LUX-Lung 4: A Phase II Trial of Afatinib in Patients With Advanced Non–Small-Cell Lung Cancer Who Progressed During Prior Treatment With Erlotinib, Gefitinib, or Both

Katakami, Nobuyuki; Atagi, Shinji; Goto, Kōichi; Hida, Toyoaki; Horai, Takeshi; Inoue, Akira; Ichinose, Yukito; Koboyashi, Kunihiko; Takeda, Koji; Kiura, Katsuyuki; Nishio, Kazuto; Seki, Yoko; Ebisawa, Ryuichi; Shahidi, Mehdi; Yamamoto, Nobuyuki

doi:10.1200/jco.2012.45.0981

Cited by 297 publications

(252 citation statements)

References 27 publications

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“…Although afatinib as single agent demonstrated high antitumor activity in preclinical model in both sensitizing EGFR mutants and resistant cells harboring T790M, the ORR with afatinib alone for Probability of survival NSCLC patients who progressed during prior treatment with gefitinib or erlotinib was disappointing with only 7% to 8% (18,40). However, a novel treatment strategy with dual blockade of EGFR with afatinib and cetuximab has increased the response rate to 29% with an improvement in median PFS of 4.7 months (20).…”

Section: Discussionmentioning

confidence: 99%

A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non–Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib

Lee

Sun

Lim

et al. 2016

Clinical Cancer Research

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Purpose: In this phase Ib/II study, we aimed to assess the safety and efficacy of afatinib plus nimotuzumab (N) in advanced nonsmall cell lung cancer (NSCLC) patients with acquired resistance to gefitinib or erlotinib.Experimental Design: In phase Ib stage, patients received afatinib (40 mg or 30 mg once daily) plus nimotuzumab (100 mg or 200 mg once weekly) for 28-day cycles to determine the recommended phase II dose (RPIID). The safety and efficacy of RPIID dose was evaluated in phase II stage.Results: In total, 50 patients were enrolled (13 to phase Ib and 37 to phase II). In the first dose-finding cohort (afatinib 40 mg plus nimotuzumab 100 mg), one patient experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and in the subsequent cohort (afatinib 40 mg plus nimotuzumab 200 mg), two DLTs (grade 3 diarrhea and grade 3 neutropenia) occurred in 2 of 6 patients. Accordingly, RPIID was determined as afatinib 40 mg plus nimotuzumab 100 mg. In 44 patients treated with RPIID, 7 (16%) patients had grade 3 toxicities; skin rash (7%), diarrhea (5%), acne (2%), and fatigue (2%). The overall response rate was 23% and the median duration of response was 4.3 months (range, 0.7-16.2 months). The median progression-free survival and overall survival were 4.0 months [95% confidence interval (CI), 2.3-5.7 months] and 11.7 months (95% CI, 9.4-14.0 months), respectively.Conclusions: Combination treatment of afatinib and nimotuzumab demonstrated an acceptable safety profile and encouraging antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib. Larger phase III trial is warranted to confirm its efficacy and safety.

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Section: Discussionmentioning

confidence: 99%

A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non–Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib

Lee

Sun

Lim

et al. 2016

Clinical Cancer Research

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“…A total number of 545 EGFR-positive patients were available for analysis from five studies (four prospective and one retrospective) after detailed screening from 909 relevant studies (17)(18)(19)(20)(21). The selection process was summarized in Figure 1.…”

Section: Included Studiesmentioning

confidence: 99%

“…Most clinical relevant EGFR mutations occurred within the four exons encoding the ATP-binding pocket of the kinase domain (exons [18][19][20][21]. The most common mutation sites were deletions in exon 19 (19 Del) and point mutation in exon 21 (21 L858R), accounting for about 85% of all EGFR mutations in lung cancer.…”

Section: Introductionmentioning

confidence: 99%

The efficacy and toxicity of afatinib in advanced EGFR-positive non-small-cell lung cancer patients after failure of first-generation tyrosine kinase inhibitors: a systematic review and meta-analysis

et al. 2017

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Background: The first generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFRTKIs), gefitinib and erlotinib, have become the standard first-line treatment for non-small-cell lung cancer (NSCLC) patients with EGFR mutation. However, there was no pooled analysis focused on the usage of the second-generation TKI, afatinib, in advanced EGFR-positive NSCLC patients after failure of first generation TKIs. Therefore, a meta-analysis was conducted to solve the above question. Methods: Electronic databases were searched for eligible literatures. ORR (objective response rate), DCR (disease controlled rate), PFS (progression-free survival), OS (overall survival) and primary grade 3/4 adverse events were pooled with the corresponding 95% confidence interval using R software. Sensitivity analyses and heterogeneity were quantitatively evaluated. Results: A total of 545 EGFR-positive patients were available for analysis from five studies after detailed screening from 909 relevant studies. The pooled ORR and DCR of afatinib in EGFR-positive patients after failure of the first generation EGFR-TKIs were 0.12 (0.08-0.19) and 0.60 (0.53-0.68), respectively. Besides, the 6 m-PFS rate, 1 y-PFS rate and 6 m-OS rate were 0.26 (0.22-0.30), 0.08 (0.06-0.10) and 0.74 (0.56-0.86). The grade 3/4 rate of diarrhea and that of skin deformity were 0.23 (0.10-0.46) and 0.14 (0.05-0.33), respectively. Sensitivity analyses revealed similar results with lower heterogeneity. Conclusions: Considering the efficacy, toxicity and current availability, afatinib could be a therapeutic option for advanced EGFR mutated NSCLC patients after the failure of 1st-generation TKIs.

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“…In the LUX-Lung 4 single-arm phase Ⅱ study from Japan, patients were enrolled with EGFR-mutant NSCLC that had progressed on gefitinib/erlotinib and chemotherapy. Treatment with afatinib was associated with a modest response rate of 8.2%, and median PFS of 4.4 mo with median OS of 19.0 mo [45] . Similarly, the larger placebo controlled trial of LUX-Lung 1 trial of afatinib after failure of chemotherapy and erlotinib or gefitinib evaluated 390 patients on afatinib and 195 patients on placebo.…”

Section: Overcoming Resistance To Egfr Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Review of the current targeted therapies for non-small-cell lung cancer

Nguyen

Neal

Wakelee

2014

WJCO

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The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790M-targeted agents CO-1686 and AZD9291, and the ALKtargeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1 , HER2 , and BRAF are covered as well.The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come. Key words: Lung cancer; Non-small cell lung cancer; Targeted therapies; Epidermal growth factor receptor; Epidermal growth factor receptor; Anaplastic lymphoma kinase; Anaplastic lymphoma kinase; Acquired resistance Core tip: The development of oncogene-directed targeted therapies has significantly changed the treatment of non-small-cell lung cancer. We review the data demonstrating efficacy of small-molecule tyrosine kinase inhibitors against epidermal growth factor receptor, anaplastic lymphoma kinase, ROS1, and other oncogenes. We also discuss the challenge of acquired resistance to these therapies and review promising agents which may overcome resistance.Nguyen KSH, Neal JW, Wakelee H. Review of the current targeted therapies for non-small-cell lung cancer.

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LUX-Lung 4: A Phase II Trial of Afatinib in Patients With Advanced Non–Small-Cell Lung Cancer Who Progressed During Prior Treatment With Erlotinib, Gefitinib, or Both

Abstract: Afatinib demonstrated modest but noteworthy efficacy in patients with NSCLC who had received third- or fourth-line treatment and who progressed while receiving erlotinib and/or gefitinib, including those with acquired resistance to erlotinib, gefitinib, or both.

Cited by 297 publications

References 27 publications

A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non–Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib

A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non–Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib

The efficacy and toxicity of afatinib in advanced EGFR-positive non-small-cell lung cancer patients after failure of first-generation tyrosine kinase inhibitors: a systematic review and meta-analysis

Review of the current targeted therapies for non-small-cell lung cancer

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