9 months, P ¼ 0.006).Conclusions: In a population largely na€ ve to HER2-targeted therapy, pyrotinib in combination with capecitabine was well-tolerated and demonstrates promising antitumor activity in patients with HER2-positive MBC.

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Section: Discussionsupporting

confidence: 83%

Safety, Efficacy, and Biomarker Analysis of Pyrotinib in Combination with Capecitabine in HER2-Positive Metastatic Breast Cancer Patients: A Phase I Clinical Trial

Guan

Chen

et al. 2019

Clinical Cancer Research

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“…As mentioned before, NGS can be used to detect mutations that would otherwise be missed by regular screening methods. Besides coalterations among the five driver genes studied here, mutations in TP53 , PIK3CA , and other genes can also co‐occur with EGFR or ALK alterations, in which case they have been shown to decrease the treatment effect of TKI therapy . For patients affected by this type of coalteration, combination therapy such as TKI plus chemotherapy should be considered.…”

Section: Discussionmentioning

confidence: 98%

“…Finally, we cannot exclude the possibility of unknown mechanisms impacting the outcomes. The pathological subtype, passenger mutations, and mutations in other genes, as well as smoking‐related genomic patterns, might influence the treatment effect. In this study, since only three of the patients harboring EGFR/ALK coalterations and receiving TKI therapy achieved PFS, we did not compare the clinical outcomes of these patients with those of the patients harboring a single EGFR or ALK alteration.…”

Section: Discussionmentioning

confidence: 99%

“…Rare driver gene mutations, such as the erb‐b2 receptor tyrosine kinase 2 ( HER2 ) mutation or MET proto‐oncogene ( MET ) exon 14 skipping, have also been found to co‐occur with other oncogenic driver mutations and were reported to respond well to TKI therapy . Meanwhile, other concomitant mutations, such as TP53 or PIK3CA mutations combined with EGFR mutations or ALK rearrangements, have been found to influence the treatment effect of TKI therapy . However, mutation testing for these genes is not routinely performed in most clinical practices.…”

Section: Introductionmentioning

confidence: 99%

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Clinical features and therapeutic options in non‐small cell lung cancer patients with concomitant mutations of EGFR, ALK, ROS1, KRAS or BRAF

Zhuang

Zhao

et al. 2019

Cancer Medicine

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Background Although oncogenic driver mutations were thought to be mutually exclusive in non‐small cell lung cancer (NSCLC), certain tumors harbor co‐occurring mutations and represent a rare molecular subtype. The evaluation of the clinical features and therapeutic response associated with this NSCLC subtype will be vital for understanding the heterogeneity of treatment response and improving the management of these patients. Methods This retrospective study included 3774 samples from patients diagnosed with NSCLC. All samples were screened for EGFR, ALK, ROS1, KRAS, and BRAF mutation using the amplification‐refractory mutation system. The relationship between concomitant driver mutations and clinicopathologic characteristics, and patient clinical outcomes were evaluated. Results Sixty‐three (1.7%) samples had more than one driver gene mutation. Among these, 43 were coalterations with an EGFR mutation, 20 with an ALK rearrangement, and eight with an ROS1 rearrangement. Except for ROS1 concomitant mutations that were more frequent in male patients (87.5%, P = 0.020), the clinicopathological features of the concomitant mutation patients were not significantly different from those harboring a single EGFR, ALK, or ROS1 mutation. Furthermore, first‐line EGFR‐TKI treatment did not significantly improve the progression‐free survival (PFS) of patients harboring EGFR concomitant mutation, compared to patients harboring a single EGFR mutation. However, for EGFR concomitant mutation patients, TKI therapy was more effective than chemotherapy (median PFS of 10.8 vs 5.2 months, P = 0.023). Lastly, KRAS mutations did not influence the EGFR‐TKI therapy treatment effect. Conclusion In this study, concomitant mutations were found in 1.7% of the NSCLC. EGFR‐TKI therapy was more effective than chemotherapy for patients harboring EGFR concomitant mutation, and ROS1 concomitant mutations were more frequent in male patients. For patients harboring coalterations with an ALK or ROS1 rearrangement, we should be cautious when considering the therapeutic options.

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“…[1][2][3] Co-occurring genetic alterations might play a role in resistance mechanisms and could potentially explain the marked diversity of individual patient outcomes. 8,9 Previous studies suggested a potential role of TP53 mutations and alterations in cell-cycle genes in poor therapeutic response. [10][11][12] However, specific co-occurring genetic alterations that affect the clinical outcomes of EGFR-TKI 3rd in addition to primary driver mutations remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Concurrent Genetic Alterations Predict the Progression to Target Therapy in EGFR-Mutated Advanced NSCLC

Kim

Lee

Shim

et al. 2019

Journal of Thoracic Oncology

112

109

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Concomitant Genetic Alterations With Response to Treatment and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With EGFR-Mutant Advanced Non–Small Cell Lung Cancer

Abstract: J. Excess body weight and the risk of primary liver cancer: an updated meta-analysis of prospective studies.

Cited by 151 publications

References 6 publications

Safety, Efficacy, and Biomarker Analysis of Pyrotinib in Combination with Capecitabine in HER2-Positive Metastatic Breast Cancer Patients: A Phase I Clinical Trial

Safety, Efficacy, and Biomarker Analysis of Pyrotinib in Combination with Capecitabine in HER2-Positive Metastatic Breast Cancer Patients: A Phase I Clinical Trial

Clinical features and therapeutic options in non‐small cell lung cancer patients with concomitant mutations of EGFR, ALK, ROS1, KRAS or BRAF

Concurrent Genetic Alterations Predict the Progression to Target Therapy in EGFR-Mutated Advanced NSCLC

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