Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial

Miller, Vincent A.; Hirsh, Vera; Cadranel, Jacques; Chen, Yuh Min; Park, Keunchil; Kim, Sang We; Zhou, Caicun; Su, Wu Chou; Wang, Mengzhao; Sun, Yan; Heo, Dae Seog; Crinò, Lucio; Tan, Eng Huat; Chao, Tsu Yi; Shahidi, Mehdi; Cong, Xiuyu Julie; Lorence, Robert M.; Yang, James Chih‐Hsin

doi:10.1016/s1470-2045(12)70087-6

Cited by 882 publications

(677 citation statements)

References 28 publications

Supporting

Mentioning

644

Contrasting

Unclassified

Order By: Relevance

“…It is becoming clearer that toxicity concerns may be manageable by careful compound design and optimization of electrophile reactivity (49). The recent emergence of several FDA-approved covalent kinase inhibitors, including Ibrutinib and Afatinib, suggests that the methods and technology for rationally designing covalent inhibitors have matured to the point that they may be broadly applicable (50,51). As a general method, the chemosensor assay presented here may be of particular use in optimizing the relative reactivity of electrophilic functional groups and kinetics of covalent inhibition of various targets due to the efficiency with which a large number of samples and time points can be monitored inexpensively and in a high-throughput format.…”

Section: Discussionmentioning

confidence: 99%

In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C

Hunter¹,

Gurbani²,

Ficarro

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

205

183

View full text Add to dashboard Cite

Significance SML-8-73-1 (SML) is the first example, to our knowledge, of a GTP-competitive inhibitor of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-Ras). A high-resolution structure of K-Ras G12C bound to SML shows K-Ras in an inactive conformation. In situ proteomic-based chemical profiling of SML demonstrates that SML is highly selective for K-Ras G12C over other small GTPases. A novel chemosensor-based assay allows measurement of covalent reaction rates between K-Ras G12C and SML and enables characterization of this reaction in the context of millimolar concentrations of GTP and GDP, well in exccss of what is found in living cells. These results demonstrate that even in the presence of high concentrations of GTP and GDP, SML is able to exchange into the GN site.

show abstract

Section: Discussionmentioning

confidence: 99%

In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C

Hunter¹,

Gurbani²,

Ficarro

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

205

183

View full text Add to dashboard Cite

show abstract

“…Afatinib (irreversible TKI) has been approved as a targeted therapy against T790M. 52 The p16 tumour suppressor gene is inactivated in >70% of human NSCLC via homozygous deletion or aberrant hypermethylation of the promoter region. 53 Smoke carcinogens may also cause LOH and chromosomal deletions in the F-HIT gene.…”

Section: Cell Signalling Pathway Activation In Neversmokersmentioning

confidence: 99%

Tobacco Smoking and Lung Cancer : Perception Changing Facts = تدخين التبغ و سرطان الرئة : إدراك تغير الحقائق

Furrukh¹

2013

SQUMJ

View full text Add to dashboard Cite

“…15,16). Although afatinib showed clinical efficacy as single agent in the TKIs-na€ ve setting (17), the response rates in acquired resistance setting were below 10% (18). In xenograft models of TKI-resistant tumors harboring T790M mutation, dual inhibition of EGFR with afatinib plus cetuximab induced encouraging tumor shrinkage (19).…”

Section: Introductionmentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial

Cited by 882 publications

References 28 publications

In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C

In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C

Tobacco Smoking and Lung Cancer : Perception Changing Facts = تدخين التبغ و سرطان الرئة : إدراك تغير الحقائق

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

Contact Info

Product

Resources

About