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Cited by Other Article(s)

Shi J, Liu X, Gao M, Yu J, Chai T, Jiang Y, Li J, Zhang Y, Wu L. Adverse event profiles of EGFR-TKI: network meta-analysis and disproportionality analysis of the FAERS database. Front Pharmacol 2025;16:1519849. [PMID: 40135231 PMCID: PMC11933087 DOI: 10.3389/fphar.2025.1519849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 02/17/2025] [Indexed: 03/27/2025] Open

Abstract

Background

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) in clinical use show promise but can cause AEs, impacting patients' wellbeing and increasing costs.

Methods

This study utilized two methods: network meta-analysis (NMA) and disproportionality analysis (DA). For NMA, we searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov up to 10 September 2024, for phase II/III RCTs comparing EGFR-TKI monotherapy with chemotherapy or other EGFR-TKIs. Using STATA 18.0, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) and assessed heterogeneity via Chi-squared and I2 tests. Adverse events (AEs) were ranked using the surface under the cumulative ranking curve (SUCRA). For DA, we analyzed FAERS data (January 2004-June 2024), evaluating AE signals with reporting odds ratios (RORs) and 95% CIs; signals were considered significant if the ROR and its 95% CI lower bound exceeded 1. Primary outcomes for NMA included all-grade AEs, grade ≥3 AEs, specific AEs, and AE-related mortality. For DA, outcomes included EGFR-TKI as the primary AE cause, time from treatment to AE, and AE-related mortality.

Results

NMA: 48% of EGFR-TKI patients experienced AEs, with 32.7% being severe. Afatinib showed highest toxicity; Icotinib was safest. Osimertinib was associated with highest risks of leukopenia (8%) and thrombocytopenia (9%). DA: Osimertinib had strongest links to cardiac diseases and blood/lymphatic disorders. Gefitinib had the strongest signal for interstitial lung diseases; Erlotinib for anorexia. Most AEs occurred within 30 days, but cardiac disorders had a median onset of 41 days. Osimertinib had the highest AE-related mortality, with cardiac disorders leading in fatalities.

Conclusion

This study used NMA and DA to explore EGFR-TKI-related AEs. Drugs varied in AE profiles, mostly mild, but Osimertinib and Dacomitinib were associated with more severe events. Osimertinib carried a high cardiac risk, delayed onset, and high mortality. Thus, comprehensive patient assessment and close monitoring are crucial with EGFR-TKI use.

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Zhou S, Kishi N, Alerasool P, Rohs NC. Adverse Event Profile of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Non-small Cell Lung Cancer: An Updated Meta-analysis. Target Oncol 2024;19:547-564. [PMID: 38824269 DOI: 10.1007/s11523-024-01073-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/14/2024] [Indexed: 06/03/2024]

Abstract

BACKGROUND

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remain the frontline standard of care for patients with EGFR-mutant non-small cell lung cancer. An updated toxicity profile of EGFR-TKIs proves valuable in guiding clinical decision making.

OBJECTIVE

This study comprehensively assessed the risk of EGFR-TKI-related adverse events (AEs) involving different systems/organs.

METHODS

We systematically searched PubMed, Embase, Web of Science, and Cochrane library for phase III randomized controlled trials comparing EGFR-TKI monotherapy with placebo or chemotherapy in patients with non-small cell lung cancer. The odds ratio (OR) of all-grade and high-grade adverse events (AEs) including dermatologic, gastrointestinal, hematologic, hepatic, and respiratory events was pooled for a meta-analysis. Subgroup analyses based on the control arm (placebo or chemotherapy) and individual EGFR-TKIs (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) were conducted.

RESULTS

Thirty-four randomized controlled trials comprising 15,887 patients were included. The pooled OR showed EGFR-TKIs were associated with a significantly increased risk of all-grade dermatologic AEs including paronychia, pruritus, rash, skin exfoliation, and skin fissures, gastrointestinal AEs including abdominal pain, diarrhea, dyspepsia, mouth ulceration, and stomatitis, hepatic AEs including elevated alanine aminotransferase and aspartate aminotransferase, and respiratory AEs including epistaxis, interstitial lung disease and rhinorrhea. Furthermore, a significantly increased risk of high-grade rash (OR 7.83, 95% confidence interval [CI] 5.11, 12.00), diarrhea (OR 2.10, 95% CI 1.44, 3.05), elevated alanine aminotransferase (OR 3.93, 95% CI 1.71, 9.03), elevated aspartate aminotransferase (OR 3.22, 95% CI 1.05, 9.92) and interstitial lung disease (OR 2.35, 95% CI 1.38, 4.01) was observed in patients receiving EGFR-TKIs. When stratified by individual EGFR-TKIs, gefitinib showed a significant association with all-grade and high-grade hepatotoxicity and interstitial lung disease.

CONCLUSIONS

Epidermal growth factor receptor tyrosine kinase inhibitors were associated with a significantly increased risk of various types of AEs. Clinicians should be vigilant about the risks of these EGFR-TKI-related AEs, particularly for severe hepatotoxicity and interstitial lung disease, to facilitate early detection and proper management.

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Zhao J, Yu X, Huang D, Ma Z, Gao B, Cui J, Chu Q, Zhou Q, Sun M, Day D, Wu J, Pan H, Wang L, Voskoboynik M, Wang Z, Liu Y, Li H, Zhang J, Peng Y, Wu YL. SAFFRON-103: a phase 1b study of the safety and efficacy of sitravatinib combined with tislelizumab in patients with locally advanced or metastatic non-small cell lung cancer. J Immunother Cancer 2023;11:jitc-2022-006055. [PMID: 36808075 PMCID: PMC9944269 DOI: 10.1136/jitc-2022-006055] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/20/2023] [Indexed: 02/22/2023] Open

Abstract

BACKGROUND

Some patients with locally advanced/metastatic non-small cell lung cancer (NSCLC) respond poorly to anti-programmed cell death protein 1 (PD-1)/anti-programmed death-ligand 1 (PD-L1) treatments. Combination with other agents may improve the outcomes. This open-label, multicenter, phase 1b trial investigated the combination of sitravatinib, a spectrum-selective tyrosine kinase inhibitor, plus anti-PD-1 antibody tislelizumab.

METHODS

Patients with locally advanced/metastatic NSCLC were enrolled (Cohorts A, B, F, H, and I; N=22-24 per cohort). Cohorts A and F included patients previously treated with systemic therapy, with anti-PD-(L)1-resistant/refractory non-squamous (cohort A) or squamous (cohort F) disease. Cohort B included patients previously treated with systemic therapy, with anti-PD-(L)1-naïve non-squamous disease. Cohorts H and I included patients without prior systemic therapy for metastatic disease, no prior anti-PD-(L)1/immunotherapy, with PD-L1-positive non-squamous (cohort H) or squamous (cohort I) histology. Patients received sitravatinib 120 mg orally one time per day plus tislelizumab 200 mg intravenously every 3 weeks, until study withdrawal, disease progression, unacceptable toxicity, or death. The primary endpoint was safety/tolerability among all treated patients (N=122). Secondary endpoints included investigator-assessed tumor responses and progression-free survival (PFS).

RESULTS

Median follow-up was 10.9 months (range: 0.4-30.6). Treatment-related adverse events (TRAEs) occurred in 98.4% of the patients, with ≥Grade 3 TRAEs in 51.6%. TRAEs led to discontinuation of either drug in 23.0% of the patients. Overall response rate was 8.7% (n/N: 2/23; 95% CI: 1.1% to 28.0%), 18.2% (4/22; 95% CI: 5.2% to 40.3%), 23.8% (5/21; 95% CI: 8.2% to 47.2%), 57.1% (12/21; 95% CI: 34.0% to 78.2%), and 30.4% (7/23; 95% CI: 13.2% to 52.9%) in cohorts A, F, B, H, and I, respectively. Median duration of response was not reached in cohort A and ranged from 6.9 to 17.9 months across other cohorts. Disease control was achieved in 78.3-90.9% of the patients. Median PFS ranged from 4.2 (cohort A) to 11.1 months (cohort H).

CONCLUSIONS

In patients with locally advanced/metastatic NSCLC, sitravatinib plus tislelizumab was tolerable for most patients, with no new safety signals and overall safety profiles consistent with known profiles of these agents. Objective responses were observed in all cohorts, including in patients naïve to systemic and anti-PD-(L)1 treatments, or with anti-PD-(L)1 resistant/refractory disease. Results support further investigation in selected NSCLC populations.

TRIAL REGISTRATION NUMBER

NCT03666143.

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Affiliation(s)

Jun Zhao Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Oncology, Peking University Cancer Hospital and Institute, Beijing, China
Xinmin Yu Department of Medical Oncology, Cancer Hospital of University of Chinese Academy of Sciences & Zhejiang Cancer Hospital, Hangzhou, China
Dingzhi Huang Department of Thoracic Medical Oncology, Tianjin Cancer Hospital, Tianjin, China
Zhiyong Ma Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University; Henan Cancer Hospital, Zhengzhou, China
Bo Gao Blacktown Hospital and University of Sydney, Sydney, New South Wales, Australia
Jiuwei Cui Cancer Center, The First Hospital of Jilin University, Changchun, China
Qian Chu Department of Oncology, Tongji Hospital, Wuhan, China
Qing Zhou Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
Meili Sun Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, China
Daphne Day Medical Oncology, Monash Health and Monash University, Melbourne, Victoria, Australia
Jingxun Wu Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, China
Hongming Pan Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
Lifeng Wang Nanjing Drum Tower Hospital, Nanjing, China
Mark Voskoboynik Medical Oncology, Nucleus Network, Melbourne, VIC, Australia and Central Clinical School, Monash University, Melbourne, Victoria, Australia
Zhehai Wang Department of Internal Medicine - Oncology, Shandong Cancer Hospital & Institute, Jinan, China
Yunpeng Liu Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
Hui Li BeiGene (Shanghai) Co., Ltd, Shanghai, China
Juan Zhang BeiGene (Beijing) Co., Ltd, Beijing, China
Yanyan Peng BeiGene (Shanghai) Co., Ltd, Shanghai, China
Yi-Long Wu Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China

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Laktionov KK, Artamonova EV, Borisova TN, Breder VV, Bychkov IM, Vladimirova LI, Volkov NM, Ergnian SM, Zhabina AS, Kononets PV, Kuzminov AE, Levchenko EV, Malikhova OA, Marinov DT, Miller SV, Moiseenko FV, Mochal’nikova VV, Novikov SN, Pikin OV, Reutova EV, Rodionov EO, Sakaeva DD, Sarantseva KA, Semenova AI, Smolin AV, Sotnikov VM, Tuzikov SA, Turkin IN, Tyurin IE, Chkhikvadze VD, Kolbanov KI, Chernykh MV, Chernichenko AV, Fedenko AA, Filonenko EV, Nevol’skikh AA, Ivanov SA, Khailova ZV, Gevorkian TG, Butenko AV, Gil’mutdinova IR, Gridneva IV, Eremushkin MA, Zernova MA, Kasparov BS, Kovlen DV, Kondrat’eva KO, Konchugova TV, Korotkova SB, Krutov AA, Obukhova OA, Ponomarenko GN, Semiglazova TI, Stepanova AM, Khulamkhanova MM. Malignant neoplasm of the bronchi and lung: Russian clinical guidelines. JOURNAL OF MODERN ONCOLOGY 2022. [DOI: 10.26442/18151434.2022.3.201848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]

Liu L, Wang C, Li S, Bai H, Wang J. Tumor immune microenvironment in epidermal growth factor receptor-mutated non-small cell lung cancer before and after epidermal growth factor receptor tyrosine kinase inhibitor treatment: a narrative review. Transl Lung Cancer Res 2021;10:3823-3839. [PMID: 34733631 PMCID: PMC8512456 DOI: 10.21037/tlcr-21-572] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/03/2021] [Indexed: 12/11/2022]

Abstract

Objective

To review and summarize the characteristics of the tumor immune microenvironment (TIME) in EGFR-mutated non-small cell lung cancer (NSCLC) after EGFR-TKI treatment and its role in TKI resistance.

Background

Lung cancer is one of the most commonly diagnosed cancer and the leading cause of death from cancer in both men and women around the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are considered a first-line treatment for EGFR-mutated NSCLC. However, almost all patients eventually develop acquired resistance to EGFR-TKIs, with a median progression-free survival (PFS) of 9–14 months. As immunotherapy has developed, it has become apparent that interactions between the TIME and tumor cells also affect EGFR-TKI treatment. The TIME comprises a variety of components but previous studies of the TIME following EGFR-TKI therapy of NSCLC are inconsistent. Here, we reviewed the characteristics of the TIME in NSCLC after EGFR-TKI treatment and its role in TKI resistance.

Methods

PubMed, Embase, and Web of Science were searched to July 1, 2021 with the following key words: “NSCLC”, “EGFR”, and “immunotherapy”.

Conclusions

The TIME of EGFR-mutated NSCLC is different from that of non-mutated NSCLC, an explanation for EGFR-mutated NSCLC displaying a poor response to ICIs. The TIME of EGFR-mutated NSCLC also changes during treatment with EGFR-TKIs. The TIME in EGFR-TKI-resistant lung cancer can be summarized as follows: (I) compared with EGFR-TKI-sensitive tumors, EGFR-TKI-resistant tumors have a greater number of immunosuppressive cells and fewer immune-activated cells, while the tumor microenvironment is in an immunosuppressive state; (II) tumor cells and immunosuppressive cells secrete multiple negative immune regulatory factors, inhibit the recognition and presentation of tumor antigens and the antitumor effect of immune cells, resulting in immune escape; 3.EGFR-TKI-resistant tumors promote EMT. These three characteristics interact, resulting in a regulatory signaling network, which together leads to EGFR-TKI resistance.

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Zhao Y, Cheng B, Chen Z, Li J, Liang H, Chen Y, Zhu F, Li C, Xu K, Xiong S, Lu W, Chen Z, Zhong R, Zhao S, Xie Z, Liu J, Liang W, He J. Toxicity profile of epidermal growth factor receptor tyrosine kinase inhibitors for patients with lung cancer: A systematic review and network meta-analysis. Crit Rev Oncol Hematol 2021;160:103305. [PMID: 33757838 DOI: 10.1016/j.critrevonc.2021.103305] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 03/16/2021] [Accepted: 03/16/2021] [Indexed: 12/24/2022] Open

Affiliation(s)

Yi Zhao Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
Bo Cheng Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
Zisheng Chen Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China; Department of Respiratory Medicine, The Sixth Affliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan 511518, China
Jianfu Li Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
Hengrui Liang Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
Ying Chen Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
Feng Zhu Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
Caichen Li Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
Ke Xu Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
Shan Xiong Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
Weixiang Lu Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
Zhuxing Chen Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
Ran Zhong Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
Shen Zhao Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510050, China
Zhanhong Xie Department of Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
Jun Liu Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
Wenhua Liang Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China; Department of Medical Oncology, The First People's Hospital of Zhaoqing, Zhaoqing 526020, China.
Jianxing He Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China.

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Lee MH, Cho KR, Choi JW, Kong DS, Seol HJ, Nam DH, Jung HA, Sun JM, Lee SH, Ahn JS, Ahn MJ, Park K, Lee JI. Immune Checkpoint Inhibitors for Non-Small-Cell Lung Cancer with Brain Metastasis : The Role of Gamma Knife Radiosurgery. J Korean Neurosurg Soc 2020;64:271-281. [PMID: 33267531 PMCID: PMC7969051 DOI: 10.3340/jkns.2020.0135] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 07/07/2020] [Indexed: 12/26/2022] Open

Abstract

Objective

Immune checkpoint inhibitors (ICIs) are approved for treating non-small-cell lung cancer (NSCLC); however, the safety and efficacy of combined ICI and Gamma Knife radiosurgery (GKS) treatment remain undefined. In this study, we retrospectively analyzed patients treated with ICIs with or without GKS at our institute to manage patients with brain metastases from NSCLC.

Methods

We retrospectively reviewed medical records of patients with brain metastases from NSCLC treated with ICIs between January 2015 and December 2017. Of 134 patients, 77 were assessable for brain responses and categorized into three groups as follows : group A, ICI alone (n=26); group B, ICI with concurrent GKS within 14 days (n=24); and group C, ICI with non-concurrent GKS (n=27).

Results

The median follow-up duration after brain metastasis diagnosis was 19.1 months (range, 1–77). At the last follow-up, 53 patients (68.8%) died, 20 were alive, and four were lost to follow-up. The estimated median overall survival (OS) of all patients from the date of brain metastasis diagnosis was 20.0 months (95% confidence interval, 12.5–27.7) (10.0, 22.5, and 42.1 months in groups A, B, and C, respectively). The OS was shorter in group A than in group C (p=0.001). The intracranial disease progression-free survival (p=0.569), local progression-free survival (p=0.457), and complication rates did not significantly differ among the groups. Twelve patients showed leptomeningeal seeding (LMS) during follow-up. The 1-year LMS-free rate in treated with ICI alone group (69.1%) was significantly lower than that in treated with GKS before ICI treatment or within 14 days group (93.2%) (p=0.004).

Conclusion

GKS with ICI showed no favorable OS outcome in treating brain metastasis from NSCLC. However, GKS with ICI did not increase the risk of complications. Furthermore, compared with ICI alone, GKS with ICI may be associated with a reduced incidence of LMS. Further understanding of the mechanism, which remains unknown, may help improve the quality of life of patients with brain metastasis.

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Affiliation(s)

Min Ho Lee Department of Neurosurgery, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, Uijeongbu, Korea.,Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Kyung-Rae Cho Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Jung Won Choi Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Doo-Sik Kong Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Ho Jun Seol Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Do-Hyun Nam Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Hyun Ae Jung Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Jong-Mu Sun Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Se-Hoon Lee Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Jin Seok Ahn Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Myung-Ju Ahn Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Keunchil Park Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Jung-Il Lee Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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KRAS mutation as a prognostic factor and predictive factor in advanced/metastatic non-small cell lung cancer: A systematic literature review and meta-analysis. Cancer Treat Res Commun 2020;24:100200. [PMID: 32750661 DOI: 10.1016/j.ctarc.2020.100200] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 07/21/2020] [Accepted: 07/23/2020] [Indexed: 01/08/2023]

Abstract

KRAS (Kirsten Rat Sarcoma) is the most common oncogenic mutation detected in patients with non-small cell lung cancer (NSCLC). However, the role of KRAS as either a prognostic factor or predictive factor (modifier of treatment effects) in NSCLC is not well established at this time. This systematic literature review (SLR) and meta-analysis synthesized the available evidence regarding the role of KRAS mutation as a predictive factor and/or prognostic factor of survival and response outcomes in patients with advanced/metastatic (stage IIIB-IV) NSCLC. Relevant clinical trials and observational studies were identified by searching MEDLINE, Embase and Cochrane Register of Controlled Trials. Meta-analyses were performed using data extracted from multivariable and univariable analyses from clinical studies to assess the empirical evidence of KRAS mutation status as a prognostic or/and predicitive factor. 43 selected studies were identified by the SLR and included in this meta-analysis. Pairwise meta-analyses of hazard ratios (HRs) reported in randomized controlled trials (RCTs) did not demonstrate a significant prognostic effect of mutant KRAS on overall survival (OS) (HR=1.10; 95% CI [0.88, 1.38]) or progression free survival (PFS) (HR=1.03; 95% CI [0.80, 1.33]). However, when conducting meta-analyses on HRs reported in observational studies, a statistically significant negative prognostic effect of mutant KRAS was observed (OS HR=1.71; 95% CI [1.07, 2.84]; PFS HR=1.18; 95% CI [1.02, 1.36]). Meta-analyses of objective response rate (ORR) in RCTs demonstrated a negative prognostic effect of mutant KRAS (RR=0.38; 95% CI [0.16, 0.63]). Limited data were available to evaluate the role of KRAS mutation as a predictive factor. In conclusion, this research offers evidence that KRAS mutation may be a negative prognostic factor for survival and response outcomes in patients with advanced/metastatic NSCLC, but further research is needed to address conflicting results on the importance of KRAS mutations as a predictive factor.

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Comparative Efficacy of Second- and Subsequent-line Treatments for Metastatic NSCLC: A Fractional Polynomials Network Meta-analysis of Cancer Immunotherapies. Clin Lung Cancer 2019;20:451-460.e5. [PMID: 31375454 DOI: 10.1016/j.cllc.2019.06.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 04/05/2019] [Accepted: 06/10/2019] [Indexed: 11/24/2022]

Abstract

BACKGROUND

Extended onset of treatment effect and longer-term survival with anti-programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) immunotherapies, atezolizumab, nivolumab, and pembrolizumab, have changed the landscape of second- or subsequent-line (2L+) treatments for adults with non-small-cell lung cancer (NSCLC). This systematic literature review included phase I to IV randomized, controlled trials of 2L+ NSCLC therapies from MEDLINE, Embase, and secondary sources.

MATERIALS AND METHODS

Studies of treatments approved in the European Union or United States had to be in English with ≥ 10 patients per arm. A fractional polynomials network meta-analysis (NMA) was conducted because traditional NMA of hazard ratios does not account for delayed onset of clinical effect or long-term survival observed in PD-L1/PD-1 inhibitor trials. Adjusted analyses accounted for treatment switching in the atezolizumab OAK trial. Expected survival time reflected area under the curve over the time horizon. Expected overall survival (OS) was ranked by median ranking with 95% credible intervals and by surface under the cumulative ranking curve. Of 25,115 screened records, 28 studies were included in the quantitative analyses of OS and progression-free survival.

RESULTS

PD-L1/PD-1 inhibitors had comparable expected 5-year OS; all performed better than other treatment options. In unadjusted analyses, surface under the cumulative ranking curve ranked nivolumab first (87.9%), followed by atezolizumab (85.8%) and pembrolizumab (82.8%). Analyses adjusted for patients switching from docetaxel to immunotherapy ranked atezolizumab first (89.6%), followed by nivolumab (86.5%) and pembrolizumab (81.9%).

CONCLUSION

This NMA applied an appropriate approach for indirect comparisons, including cancer immunotherapies, and supported robustness of PD-L1/PD-1 immunotherapies for 2L+ treatment of NSCLC.

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Debieuvre D, Moreau L, Coudert M, Locher C, Asselain B, Coëtmeur D, Dayen C, Goupil F, Martin F, Brun P, De Faverges G, Hauss PA, Gally S, Ben Hadj Yahia B, Grivaux M. [Second- or third-line treatment with erlotinib in EGFR wild-type non-small cell lung cancer: Real-life data]. Rev Mal Respir 2019;36:649-663. [PMID: 31204231 DOI: 10.1016/j.rmr.2019.03.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 03/16/2019] [Indexed: 01/29/2023]

Connock M, Armoiry X, Tsertsvadze A, Melendez-Torres GJ, Royle P, Andronis L, Clarke A. Comparative survival benefit of currently licensed second or third line treatments for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) negative advanced or metastatic non-small cell lung cancer: a systematic review and secondary analysis of trials. BMC Cancer 2019;19:392. [PMID: 31023244 PMCID: PMC6485098 DOI: 10.1186/s12885-019-5507-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 03/21/2019] [Indexed: 01/30/2023] Open

Abstract

BACKGROUND

A review of therapies for advanced cancers licenced by the EMA between 2009 and 2013 concluded that for more than half of these drugs there was little evidence of overall survival or quality of life benefit. Recent years have witnessed a growing number of licensed second-line pharmacotherapies for advanced/metastatic non-small cell lung cancer (NSCLC). With the aim of gauging patient survival benefit, we conducted a systematic review of randomised controlled trials (RCT) and compared survival outcomes from available licensed treatments for patients with advanced/metastatic NSCLC.

METHODS

RCTs of second/third line treatments in participants with advanced/metastatic NSCLC and negative/low expression of Anaplastic Lymphoma Kinase (ALK) and of Epidermal Growth Factor Receptor (EGFR) were included. We searched electronic databases (MEDLINE; EMBASE; Web of Science) from January, 2000 up to July, 2017. Two or more independent reviewers screened bibliographic records, extracted data, and assessed risk of bias of studies. Published Kaplan Meier plots for OS and PFS along with restricted-mean-survival methods and parametric modelling were used to estimate the survival outcomes as mean number of months of survival. Network meta-analysis was undertaken to rank interventions and to make indirect comparisons.

RESULTS

We included 11 RCTs with data for 7581 participants that compared nine different drugs. In studies of patients regardless of histology groups, targeted drugs (ramucirumab and nintedanib) yielded small overall survival gains of < 2.5 months over docetaxel, erlotinib provided no benefit, while immunotherapies (atezolizumab and pembrolizumab) delivered 5 to 6 months gain. Studies with patients stratified by histology confirmed the apparent superiority of immunotherapy (nivolumab and atezolizumab) over targeted treatments (ramucirumab, nintedanib, afatinib) providing between about 4 to 8 months OS gain over docetaxel. In network analysis immunotherapies consistently ranked higher than alternatives irrespective of population histology and outcome measure.

CONCLUSION

Our review indicates that nivolumab, pembrolizumab and atezolizumab provide superior survival benefits compared to other licensed drugs for late stage NSCLC. Patient gains from these immunotherapies are substantial compared to the expected average survival with chemotherapy (docetaxel) of < 1 year for people with squamous histology and about 1.25 year for those with non-squamous histology.

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Vickers AD, Winfree KB, Cuyun Carter G, Kiiskinen U, Jen MH, Stull D, Kaye JA, Carbone DP. Relative efficacy of interventions in the treatment of second-line non-small cell lung cancer: a systematic review and network meta-analysis. BMC Cancer 2019;19:353. [PMID: 30987609 PMCID: PMC6466705 DOI: 10.1186/s12885-019-5569-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 04/02/2019] [Indexed: 12/22/2022] Open

Abstract

BACKGROUND

Locally advanced or metastatic non-small cell lung cancer (NSCLC) that has progressed after first-line treatment has a poor prognosis. Recent randomized clinical trials (RCTs) have demonstrated survival benefits of alternative treatments to docetaxel. However, information is lacking on which patients benefit the most and what drug or regimen is optimal. We report a systematic review and network meta-analysis (NMA) of second-line treatments in all subgroup combinations determined by histology, programmed death ligand 1 (PD-L1) expression, and epidermal growth factor receptor (EGFR) mutation.

METHODS

MEDLINE, PubMed, EMBASE, Biosciences Information Service (using the Dialog Platform), Cochrane Library, and abstracts from scientific meetings were searched for RCTs published up to September 2015. Key outcomes were overall survival (OS) and progression-free survival (PFS). Bayesian hierarchical exchangeable NMAs were conducted to calculate mean survival times and relative differences for eight subgroups, using docetaxel as the reference comparator. For OS, the NMA was based on hazard ratios applied to a first-order fractional polynomial model fitted to the reference treatment. For PFS, a second-order fractional polynomial model was fitted to reconstructed patient-level data for the entire network of evidence.

RESULTS

The search identified 30 studies containing 17 different treatment regimens. Docetaxel plus ramucirumab was associated with a significant improvement in OS and PFS, relative to docetaxel, regardless of patient type. Docetaxel plus nintedanib showed similar efficacy to docetaxel plus ramucirumab in the nonsquamous populations. EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib showed superior levels of efficacy in EGFR mutation-positive populations and the one PD-1 immunotherapy (nivolumab) studied showed superior efficacy in the populations exhibiting high PD-L1 expression.

CONCLUSIONS

In the absence of head-to-head comparisons, we performed a mixed-treatment analysis to synthesize evidence of the efficacy of each treatment. Benefits are optimized by targeting specific treatments to individual patients guided by histology, PD-L1 expression, and EGFR mutation status.

SYSTEMATIC REVIEW REGISTRATION

This review is registered in PROSPERO (registration number: CRD42014013780 available at www.crd.york.ac.uk/PROSPERO ).

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Germonpré P, Van den Wyngaert T. Second-line erlotinib after failure of pemetrexed-containing chemotherapy in advanced non-small cell lung cancer (NSCLC): Real-world effectiveness, safety and tolerability. PLoS One 2019;14:e0215135. [PMID: 30973926 PMCID: PMC6459587 DOI: 10.1371/journal.pone.0215135] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 03/27/2019] [Indexed: 12/22/2022] Open

Abstract

INTRODUCTION

Little data is available on patients with advanced non-squamous NSCLC treated with erlotinib specifically after failure of first-line pemetrexed-containing chemotherapy. We assessed the effectiveness, safety and tolerability of erlotinib in a real-world setting.

METHODS

Prospective single-arm, open-label, multicenter, non-interventional study of erlotinib (150mg daily) in inoperable stage III/IV NSCLC after progression on first-line pemetrexed-containing chemotherapy without EGFR-mutation selection. Patients were followed according to routine practice and response assessment was performed using RECIST 1.1. The primary end point was progression-free survival (PFS). Secondary end points included best confirmed overall response rate (ORR), disease control rate (DCR), and overall survival (OS). Adverse events were recorded. An independent dataset was used to validate the results.

RESULTS

In all, 59 patients were screened, 57 enrolled, and 54 (36 men; median age 65 years) included in the per-protocol analysis. Median PFS was 1.8 (95% CI 1.4-2.6) months, with 11% (95% CI 5-21%) alive and progression-free at 6 months. The ORR was 0.0% (97.5% CI 0.0-6.8%) and the DCR 34.6% (95% CI 21.9-49.0%). Median overall survival was 5.8 (95% CI 3.3-8.6) months with 28% (95% CI 17-42%) alive at one year. Rash occurred in 60.7% (95% CI 46.7-73.5%), with severe rash in 12.5% (95% CI 5.1-24.1%). Any grade diarrhea was observed in 42.8% (95% CI 29.7-56.8%), with grade 3 occurring in 7.1% (95% CI 1.9-17.2%). Erlotinib was stopped in 21.0% (95% CI 11.3-33.9%) of patients due to adverse events, which were treatment related in 7%.

CONCLUSION

Second-line erlotinib after pemetrexed treatment results in similar real-world outcomes as reported after non-pemetrexed containing first-line therapy. However, the overall duration of response in unselected patients remains limited and other effective treatments have in the meantime been introduced. No new safety signals were detected.

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Rulli E, Ghilotti F, Biagioli E, Porcu L, Marabese M, D'Incalci M, Bellocco R, Torri V. Assessment of proportional hazard assumption in aggregate data: a systematic review on statistical methodology in clinical trials using time-to-event endpoint. Br J Cancer 2018;119:1456-1463. [PMID: 30420618 PMCID: PMC6288087 DOI: 10.1038/s41416-018-0302-8] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 09/18/2018] [Accepted: 09/21/2018] [Indexed: 01/15/2023] Open

Garassino MC, Kawaguchi T, Gregorc V, Rulli E, Ando M, Marsoni S, Isa SI, Novello S, Farina G, Barni S, Torri V, Cinquini M. Chemotherapy versus erlotinib as second-line treatment in patients with advanced non-small cell lung cancer and wild-type epidermal growth factor receptor: an individual patient data (IPD) analysis. ESMO Open 2018;3:e000327. [PMID: 30555723 PMCID: PMC6267321 DOI: 10.1136/esmoopen-2018-000327] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 03/15/2018] [Accepted: 03/19/2018] [Indexed: 11/28/2022] Open

Zhang N, Guo N, Tian L, Miao Z. Systematic review and meta-analysis of third-line salvage therapy for the treatment of advanced non-small-cell lung cancer: A meta-analysis of randomized controlled trials. Oncotarget 2018;9:35439-35447. [PMID: 30459935 PMCID: PMC6226041 DOI: 10.18632/oncotarget.24967] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 10/28/2017] [Indexed: 12/26/2022] Open

Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, Mok TS, Reck M, Van Schil PE, Hellmann MD, Peters S. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29:iv192-iv237. [PMID: 30285222 DOI: 10.1093/annonc/mdy275] [Citation(s) in RCA: 1588] [Impact Index Per Article: 226.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open

Armoiry X, Tsertsvadze A, Connock M, Royle P, Melendez-Torres GJ, Souquet PJ, Clarke A. Comparative efficacy and safety of licensed treatments for previously treated non-small cell lung cancer: A systematic review and network meta-analysis. PLoS One 2018;13:e0199575. [PMID: 30044785 PMCID: PMC6059384 DOI: 10.1371/journal.pone.0199575] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 06/08/2018] [Indexed: 12/16/2022] Open

Abstract

PURPOSE

This systematic review with network meta-analysis compared the efficacy and safety of currently licensed second-line treatments in patients with late stage non-small cell lung cancer (NSCLC).

METHODS

Randomised controlled trials (RCTs) of participants with advanced/metastatic NSCLC receiving second/third line treatments were screened. We searched electronic databases (MEDLINE; EMBASE; Web of Science) from January, 2000 to July, 2017. Two reviewers screened bibliographic records, extracted data, and assessed risk of bias of included studies. The outcomes were overall survival (OS), progression-free survival (PFS), and drug-related grade 3-5 adverse-events (AEs). We pooled study-specific hazard ratios (HR; for OS and PFS) and risk ratios (RR; for AEs) using conventional and network-meta-analyses, and ranked interventions by the surface under the cumulative ranking curve.

FINDINGS

We included 11 RCTs (7,581 participants) comparing nine drugs. All drugs except for erlotinib significantly improved OS compared to docetaxel. Nivolumab was the highest ranking drug followed by atezolizumab and pembrolizumab. There was no significant difference in OS across these three drugs (HR = 0.98, 95% CI 0.79, 1.21 for nivolumab vs atezolizumab; HR = 0.98, 95% CI 0.77, 1.25 for nivolumab vs pembrolizumab). For PFS, ramucirumab + docetaxel and nivolumab were the drugs with the highest ranking. All interventions except ramucirumab + docetaxel had a reduced risk for severe drug-related AEs vs. docetaxel. Of the drugs with the highest ranking on AEs, nivolumab was significantly safer compared to atezolizumab (RR = 0.55, 95% CI 0.38, 0.79) or pembrolizumab (RR = 0.52, 95% CI 0.34, 0.81).

IMPLICATIONS

Nivolumab, pembrolizumab and atezolizumab exhibited superior benefit/risk balance compared to other licensed drugs used late stage NSCLC. Our results indicate that the use of immunotherapies in people diagnosed with non-specific late stage NSCLC should be promoted. The use of docetaxel may now be judged irrelevant as a comparator intervention for approval of new drugs for second line treatment of NSCLC.

STUDY REGISTRATION NUMBER

PROSPERO CRD42017065928.

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McKeage M, Elwood M, Tin Tin S, Khwaounjoo P, Aye P, Li A, Sheath K, Shepherd P, Laking G, Kingston N, Lewis C, Love D. EGFR Mutation Testing of non-squamous NSCLC: Impact and Uptake during Implementation of Testing Guidelines in a Population-Based Registry Cohort from Northern New Zealand. Target Oncol 2018;12:663-675. [PMID: 28699084 DOI: 10.1007/s11523-017-0515-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]

Abstract

BACKGROUND

Since 2013, clinical practice guidelines recommend EGFR mutation testing of non-squamous NSCLC to select advanced-stage patients for first-line treatment using EGFR-TKIs.

OBJECTIVE

We aimed to determine population-based trends in the real-world uptake and impact in routine practice of these recently updated testing guidelines.

PATIENTS AND METHODS

A population-based observational study was conducted of notifications to the New Zealand Cancer Registry of patients eligible for EGFR testing diagnosed in northern New Zealand between January 2010 and April 2014. The main study variable was EGFR mutation testing. Main outcome measures (overall survival and dispensing of EGFR-TKIs) were extracted from prospectively archived electronic databases until October 2015.

RESULTS

The population-based cohort of 1857 patients had an average age of 70 years. Most had adenocarcinoma and metastatic disease at diagnosis. EGFR testing was undertaken in 500 patients (27%) with mutations detected in 109 patients (22%). EGFR testing increased during the period of study from <5% to 67% of patients (P < 0.0001). Full uptake of testing by all eligible patients was limited by a lack of availability of specimens for testing and variable testing referral practices. The proportion of patients treated with EGFR-TKIs decreased during the same time period, both among untested patients (from 12.2% to 2.8% (P < 0.0001)) and in the population as a whole (from 13.7% to 10.6% (P < 0.05)). EGFR testing was associated with prolonged overall survival (Adjusted HR = 0.76 (95% CI, 0.65-0.89) Log-rank P < 0.0001) due at least in part to the much longer overall survival achieved by mutation-positive patients, of whom 79% received EGFR-TKIs. Compared to untested EGFR-TKI-treated patients, mutation-positive EGFR-TKI-treated patients received EGFR-TKIs for longer, and survived longer both from the start of EGFR-TKI treatment and date of their diagnosis.

CONCLUSIONS

In this real world setting, high uptake of EGFR testing was achieved and associated with major changes in EGFR-TKI prescribing and improved health outcomes. Modifiable factors determined testing uptake. Study registration ACTRN12615000998549.

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Suh CH, Park HS, Kim KW, Pyo J, Hatabu H, Nishino M. Pneumonitis in advanced non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitor: Meta-analysis of 153 cohorts with 15,713 patients: Meta-analysis of incidence and risk factors of EGFR-TKI pneumonitis in NSCLC. Lung Cancer 2018;123:60-69. [PMID: 30089596 DOI: 10.1016/j.lungcan.2018.06.032] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 06/27/2018] [Accepted: 06/30/2018] [Indexed: 01/06/2023]

Abstract

PURPOSE

Pneumonitis is a significant toxicity of EGFR tyrosine kinase inhibitors (EGFR-TKI) in non-small-cell lung cancer (NSCLC) patients. We studied the incidence of pneumonitis in clinical trials of EGFR-TKI published in 2003-2017, and performed subgroups analyses to identity predisposing factors.

METHODS

Ovid-MEDLINE and EMBASE search up to 4/17/17 using the keywords, "erlotinib", "gefitinib", "afatinib", "osimertinib", and "lung cancer", resulted in a total of 153 eligible trial cohorts with 15,713 advanced NSCLC patients treated with EGFR-TKI. The pooled incidence of all-grade, high-grade, and grade 5 pneumonitis was obtained. Subgroup analyses were performed with meta-regression using study-level covariates.

RESULTS

Among the patients without prior exposure to EGFR-TKI, the overall incidence was 1.12% (95% CI:0.79-1.58%) for all-grade, 0.61% (95% CI:0.40-0.93%) for high-grade, and 0.20% (95% CI:0.11-0.38%) for grade 5 pneumonitis. The incidence was significantly higher in Japanese studies compared to studies of non-Japan origin, for all-grade (4.77% vs. 0.55%, p < 0.001), high grade (2.49% vs. 0.37%, p < 0.001), and grade 5 pneumonitis (1.00% vs. 0.18%, p < 0.001). Multivariate analyses demonstrated higher odds of pneumonitis in Japanese studies for all-grade (odds ratio [OR]: 5.04; 95% CI:3.14-8.11, p < 0.001), high-grade (OR: 4.45; 95% CI:2.50-7.93, p < 0.001), and grade 5 pneumonitis (OR: 4.55; 95% CI:2.20-9.44, p < 0.001) compared to others, after adjusting for types of EGFR-TKI and lines of therapy. In patients with EGFR retreatment analyzed separately, the pooled incidence was 1.13% (95% CI:0.40-3.15%) for all-grade, 0.49% (95% CI:0.21-1.11%) for high-grade, and 0.16% (95% CI:0.04-0.65%) for grade 5 pneumonitis.

CONCLUSIONS

The overall incidence of EGFR-TKI pneumonitis was 1.12% in patients without prior exposure to EGFR-TKI, and 1.13% in EGFR-TKI retreatment group. The cohorts from Japan had significantly higher incidence of pneumonitis, providing insights for further mechanistic studies.

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Brueckl WM, Achenbach HJ, Ficker JH, Schuette W. Erlotinib treatment after platinum-based therapy in elderly patients with non-small-cell lung cancer in routine clinical practice - results from the ElderTac study. BMC Cancer 2018;18:333. [PMID: 29587656 PMCID: PMC5870245 DOI: 10.1186/s12885-018-4208-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 03/09/2018] [Indexed: 02/06/2023] Open

Abstract

Background

In this prospective non-interventional study, the effectiveness and tolerability of erlotinib in elderly patients with non-small-cell lung cancer (NSCLC) after ≥1 platinum-based chemotherapy were assessed.

Methods

A total of 385 patients ≥65 years of age with advanced NSCLC receiving erlotinib were observed over 12 months. The primary endpoint was the 1-year overall survival (OS) rate.

Results

Patients were predominantly Caucasian (99.2%), a mean of 73 years old; 24.7% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2. Most common tumor histologies were adenocarcinoma (64.9%) and squamous cell carcinoma (22.3%). Of 119 patients tested, 15.1% had an activating epidermal growth factor receptor gene (EGFR) mutation. The 1-year OS rate was 31% (95% CI 25–36) with a median OS of 7.1 months (95% CI 6.0–7.9). OS was significantly better in females than males (p = 0.0258) and in patients with an EGFR mutation compared to EGFR wild-type patients (p = 0.0004). OS was not affected by age (p = 0.3436) and ECOG PS (p = 0.5364). Patients with squamous NSCLC tended to live longer than patients with non-squamous EGFR wild-type tumors (median OS: 8.6 vs 5.5 months). Cough and dyspnea improved during the observation period. The erlotinib safety profile was comparable to that in previous studies with rash (45.2%) and diarrhea (22.6%) being the most frequently reported adverse events.

Conclusions

Erlotinib represents a suitable palliative treatment option in further therapy lines for elderly patients with advanced NSCLC. The results obtained under real-life conditions add to our understanding of the benefits and risks of erlotinib in routine clinical practice.

Trial registration

BfArM (https://www.bfarm.de; ML23023); ClinicalTrials.gov (NCT01535729; 20 Feb 2012).

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Itchins M, Clarke S, Pavlakis N. Do EGFR tyrosine kinase inhibitors (TKIs) still have a role in EGFR wild-type pre-treated advanced non-small cell lung cancer (NSCLC)?-the shifting paradigm of therapeutics. Transl Lung Cancer Res 2018. [PMID: 29531903 DOI: 10.21037/tlcr.2018.01.06] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]

Bronte G, Franchina T, Alù M, Sortino G, Celesia C, Passiglia F, Savio G, Laudani A, Russo A, Picone A, Rizzo S, De Tursi M, Gambale E, Bazan V, Natoli C, Blasi L, Adamo V, Russo A. The comparison of outcomes from tyrosine kinase inhibitor monotherapy in second- or third-line for advanced non-small-cell lung cancer patients with wild-type or unknown EGFR status. Oncotarget 2017;7:35803-35812. [PMID: 26993607 PMCID: PMC5094963 DOI: 10.18632/oncotarget.8130] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 02/28/2016] [Indexed: 01/24/2023] Open

Affiliation(s)

Giuseppe Bronte Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
Tindara Franchina Medical Oncology Unit-AOOR Papardo-Piemonte, Messina and Department of Human Pathology, University of Messina, Messina, Italy
Massimiliano Alù Medical Oncology Unit, A.R.N.A.S. Civico, Palermo, Italy
Giovanni Sortino Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
Claudia Celesia Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
Francesco Passiglia Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
Giuseppina Savio Medical Oncology Unit, A.R.N.A.S. Civico, Palermo, Italy
Agata Laudani Medical Oncology Unit, A.R.N.A.S. Civico, Palermo, Italy
Alessandro Russo Medical Oncology Unit-AOOR Papardo-Piemonte, Messina and Department of Human Pathology, University of Messina, Messina, Italy
Antonio Picone Medical Oncology Unit-AOOR Papardo-Piemonte, Messina and Department of Human Pathology, University of Messina, Messina, Italy
Sergio Rizzo Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
Michele De Tursi Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio", Chieti, Italy
Elisabetta Gambale Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio", Chieti, Italy
Viviana Bazan Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
Clara Natoli Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio", Chieti, Italy
Livio Blasi Medical Oncology Unit, A.R.N.A.S. Civico, Palermo, Italy
Vincenzo Adamo Medical Oncology Unit-AOOR Papardo-Piemonte, Messina and Department of Human Pathology, University of Messina, Messina, Italy
Antonio Russo Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy

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Effectiveness and safety of nivolumab in advanced non-small cell lung cancer: The real-life data. Lung Cancer 2017;126:217-223. [PMID: 29254746 DOI: 10.1016/j.lungcan.2017.11.015] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 04/12/2017] [Accepted: 11/17/2017] [Indexed: 12/23/2022]

Wu D, Duan C, Wu F, Chen L, Chen S. Which treatment is preferred for advanced non-small-cell lung cancer with wild-type epidermal growth factor receptor in second-line therapy? A meta-analysis comparing immune checkpoint inhibitor, tyrosine kinase inhibitor and chemotherapy. Oncotarget 2017;8:66491-66503. [PMID: 29029530 PMCID: PMC5630430 DOI: 10.18632/oncotarget.20281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2017] [Accepted: 07/26/2017] [Indexed: 12/26/2022] Open

Battisti NML, Sehovic M, Extermann M. Assessment of the External Validity of the National Comprehensive Cancer Network and European Society for Medical Oncology Guidelines for Non–Small-Cell Lung Cancer in a Population of Patients Aged 80 Years and Older. Clin Lung Cancer 2017;18:460-471. [DOI: 10.1016/j.cllc.2017.03.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Revised: 03/04/2017] [Accepted: 03/06/2017] [Indexed: 12/25/2022]

The Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer Harboring Wild-type Epidermal Growth Factor Receptor: A Meta-analysis of 25 RCTs. Am J Clin Oncol 2017;40:362-369. [PMID: 25647830 DOI: 10.1097/coc.0000000000000179] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]

Abstract

OBJECTIVE

To determine the efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) patients with wild-type (WT) EGFR tumors, we performed an indirect meta-analysis to assess the treatment effects of EGFR-TKIs in such patients.

METHODS

We searched for randomized controlled trials in Medline, Embase, the Cochrane controlled trials register, the Science Citation Index, and the American Society of Clinical Oncology annual meetings. Effect measures used were hazard ratios (HR) for progression-free survival (PFS) and overall survival.

RESULTS

Out of 2134 retrieved articles, 25 randomized controlled trials including more than 4467 patients were identified. This pooled analysis showed the inferior efficacy of TKI over chemotherapy among patients with WT EGFR NSCLC in terms of PFS (HR, 1.37; 95% confidence interval [CI]: 1.10, 1.72; P=0.006). When used as first-line treatment, TKIs have also fared worse than chemotherapy when compared with standard platinum doublet regimens in patients with WT EGFR in terms of PFS (HR, 2.15; 95% CI: 1.68, 2.76; P<0.001). And, the same inferior trend was found with TKIs in those trials of second-line/third-line treatment in terms of PFS (HR, 1.35; 95% CI: 1.13, 1.61; P<0.001). However, according to the pooled results, EGFR-TKIs still produced a reduction of 19% in the risk of progression over placebo in such WT EGFR patients ineligible for further chemotherapy (HR, 0.81; 95% CI: 0.68, 0.97; P=0.02). Furthermore, addition of EGFR-TKI to chemotherapy resulted in an improvement of PFS over chemotherapy alone (HR, 0.83; 95% CI: 0.71, 0.96; P=0.01).

CONCLUSIONS

Among patients with advanced NSCLC harboring WT EGFR, EGFR-TKIs were inferior to standard chemotherapy both for first-line treatment and for second-line/third-line treatment, but still superior to placebo in patients unfit for further chemotherapy. And, addition of EGFR-TKIs to chemotherapy could provide additive benefit over chemotherapy alone in such patients.

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Lazzari C, Karachaliou N, Gregorc V, Bulotta A, Gonzalez-Cao M, Verlicchi A, Altavilla G, Rosell R, Santarpia M. Second-line therapy of squamous non-small cell lung cancer: an evolving landscape. Expert Rev Respir Med 2017;11:469-479. [PMID: 28467720 DOI: 10.1080/17476348.2017.1326822] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]

Tarhini AA, Rafique I, Floros T, Tran P, Gooding WE, Villaruz LC, Burns TF, Friedland DM, Petro DP, Farooqui M, Gomez-Garcia J, Gaither-Davis A, Dacic S, Argiris A, Socinski MA, Stabile LP, Siegfried JM. Phase 1/2 study of rilotumumab (AMG 102), a hepatocyte growth factor inhibitor, and erlotinib in patients with advanced non-small cell lung cancer. Cancer 2017;123:2936-2944. [PMID: 28472537 DOI: 10.1002/cncr.30717] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 01/09/2017] [Accepted: 01/11/2017] [Indexed: 11/06/2022]

Abstract

BACKGROUND

Activation of the mesenchymal-epidermal transition factor (MET) tyrosine kinase and its ligand, hepatocyte growth factor (HGF), is implicated in resistance to epidermal growth factor receptor (EGFR) inhibitors. In this phase 1/2 trial, rilotumumab (an anti-HGF antibody) combined with erlotinib was evaluated in patients with metastatic, previously treated non-small cell lung cancer.

METHODS

In phase 1, a dose de-escalation design was adopted with rilotumumab starting at 15 mg/kg intravenously every 3 weeks and oral erlotinib 150 mg daily. In phase 2, the disease control rate (DCR) (according to Response Evaluation Criteria in Solid Tumors) of the combination was evaluated using a Simon 2-stage design. The biomarkers examined included 10 plasma-circulating molecules associated with the EGFR and MET pathways.

RESULTS

Without indications for de-escalation, the recommended phase 2 dose was dose level 0. Overall, 45 response-evaluable patients were enrolled (13 with squamous carcinoma, 32 with adenocarcinoma; 2 had confirmed EGFR mutations, 33 had confirmed wild-type [WT] EGFR, and 7 had KRAS mutations). The DCR for all patients was 60% (90% confidence interval [CI], 47.1%-71.3%). Median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 6.6 months (90% CI, 5.6-8.9 months). Among patients with WT EGFR, the DCR was 60.6% (90% CI, 46.3%-73.3%), median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 7.0 months (90% CI, 5.6-13.4 months). Elevated baseline levels of neuregulin 1 were associated with longer progression-free survival (hazard ratio, 0.41; 95% CI, 0.19-0.87), whereas elevated amphiregulin levels were associated with more rapid progression (hazard ratio, 2.14; 95% CI, 1.48-3.08).

CONCLUSIONS

Combined rilotumumab and erlotinib had an acceptable safety profile, and the DCR met the prespecified criteria for success. In the EGFR WT group, the DCR exceeded published reports for erlotinib alone. High circulating levels of neuregulin 1 may indicate sensitivity to this combination. Cancer 2017;123:2936-44. © 2017 American Cancer Society.

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Affiliation(s)

Ahmad A Tarhini Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.,University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, Pennsylvania
Imran Rafique University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, Pennsylvania
Theofanis Floros Department of Medicine, Athens Naval & Veterans Hospital, Athens, Greece
Phu Tran University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, Pennsylvania
William E Gooding University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, Pennsylvania
Liza C Villaruz Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.,University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, Pennsylvania
Timothy F Burns Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.,University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, Pennsylvania.,Department of Medicine, Athens Naval & Veterans Hospital, Athens, Greece
David M Friedland University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, Pennsylvania
Daniel P Petro University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, Pennsylvania
Mariya Farooqui Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota
Jose Gomez-Garcia Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota
Autumn Gaither-Davis University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, Pennsylvania.,Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
Sanja Dacic Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.,University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, Pennsylvania
Athanassios Argiris University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, Pennsylvania
Mark A Socinski University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, Pennsylvania
Laura P Stabile University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, Pennsylvania.,Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
Jill M Siegfried Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota

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Zugazagoitia J, Díaz A, Jimenez E, Nuñez JA, Iglesias L, Ponce-Aix S, Paz-Ares L. Second-line Treatment of Non-Small Cell Lung Cancer: Focus on the Clinical Development of Dacomitinib. Front Med (Lausanne) 2017;4:36. [PMID: 28424775 PMCID: PMC5380728 DOI: 10.3389/fmed.2017.00036] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 03/17/2017] [Indexed: 12/26/2022] Open

Abstract

Dacomitinib is a second-generation, irreversible, covalent pan-HER tyrosine-kinase inhibitor (TKI). It showed potent EGFR signaling inhibition in experimental models, including first-generation TKI-resistant non-small cell lung cancer (NSCLC) cell lines. This preclinical efficacy did not translate into clinically meaningful treatment benefits for advanced, pretreated, molecularly unselected NSCLC patients enrolled in two parallel phase III trials. Dacomitinib and erlotinib showed overlapping efficacy data in chemotherapy-pretreated EGFR wild-type (WT) patients in the ARCHER 1009 trial. Similarly, it failed to demonstrate any survival benefits as compared to placebo in EGFR WT subsets progressing on chemotherapy and at least one previous first-generation TKI (erlotinib or gefitinib) in the BR.26 trial. In the case of EGFR-mutant NSCLCs, a pooled analysis of the ARCHER 1009 and ARCHER 1028 trials comparing the efficacy of dacomitinib vs. erlotinib in chemotherapy-pretreated, EGFR TKI-naïve patients showed a trend to a longer progression-free survival (PFS) and overall survival in favor of dacomitinib that did not reach statistical significance, with a higher rate of treatment related adverse events (mainly skin rash, paronychia, and gastrointestinal toxicities). On the other hand, the clinical activity in patients with EGFR-mutant NSCLCs with acquired TKI resistance that were included in phase II/III trials was equally poor (response rate <10%; PFS 3-4 months). Therefore, with the results of the ARCHER 1050 trial (NCT01774721) still pending, the current clinical development of dacomitinib is largely focused on EGFR-mutant, TKI-naïve patients. Here, we review the most relevant clinical data of dacomitinib in advanced NSCLC. We discuss the potential role of dacomitinib in pretreated EGFR WT and EGFR-mutant (TKI-naïve and TKI-resistant) patients. Finally, we briefly comment the available clinical data of dacomitinib in HER2-mutant NSCLC patients.

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Second-Line Treatment of Non-Small Cell Lung Cancer: New Developments for Tumours Not Harbouring Targetable Oncogenic Driver Mutations. Drugs 2017;76:1321-36. [PMID: 27557830 DOI: 10.1007/s40265-016-0628-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]

Köhler J. Second-Line Treatment of NSCLC-The Pan-ErbB Inhibitor Afatinib in Times of Shifting Paradigms. Front Med (Lausanne) 2017;4:9. [PMID: 28243590 PMCID: PMC5303897 DOI: 10.3389/fmed.2017.00009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 01/20/2017] [Indexed: 12/22/2022] Open

Durm G, Hanna N. Second-Line Chemotherapy and Beyond for Non-Small Cell Lung Cancer. Hematol Oncol Clin North Am 2017;31:71-81. [PMID: 27912835 DOI: 10.1016/j.hoc.2016.08.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]

Lazzari C, Bulotta A, Ducceschi M, Viganò MG, Brioschi E, Corti F, Gianni L, Gregorc V. Historical Evolution of Second-Line Therapy in Non-Small Cell Lung Cancer. Front Med (Lausanne) 2017;4:4. [PMID: 28168189 PMCID: PMC5253463 DOI: 10.3389/fmed.2017.00004] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 01/06/2017] [Indexed: 12/26/2022] Open

Lee MH, Kong DS, Seol HJ, Nam DH, Lee JI. The Influence of Biomarker Mutations and Systemic Treatment on Cerebral Metastases from NSCLC Treated with Radiosurgery. J Korean Neurosurg Soc 2016;60:21-29. [PMID: 28061489 PMCID: PMC5223759 DOI: 10.3340/jkns.2016.0404.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 08/22/2016] [Accepted: 08/30/2016] [Indexed: 01/10/2023] Open

Abstract

Objective

The purpose of this study was to analyze outcomes and identify prognostic factors in patients with cerebral metastases from non-small cell lung cancer (NSCLC) treated with gamma knife radiosurgery (GKS) particularly, focusing on associations of biomarkers and systemic treatments.

Methods

We retrospectively reviewed the medical records of 134 patients who underwent GKS for brain metastases due to NSCLC between January 2002 and December 2012. Representative biomarkers including epidermal growth factor receptor (EGFR) mutation, K-ras mutation, and anaplastic lymphoma kinase (ALK) mutation status were investigated.

Results

The median overall survival after GKS was 22.0 months (95% confidence interval [CI], 8.8–35.1 months). During follow-up, 63 patients underwent salvage treatment after GKS. The median salvage treatment-free survival was 7.9 months (95% CI, 5.2–10.6 months). Multivariate analysis revealed that lower recursive partition analysis (RPA) class, small number of brain lesions, EGFR mutation (+), and ALK mutation (+) were independent positive prognostic factors associated with longer overall survival. Patients who received target agents 30 days after GKS experienced significant improvements in overall survival and salvage treatment-free survival than patients who never received target agents and patients who received target agents before GKS or within 30 days (median overall survival: 5.0 months vs. 18.2 months, and 48.0 months with p-value=0.026; median salvage treatment-free survival: 4.3 months vs. 6.1 months and 16.6 months with p-value=0.006, respectively). To assess the influence of target agents on the pattern of progression, cases that showed local recurrence and new lesion formation were analyzed according to target agents, but no significant effects were identified.

Conclusion

The prognosis of patients with brain metastases of NSCLC after GKS significantly differed according to specific biomarkers (EGFR and ALK mutations). Our results show that target agents combined with GKS was related to significantly longer overall survival, and salvage treatment-free survival. However, target agents were not specifically associated with improved local control of the lesion treated by GKS either development of new lesions. Therefore, it seems that currently popular target agents do not affect brain lesions themselves, and can prolong survival by controlling systemic disease status.

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The Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Molecularly Selected Patients with Non-Small Cell Lung Cancer: A Meta-Analysis of 30 Randomized Controlled Trials. Target Oncol 2016. [PMID: 26206590 DOI: 10.1007/s11523-015-0376-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]

Abstract

OBJECTIVE

To determine the efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in molecularly selected patients with advanced non-small cell lung cancer (NSCLC), we performed this pooled analysis.

METHOD

Randomized trials of EGFR-TKIs as treatment for advanced NSCLC were included for this meta-analysis. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data. Pooled estimates of treatment efficacy of EGFR-TKIs in the selected patients by EGFR-mutation status were calculated.

RESULTS

Out of 2134 retrieved articles, 30 randomized controlled trials (RCTs) enrolling more than 4053 patients with wild-type EGFR tumors and 1592 patients with mutant EGFR tumors were identified. For EGFR mutant patients, EGFR-TKIs treatment improved progression-free survival (PFS) compared with chemotherapy: the summary HRs were 0.41 (p < 0.00001) for the first-line setting and 0.46 (p = 0.02) for second/third-line setting, respectively. Also, the same superior trend was found with TKIs maintenance over placebo (HR = 0.14, p < 0.00001) and with TKIs combined with chemotherapy over chemotherapy (HR = 0.49, p = .002) in both the first-line and maintenance therapy settings. For EGFR wild-type patients, EGFR-TKIs have fared worse than chemotherapy in the first-line setting (HR = 1.65, p = .03) and in the second/third-line setting (HR = 1.27, p = .005). However, EGFR-TKIs maintenance still produced a reduction of 19 % in the risk of progression over placebo (HR = 0.81, p = .02). Furthermore, EGFR-TKIs added to chemotherapy as first-line treatment resulted in an improvement of PFS over chemotherapy alone in such wild-type EGFR patients (HR = 0.82, p = .03). In overall survival (OS) analysis, only EGFR-TKIs single agent was inferior to chemotherapy in EGFR wild-type patients (HR = 1.13, p = .02). No statistically significant difference in terms of OS was observed in any other subgroup analysis.

CONCLUSIONS

For EGFR mutant patients, EGFR-TKIs therapy produced a prominent PFS benefit in all settings. Among EGFR wild-type patients, EGFR-TKIs were inferior to chemotherapy both for first-line treatment and for second/third-line treatment. However, EGFR-TKIs maintenance and addition of EGFR-TKIs to chemotherapy could provide additive benefit over chemotherapy alone in such EGFR wild-type patients.

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Kim J, Cho CK, Yoo HS. Survival Analysis of Advanced Non-Small Cell Lung Cancer Patients Treated by Using Wheel Balance Cancer Therapy. Integr Cancer Ther 2016;15:467-477. [PMID: 27151594 PMCID: PMC5739164 DOI: 10.1177/1534735416639714] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Revised: 12/18/2015] [Accepted: 02/25/2016] [Indexed: 12/15/2022] Open

Abstract

Objective To investigate the clinical effect and the overall survival (OS) rate of patients with advanced non-small cell lung cancer (NSCLC) who have undergone Wheel Balance Cancer Therapy (WBCT). Methods The cases of 33 patients with advanced NSCLC who were treated with WBCT at the East West Cancer Center (EWCC) between October 4, 2004, and October 3, 2013, without undergoing concurrent conventional treatment were analyzed. The Kaplan-Meier method was used to estimate the OS of the cases, and the median OS was calculated according to age, Eastern Cooperative Oncology Group Performance Status (ECOG PS), conventional-treatment history, WBCT treatment duration, and histological tumor type. Results The median OS of all patients was 31.1 (95% confidence interval [CI] = 3.5-58.7) months; the OS rates were 63.6% and 24.2% at years 1 and 2, respectively. The median OS rates of patients under and over 65 years were 45.2 (95% CI = 13.5-76.9) and 19.5 (95% CI = 7.1-31.8) months, respectively (P = .189). The median OS rates of patients who received WBCT for >14 days but <28 days and those who received WBCT for ≥28 days were 16.2 (95% CI = 13.3-19.2) and 45.2 (95% CI = 14.4-76.0) months, respectively (P = .437). The median OS rates of patients who had undergone prior conventional treatment and those who had not were 45.2 (95% CI = 9.1-81.3) and 3.9 (95% CI = unable to calculate) months, respectively (P = .000). The median OS rates of patients with squamous cell carcinoma (SCC) and non-SCC lung cancer were 5.6 (95% CI = unable to calculate) and 45.2 (95% CI = 9.1-81.3) months, respectively (P = .262). The median OS rate of patients with ECOG PS ≥3 was 14.3 (95% CI = 8.8-19.8) months; that of patients ECOG PS <3 could not be calculated. However, the mean OS rates of patients with ECOG PS <3 and with ECOG PS ≥3 were 85.7 (95% CI = 58.4-113.0) and 12.7 (95% CI = 8.5-16.9) months, respectively (P = .000). No severe adverse events were encountered. Conclusions Our study indicates that WBCT might be effective to prolong the length of survival for patients with advanced NSCLC who have previously undergone conventional treatment and have an ECOG PS <3.

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Incremental Innovation and Progress in Advanced Squamous Cell Lung Cancer: Current Status and Future Impact of Treatment. J Thorac Oncol 2016;11:2066-2081. [DOI: 10.1016/j.jtho.2016.08.138] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 08/09/2016] [Accepted: 08/19/2016] [Indexed: 11/20/2022]

Måreng AS, Langer SW, Bodtger U. Primary pulmonary adenocarcinoma in a 16-year-old boy - a five-year follow-up. Eur Clin Respir J 2016;3:32633. [PMID: 27834176 PMCID: PMC5102103 DOI: 10.3402/ecrj.v3.32633] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 10/05/2016] [Accepted: 10/06/2016] [Indexed: 11/29/2022] Open

Liu G, Zhang J, Zhou ZY, Li J, Cai X, Signorovitch J. Association between time to progression and subsequent survival inceritinib-treated patients with advanced ALK-positive non-small-cell lung cancer. Curr Med Res Opin 2016;32:1911-1918. [PMID: 27488695 DOI: 10.1080/03007995.2016.1220934] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]

From 2000 to 2016: Which Second-Line Treatment in Advanced Non-Small Cell Lung Cancer? Curr Treat Options Oncol 2016;17:59. [DOI: 10.1007/s11864-016-0437-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]

Novello S, Barlesi F, Califano R, Cufer T, Ekman S, Levra MG, Kerr K, Popat S, Reck M, Senan S, Simo G, Vansteenkiste J, Peters S. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016;27:v1-v27. [DOI: 10.1093/annonc/mdw326] [Citation(s) in RCA: 654] [Impact Index Per Article: 72.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open

Monnet I, Audigier-Valette C, Girard N, Vergnenègre A, Molinier O, Souquet PJ, Blanchon F, Bonnetain F, Taguieva-Pioger N, Lamour C, Wislez M. Real-life effectiveness of erlotinib as second-line treatment of stage IIIB/IV squamous non-small cell lung cancer: Results of the PEPiTA observational study. Lung Cancer 2016;98:84-90. [PMID: 27393512 DOI: 10.1016/j.lungcan.2016.05.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 04/12/2016] [Accepted: 05/24/2016] [Indexed: 10/21/2022]

Neumair P, Joos L, Warschkow R, Dutly A, Ess S, Hitz F, Früh M, Brutsche M, Baty F, Krähenbühl S, Cerny T, Joerger M. Erlotinib has comparable clinical efficacy to chemotherapy in pretreated patients with advanced non-small cell lung cancer (NSCLC): A propensity-adjusted, outcomes research-based study. Lung Cancer 2016;100:38-44. [PMID: 27597279 DOI: 10.1016/j.lungcan.2016.07.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 07/26/2016] [Accepted: 07/27/2016] [Indexed: 10/21/2022]

Abstract

OBJECTIVES

Controversy exists about the integration of erlotinib in patients with EGFR wildtype, advanced NSCLC.

MATERIALS AND METHODS

We included patients with advanced NSCLC receiving at least two lines of palliative systemic treatment between January 2005 and December 2014 and not harbouring targetable driver mutations. Primary study endpoint was overall survival (OS), secondary endpoint progression-free survival (PFS). We used Kaplan-Meier statistics, multivariate Cox regression and Propensity score or Inverse Probability Weights (IPW) matching to compare clinical outcome between patients receiving erlotinib in second or further line and those receiving chemotherapy only. The study had a power of 90% to detect a survival superiority of 30%.

RESULTS

From a total of 827 patients, we excluded 171 patients with potentially curative treatment, 189 receiving treatment outside of our institute, 206 receiving no or only one line of systemic treatment, 6 with ALK translocations and 28 with EGFR mutations. From 227 patients in the final efficacy analysis, 125 patients received erlotinib in second (89 patients), third (28) or further-line (8), and 102 patients received chemotherapy only. Women and never smokers were significantly overrepresented in the erlotinib group. Both OS (hazard ratio (HR)=1.14, 95% CI 0.80-1.63, P=0.448) and PFS (HR=1.20, 95% CI 0.95-1.52, P=0.119) were similar in the erlotinib compared to the chemotherapy group using IPW-adjusted Cox regression analysis treating the use of erlotinib as a time-dependent covariate starting from second-line treatment and stratified for ECOG performance status and treatment line. ECOG performance status was the most powerful covariate to select patients for erlotinib treatment.

CONCLUSION

The present study suggests erlotinib to have similar clinical efficacy compared to chemotherapy in patients with pretreated advanced NSCLC and no known molecular targetable alterations.

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Tomasini P, Barlesi F, Mascaux C, Greillier L. Pemetrexed for advanced stage nonsquamous non-small cell lung cancer: latest evidence about its extended use and outcomes. Ther Adv Med Oncol 2016;8:198-208. [PMID: 27239238 DOI: 10.1177/1758834016644155] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open

Greenhalgh J, Bagust A, Boland A, Dwan K, Beale S, Hockenhull J, Proudlove C, Dundar Y, Richardson M, Dickson R, Mullard A, Marshall E. Erlotinib and gefitinib for treating non-small cell lung cancer that has progressed following prior chemotherapy (review of NICE technology appraisals 162 and 175): a systematic review and economic evaluation. Health Technol Assess 2016;19:1-134. [PMID: 26134145 DOI: 10.3310/hta19470] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open

Abstract

BACKGROUND

Lung cancer is the second most diagnosed cancer in the UK. Over 70% of lung cancers are non-small cell lung cancers (NSCLCs). Patients with stage III or IV NSCLC may be offered treatment to improve survival, disease control and quality of life. One-third of these patients receive further treatment following disease progression; these treatments are the focus of this systematic review.

OBJECTIVES

To appraise the clinical effectiveness and cost-effectiveness of erlotinib [Tarceva(®), Roche (UK) Ltd] and gefitinib (IRESSA(®), AstraZeneca) compared with each other, docetaxel or best supportive care (BSC) for the treatment of NSCLC after disease progression following prior chemotherapy. The effectiveness of treatment with gefitinib was considered only for patients with epidermal growth factor mutation-positive (EGFR M+) disease.

DATA SOURCES

Four electronic databases (EMBASE, MEDLINE, The Cochrane Library, PubMed) were searched for randomised controlled trials (RCTs) and economic evaluations. Manufacturers' evidence submissions to the National Institute for Health and Care Excellence were also considered.

REVIEW METHODS

Outcomes for three distinct patient groups based on EGFR mutation status [EGFR M+, epidermal growth factor mutation negative (EGFR M-) and epidermal growth factor mutation status unknown (EGFR unknown)] were considered. Heterogeneity of the data precluded statistical analysis. A de novo economic model was developed to compare treatments (incremental cost per quality-adjusted life-year gained).

RESULTS

Twelve trials were included in the review. The use of gefitinib was compared with chemotherapy (n = 6) or BSC (n = 1), and the use of erlotinib was compared with chemotherapy (n = 3) or BSC (n = 1). One trial compared the use of gefitinib with the use of erlotinib. No trials included solely EGFR M+ patients; all data were derived from retrospective subgroup analyses from six RCTs [Kim ST, Uhm JE, Lee J, Sun JM, Sohn I, Kim SW, et al. Randomized phase II study of gefitinib versus erlotinib in patients with advanced non-small cell lung cancer who failed previous chemotherapy. Lung Cancer 2012;75:82-8, V-15-32, Tarceva In Treatment of Advanced NSCLC (TITAN), BR.21, IRESSA Survival Evaluation in Lung cancer (ISEL) and IRESSA NSCLC Trial Evaluating REsponse and Survival versus Taxotere (INTEREST)]. These limited data precluded conclusions regarding the clinical effectiveness of any treatment for EGFR M+ patients. For EGFR M- patients, data were derived from the TArceva Italian Lung Optimization tRial (TAILOR) trial and Docetaxel and Erlotinib Lung Cancer Trial (DELTA). Retrospective data were also derived from subgroup analyses of BR.21, Kim et al., TITAN, INTEREST and ISEL. The only statistically significant reported results were for progression-free survival (PFS) for TAILOR and DELTA, and favoured docetaxel over erlotinib [TAILOR hazard ratio (HR) 1.39, 95% confidence interval (CI) 1.06 to 1.82; DELTA HR 1.44, 95% CI 1.08 to 1.92]. In EGFR unknown patients, nine trials (INTEREST, IRESSA as Second-line Therapy in Advanced NSCLC - KoreA, Li, Second-line Indication of Gefitinib in NSCLC, V-15-32, ISEL, DELTA, TITAN and BR.21) reported overall survival data and only one (BR.21) reported a statistically significant result favouring the use of erlotinib over BSC (HR 0.7, 95% CI 0.58 to 0.85). For PFS, BR.21 favoured the use of erlotinib when compared with BSC (HR 0.61, 95% CI 0.51 to 0.74) and the use of gefitinib was favoured when compared with BSC (HR 0.82, 95% CI 0.73 to 0.92) in ISEL. Limitations in the clinical data precluded assessment of cost-effectiveness of treatments for an EGFR M+ population by the Assessment Group (AG). The AG's economic model suggested that for the EGFR M- population, the use of erlotinib was not cost-effective compared with the use of docetaxel and compared with BSC. For EGFR unknown patients, the use of erlotinib was not cost-effective when compared with BSC.

CONCLUSIONS/FUTURE WORK

The lack of clinical data available for distinct patient populations limited the conclusions of the assessment. Future trials should distinguish between patients with EGFR M+ and EGFR M- disease.

FUNDING

The National Institute for Health Research Health Technology Assessment programme.

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Li G, Gao S, Sheng Z, Li B. The Efficacy of Single-Agent Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Biologically Selected Patients with Non-Small-Cell Lung Cancer: A Meta-Analysis of 19 Randomized Controlled Trials. Chemotherapy 2016;61:179-89. [DOI: 10.1159/000442344] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 11/09/2015] [Indexed: 11/19/2022]

Abstract Objective: To determine the efficacy of first-generation single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in advanced non-small-cell lung cancer patients with known EGFR mutation status, we undertook this pooled analysis. Method: We searched for randomized controlled trials (RCTs) in Medline, Embase, the Cochrane Controlled Trials Register, the Science Citation Index, and the American Society of Clinical Oncology annual meetings. Results: Out of 2,129 retrieved articles, 19 RCTs enrolling 2,016 patients with wild-type EGFR tumors and 1,034 patients with mutant EGFR tumors were identified. For these EGFR mutant patients, single-agent EGFR-TKI therapy improved progression-free survival (PFS) over chemotherapy: the summary hazard ratios (HRs) were 0.41 (p < 0.001) for the first-line setting and 0.46 (p = 0.02) for the second-/third-line setting. For those EGFR wild-type patients, single-agent EGFR-TKI therapy did not do as well as chemotherapy in the first-line setting (HR = 1.65, p = 0.03) and in the second-/third-line setting (HR = 1.27, p = 0.006). No statistically significant difference was observed in terms of overall survival (OS). Using platinum-based doublet chemotherapy as a common comparator, indirect comparison showed the superior efficacy of single-agent EGFR-TKI therapy over EGFR-TKIs added to chemotherapy in PFS [HR = 1.35 (1.03, 1.77), p = 0.03]. Additionally, a marginal trend towards the same direction was found in the OS analysis [HR = 1.16 (0.99, 1.35), p = 0.06]. Interestingly, for those EGFR wild-type tumors, single-agent EGFR-TKI therapy was inferior to EGFR-TKIs added to chemotherapy in PFS [HR = 0.38 (0.33, 0.44), p < 0.001] and OS [HR = 0.83 (0.71, 0.97), p = 0.02]. Conclusions: For these EGFR mutant patients, single-agent EGFR-TKI therapy prolonged PFS over chemotherapy. However, single-agent EGFR-TKI therapy was inferior to chemotherapy in PFS for those EGFR wild-type patients. Single-agent EGFR-TKI therapy could improve PFS over the combination of EGFR-TKIs and chemotherapy in these EGFR mutant patients. However, EGFR-TKIs combined with chemotherapy could provide additive PFS and OS benefit over single-agent EGFR-TKI therapy in those EGFR wild-type patients. Collapse

Xu N, Fang W, Mu L, Tang Y, Gao L, Ren S, Cao D, Zhou L, Zhang A, Liu D, Zhou C, Wong KK, Yu L, Zhang L, Chen L. Overexpression of wildtype EGFR is tumorigenic and denotes a therapeutic target in non-small cell lung cancer. Oncotarget 2016;7:3884-3896. [PMID: 26646697 PMCID: PMC4826177 DOI: 10.18632/oncotarget.6461] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 11/15/2015] [Indexed: 01/08/2023] Open

Mitsuoka S, Kawaguchi T, Kubo A, Isa SI, Asai K, Uji M, Watanabe T, Sawa K, Yoshimoto N, Oka T, Nakai T, Suzumura T, Tanaka H, Matsuura K, Kimura T, Yoshimura N, Kudoh S, Hirata K. Epidermal growth factor receptor tyrosine kinase inhibitors in previously treated advanced non-small-cell lung cancer with wild-type EGFR. Expert Opin Pharmacother 2016;17:193-203. [PMID: 26781399 DOI: 10.1517/14656566.2016.1109635] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]

Affiliation(s)

Shigeki Mitsuoka a Department of Respiratory Medicine, Graduate School of Medicine , Osaka City University , Osaka , Japan
Tomoya Kawaguchi a Department of Respiratory Medicine, Graduate School of Medicine , Osaka City University , Osaka , Japan
Akihito Kubo b Department of Respiratory Medicine , Aichi Medical University School of Medicine , Aichi , Japan
Shun-ichi Isa c Clinical Research Center , National Hospital Organization Kinki-chuo Chest Medical Center , Osaka , Japan
Kazuhisa Asai a Department of Respiratory Medicine, Graduate School of Medicine , Osaka City University , Osaka , Japan
Masato Uji a Department of Respiratory Medicine, Graduate School of Medicine , Osaka City University , Osaka , Japan
Tetsuya Watanabe a Department of Respiratory Medicine, Graduate School of Medicine , Osaka City University , Osaka , Japan
Kenji Sawa a Department of Respiratory Medicine, Graduate School of Medicine , Osaka City University , Osaka , Japan
Naoki Yoshimoto a Department of Respiratory Medicine, Graduate School of Medicine , Osaka City University , Osaka , Japan
Takako Oka a Department of Respiratory Medicine, Graduate School of Medicine , Osaka City University , Osaka , Japan
Toshiyuki Nakai a Department of Respiratory Medicine, Graduate School of Medicine , Osaka City University , Osaka , Japan
Tomohiro Suzumura a Department of Respiratory Medicine, Graduate School of Medicine , Osaka City University , Osaka , Japan
Hidenori Tanaka a Department of Respiratory Medicine, Graduate School of Medicine , Osaka City University , Osaka , Japan
Kuniomi Matsuura a Department of Respiratory Medicine, Graduate School of Medicine , Osaka City University , Osaka , Japan
Tatsuo Kimura a Department of Respiratory Medicine, Graduate School of Medicine , Osaka City University , Osaka , Japan
Naruo Yoshimura a Department of Respiratory Medicine, Graduate School of Medicine , Osaka City University , Osaka , Japan
Shinzoh Kudoh a Department of Respiratory Medicine, Graduate School of Medicine , Osaka City University , Osaka , Japan
Kazuto Hirata a Department of Respiratory Medicine, Graduate School of Medicine , Osaka City University , Osaka , Japan

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Ma H, Tian X, Zeng XT, Zhang Y, Wang Y, Wang F, Zhou JG. The Efficacy of Erlotinib Versus Conventional Chemotherapy for Advanced Nonsmall-Cell Lung Cancer: A PRISMA-Compliant Systematic Review With Meta-Regression and Meta-Analysis. Medicine (Baltimore) 2016;95:e2495. [PMID: 26765461 PMCID: PMC4718287 DOI: 10.1097/md.0000000000002495] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open

Abstract

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer deaths. Erlotinib is the first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), the National Comprehensive Cancer Network (NCCN) guidelines recommend it as a first-line agent in patients with sensitizing EGFR mutations.We conducted a meta-analysis to compare the efficacy of erlotinib and chemotherapy for advanced NSCLC, and evaluated the efficacy of them to provide references for further clinical practice and research.PubMed, EMBASE, CBM, CNKI, WanFang database, The Cochrane library, and Web of Science, as well as abstracts presented at ASCO conferences and ClinicalTrials.gov were searched to identify relevant studies. HR with 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS), relative risk (RR) with 95% CIs for objective response rate (ORR) and 1-year survival rate (OSR) were all extracted. If the I was ≤40%, then the trial was considered to be heterogeneous, and a fixed-effects model was selected. Otherwise, a random-effects model was used. Meta-regression and sensitivity analyses were conducted to determine the possible heterogeneity causes and to further identify the influence of the various exclusion criteria on the overall risk estimate.The pooled analysis demonstrated a PFS HR of 0.93 (95% CI = 0.73, 1.19) for erlotinib versus chemotherapy and an ORR of 18.43% versus 22.07%, respectively. The OS HR was 1.02 (95%CI = 0.93, 1.12). The HRs for PFS estimated based on 10 trials involving 1101 patients were 0.22 (95% CI = 0.15, 0.29) and 1.27 (95% CI = 1.04, 1.48) in EGFR mutation-type and wild-type patients, respectively. The HRs for OS calculated from 4 studies including 681 participants were 0.83 (95% CI = 0.61, 1.05) and 0.86 (95% CI = 0.68, 1.04) in EGFR mutation-type and wild-type patients, respectively. The 1-year survival rates were 31.31% and 32.41%, respectively.Overall, the present meta-analysis suggested that erlotinib did not improve the ORR, PFS, OS or the 1-year survival rate for whole patients. However, erlotinib could benefit patients with EGFR mutation in terms of PFS, but the OS does not benefit from it for these patients. Further studies of erlotinib for these subgroup patients are warranted.

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