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
Abstract
Background Afatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors.Methods In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0-2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib. We used a computer-generated sequence to randomly allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all patients received best supportive care. Randomisation was done in blocks of three and was stratified by sex and baseline ECOG performance status (0-1 vs 2). Investigators, patients, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival (from date of randomisation to death), analysed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00656136.Findings Between May 26, 2008, and Sept 21, 2009, we identified 697 patients, 585 of whom were randomly allocated to treatment (390 to afatinib, 195 to placebo). Median overall survival was 10·8 months (95% CI 10·0-12·0) in the afatinib group and 12·0 months (10·2-14·3) in the placebo group (hazard ratio 1·08, 95% CI 0·86-1·35; p=0·74). Median progression-free survival was longer in the afatinib group (3·3 months, 95% CI 2·79-4·40) than it was in the placebo group (1·1 months, 0·95-1·68; hazard ratio 0·38, 95% CI 0·31-0·48; p<0·0001). No complete responses to treatment were noted; 29 (7%) patients had a partial response in the afatinib group, as did one patient in the placebo group. Subsequent cancer treatment was given to 257 (68%) patients in the afatinib group and 153 (79%) patients in the placebo group. The most common adverse events in the afatinib group were diarrhoea (339 [87%] of 390 patients; 66 [17%] were grade 3) and rash or acne (305 [78%] patients; 56 [14%] were grade 3). These events occurred less often in the placebo group (18 [9%] of 195 patients had diarrhoea; 31 [16%] had rash or acne), all being grade 1 or 2. Drug-related serious adverse events occurred in 39 (10%) patients in the afatinib group and one (<1%) patient in the placebo group. We recorded two possibly treatment-related deaths in the afatinib group.Interpretation Although we recorded no benefit in terms of overall survival with afatinib (which might have been affected by cancer treatments given after progression in both groups), our findings for progression-free survival and response to treatment suggest that afatinib could be of some benefit to patients with advanced lung adenocarcinoma who have failed at least 12 weeks of previous EGFR tyrosine-kinase inhibitor treatment.Funding Boehringer Ingelheim Inc.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
As monotherapy, afatinib and dacomitinib fail to overcome T790M-mediated resistance in patients because effective preclinical concentrations cannot be reached due to wild-type EGFR toxicity.
“However, as monotherapy, they have failed to overcome T790M-mediated resistance in patients (28, 29), because concentrations at which these irreversible TKIs overcome T790M activity pre-clinically are not achievable in humans due to dose-limiting toxicity related to non-selective inhibition of wild-type EGFR (30).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [28]
Afatinib cannot inhibit T790M in patients because of an insufficient therapeutic window.
“However, we know from clinical experience that afatinib is unable to inhibit T790M in the clinic due to a lack of a therapeutic window”
Afatinib monotherapy trials in patients with acquired resistance to erlotinib or gefitinib showed a response rate below 10% and progression-free survival of about 4 months.
“For example, studies of afatinib monotherapy showed a response rate of less than 10% among patients with acquired resistance to erlotinib or gefitinib, with a progression-free survival of approximately 4 months.13,15”
From Rociletinib in <i>EGFR</i>-Mutated Non–Small-Cell Lung Cancer (2015) · cites this paper as [13]
In patients, afatinib is effective only in EGFR TKI-naive EGFR-mutant cancers and has a response rate below 10% in NSCLC that has become resistant to gefitinib or erlotinib.
“However, in lung cancer patients, afatinib is only effective in EGFR TKI naive EGFR mutant cancers and has a RR of < 10% in patients with NSCLC that have developed resistance to gefitinib or erlotinib (13).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [13]
Neither Afatinib nor Neratinib nor Dacomitinib demonstrated significant activity as single agent in patients harboring T790M mutations.
“neither Afatinib [76] nor Neratinib [77] nor Dacomitinib [78] demonstrated significant activity as single agent in patients harboring the T790M mutations.”
From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [76]
Afatinib failed to overcome EGFR T790M-mediated resistance in patients.
“However, for EGFR T790M mutated lung cancer, it failed to overcome EGFR T790M-mediated resistance in patients [36, 37].”
In LUX-Lung 1, 63% of patients in the afatinib group and 76% in the control group received at least one subsequent regimen.
“Sixty-three percent of the patients in the afatinib group and 76% in the control group received ≥ one subsequent regimen (all mutation statuses).15”
From Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update (2015) · cites this paper as [15]
In LUX-Lung 1, response rate was 7% versus 0.5%.
“Response rate was 7% versus 0.5%.”
From Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update (2015) · cites this paper as [15]
In a prespecified analysis of LUX-Lung 1, among participants with a complete or partial response to a first-line EGFR TKI whose tumors had known EGFR mutation test results, the HR for PFS was significant (0.23), but the HR for OS was not (0.90) in the afatinib arm.
“In a prespecified analysis, participants with a complete or partial response to a first-line EGFR TKI whose tumors also had known EGFR mutation test results (58 [88%] of 66), the HR for PFS was significant (0.23), but the HR for OS was not (0.90) in the afatinib arm.”
From Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update (2015) · cites this paper as [15]
Some second-line studies included patients who had received more than two previous regimens.
“Some of the second-line studies included patients who had received > two previous regimens.15,23,47,48,51,65”
From Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update (2015) · cites this paper as [15]
In the LUX-Lung 1 trial, there was no improvement in the primary end point of OS between afatinib and placebo, although PFS was longer in the afatinib group (3.3 vs 1.1 months; HR, 0.38; 95% CI, 0.31 to 0.48; P < .001).
“The study found no improvement in the primary end point of OS between patients randomly assigned to afatinib and those randomly assigned to placebo, although PFS was longer in the afatinib group (3.3 v 1.1 months; HR, 0.38; 95% CI, 0.31 to 0.48; P < .001).”
From Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update (2015) · cites this paper as [15]
Among 96 patients with EGFR mutation-positive tumors in LUX-Lung 1, PFS was 3.3 months with afatinib and 1.0 month with placebo (HR, 0.55; 95% CI, 0.31 to 0.85; P = .009).
“Among these 96 patients, PFS was 3.3 months for those who received afatinib and 1.0 month for those who received placebo (HR, 0.55; 95% CI, 0.31 to 0.85; P = .009).15”
From Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update (2015) · cites this paper as [15]
Cites
Aaronson, N. K., Ahmedzai, S., Bergman, B., Bullinger, M., Cull, A., Duez, N. J., Filiberti, A., Flechtner, H., Fleishman, S. B., Haes, J. C. J. M. D., et al. (1993) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/85.5.365 · Cited by 16,005 · see citing works
Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma
Mok, T. S., Wu, Y.-L., Thongprasert, S., Yang, C.-H., Chu, D.-T., Saijo, N., Sunpaweravong, P., Han, B., Margono, B., Ichinose, Y., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810699 · Cited by 8,261 · see citing works
Self-citationErlotinib in Previously Treated Non–Small-Cell Lung Cancer
Shepherd, F. A., Rodrigues Pereira, J., Ciuleanu, T., Tan, E. H., Hirsh, V., Thongprasert, S., Campos, D., Maoleekoonpiroj, S., Smylie, M., Martins, R., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa050753 · Cited by 5,419 · see citing works
Self-citationScagliotti, G. V., Parikh, P., von Pawel, J., Biesma, B., Vansteenkiste, J., Manegold, C., Serwatowski, P., Gatzemeier, U., Digumarti, R., Zukin, M., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.15.0375 · Cited by 3,203 · see citing works
Self-citationFayers, P. M., Aaronson, N. K., Bjordal, K., Groenvold, M., Curran, D., & Bottomley, A. (2001) · Research at the University of Copenhagen (University of Copenhagen) · Cited by 2,520 · see citing works
BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models
Li, D., Ambrogio, L., Shimamura, T., Kubo, S., Takahashi, M., Chirieac, L. R., Padera, R. F., Shapiro, G. I., Baum, A., Himmelsbach, F., et al. (2008) · Oncogene · doi:10.1038/onc.2008.109 · Cited by 1,447 · see citing works
Pirker, R., Pereira, J. R., Szczęsna, A., von Pawel, J., Krzakowski, M. J., Ramlau, R., Vynnychenko, I. O., Park, K., Yu, C.-T., Ganul, V., et al. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60569-9 · Cited by 1,346 · see citing works
Self-citationRational, biologically based treatment of EGFR-mutant non-small-cell lung cancer
Pao, W., & Chmielecki, J. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2947 · Cited by 1,083 · see citing works
Bergman, B., Aaronson, N. K., Ahmedzai, S. H., Kaasa, S., & Sullivan, M. (1994) · European Journal of Cancer · doi:10.1016/0959-8049(94)90535-5 · Cited by 892 · see citing works
Robins, J. M., & Finkelstein, D. M. (2000) · Biometrics · doi:10.1111/j.0006-341x.2000.00779.x · Cited by 877 · see citing works
Jackman, D., Pao, W., Riely, G. J., Engelman, J. A., Kris, M. G., Jänne, P. A., Lynch, T., Johnson, B. E., & Miller, V. A. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.24.7049 · Cited by 793 · see citing works
Self-citationReck, M., von Pawel, J., Zatloukal, P., Ramlau, R., Gorbounova, V., Hirsh, V., Leighl, N., Mezger, J., Archer, V., Moore, N., et al. (2010) · Annals of Oncology · doi:10.1093/annonc/mdq020 · Cited by 638 · see citing works
Self-citationPao, W. J., & Miller, V. A. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.07.799 · Cited by 628 · see citing works
Self-citationOxnard, G. R., Arcila, M. E., Sima, C. S., Riely, G. J., Chmielecki, J., Kris, M. G., Pao, W., Ladanyi, M., & Miller, V. A. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2692 · Cited by 627 · see citing works
Self-citationSequist, L. V. D., Besse, B., Lynch, T. J., Miller, V. A., Wong, K., Gitlitz, B. J., Eaton, K. D., Zacharchuk, C., Freyman, A., Powell, C., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.9414 · Cited by 432 · see citing works
Self-citationChaft, J. E., Oxnard, G. R., Sima, C. S., Kris, M. G., Miller, V. A., & Riely, G. J. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1468 · Cited by 418 · see citing works
Self-citationYang, J. C., Shih, J., Su, W., Hsia, T., Tsai, C., Ou, S. I., Yu, C., Chang, G., Ho, C., Sequist, L. V. D., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70086-4 · Cited by 410 · see citing works
Self-citationYap, T. A., Vidal, L., Adam, J., Stephens, P., Spicer, J., Shaw, H., Ang, J., Temple, G., Bell, S., Shahidi, M., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.26.7278 · Cited by 349 · see citing works
Self-citationRiely, G. J., Kris, M. G., Zhao, B., Akhurst, T. J., Milton, D. T., Moore, E., Tyson, L. B., Pao, W. J., Rizvi, N. A., Schwartz, L. H., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-0560 · Cited by 288 · see citing works
Self-citationEndpoints for Assessing Drug Activity in Clinical Trials
Pazdur, R. M. (2008) · The Oncologist · doi:10.1634/theoncologist.13-s2-19 · Cited by 287 · see citing works
Kobayashi, S., Ji, H., Yuza, Y., Meyerson, M., Wong, K.-K., Tenen, D. G., & Halmos, B. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1346 · Cited by 272 · see citing works
Sos, M. L., Rode, H. B., Heynck, S., Peifer, M., Fischer, F., Klüter, S., Pawar, V. G., Reuter, C., Heuckmann, J. M., Weiss, J., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3106 · Cited by 220 · see citing works
Jin, H., Tu, D., Zhao, N., Shepherd, L. E., & Goss, P. E. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.34.4010 · Cited by 159 · see citing works
Janjigian, Y. Y., Azzoli, C. G., Krug, L. M., Pereira, L. K., Rizvi, N. A., Pietanza, M. C., Kris, M. G., Ginsberg, M. S., Pao, W. J., Miller, V. A., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2662 · Cited by 122 · see citing works
Self-citationSholl, L. M., Xiao, Y., Joshi, V. A., Yeap, B. Y., Cioffredi, L., Jackman, D. M., Lee, C., Janne, P. A., & Lindeman, N. I. (2010) · American Journal of Clinical Pathology · doi:10.1309/ajcpst1cthzs3psz · Cited by 116 · see citing works
Johnson, M. L., Riely, G. J., Rizvi, N. A., Azzoli, C. G., Kris, M. G., Sima, C. S., Ginsberg, M. S., Pao, W. J., & Miller, V. A. (2011) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3182161508 · Cited by 91 · see citing works
Self-citationPietanza, M. C., Lynch, T. J., Lara, P. N., Cho, J., Yanagihara, R. H., Vrindavanam, N. S., Chowhan, N. M., Gadgeel, S. M., Pennell, N. A., Funke, R. P., et al. (2011) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e31822eebf9 · Cited by 52 · see citing works
Self-citationLee, J., Hirsh, V., Park, K., Qin, S., Blajman, C., Perng, R.-P., Emerson, L., Langmuir, P. B., & Manegold, C. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2010.28.15_suppl.7525 · Cited by 52 · see citing works
Self-citationHeigener, D. F., & Reck, M. (2010) · Advances in Therapy · doi:10.1007/s12325-010-0096-4 · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Sequist, L. V., Yang, J. C.-H., Yamamoto, N., O'Byrne, K., Hirsh, V., Mok, T., Geater, S. L., Orlov, S., Tsai, C.-M., Boyer, M., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.44.2806 · Cited by 3,228 · see citing works
Self-citationOverall Survival with Osimertinib in Untreated, <i>EGFR</i> -Mutated Advanced NSCLC
Ramalingam, S. S., Vansteenkiste, J., Planchard, D., Cho, B. C., Gray, J. E., Ohe, Y., Zhou, C., Reungwetwattana, T., Cheng, Y., Chewaskulyong, B., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1913662 · Cited by 2,914 · see citing works
Self-citationZhou, Y., Wang, J., Gu, Z., Wang, S., Zhu, W., Aceña, J. L., Soloshonok, V. A., Izawa, K., & Liu, H. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.5b00392 · Cited by 2,824 · see citing works
Cross, D. A. E., Ashton, S. E., Ghiorghiu, S., Eberlein, C., Nebhan, C. A., Spitzler, P. J., Orme, J. P., Finlay, M. R. V., Ward, R. A., Mellor, M. J., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0337 · Cited by 2,246 · see citing works
AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer
Jänne, P. A., Yang, J. C.-H., Kim, D.-W., Planchard, D., Ohe, Y., Ramalingam, S. S., Ahn, M.-J., Kim, S.-W., Su, W.-C., Horn, L., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1411817 · Cited by 2,116 · see citing works
Self-citationSmall molecules in targeted cancer therapy: advances, challenges, and future perspectives
Zhong, L., Li, Y., Xiong, L., Wang, W., Wu, M., Yuan, T., Yang, W. M., Tian, C., Miao, Z., Wang, T., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00572-w · Cited by 1,735 · see citing works
Ceritinib in <i>ALK</i> -Rearranged Non–Small-Cell Lung Cancer
Shaw, A. T., Kim, D.-W., Mehra, R., Tan, D. S. W., Felip, E., Chow, L. Q. M., Camidge, D. R., Vansteenkiste, J., Sharma, S., De Pas, T., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1311107 · Cited by 1,495 · see citing works
Non–Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology
Ettinger, D. S., Wood, D. E., Aisner, D. L., Akerley, W., Bauman, J. R., Chirieac, L. R., D’Amico, T. A., DeCamp, M. M., Dilling, T. J., Dobelbower, M. C., et al. (2017) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2017.0050 · Cited by 1,305 · see citing works
Park, K., Tan, E.-H., O'Byrne, K., Zhang, L., Boyer, M., Mok, T., Hirsh, V., Yang, J. C.-H., Lee, K. H., Lu, S., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30033-x · Cited by 1,183 · see citing works
Self-citationAcquired resistance to TKIs in solid tumours: learning from lung cancer
Camidge, D. R., Pao, W., & Sequist, L. V. (2014) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2014.104 · Cited by 862 · see citing works
Masters, G. A., Temin, S., Azzoli, C. G., Giaccone, G., Baker, S., Brahmer, J. R., Ellis, P. M., Gajra, A., Rackear, N., Schiller, J. H., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.62.1342 · Cited by 850 · see citing works
Targeted therapy for non-small cell lung cancer: current standards and the promise of the future.
(2015) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2218-6751.2014.05.01 · Cited by 716 · see citing works
Takezawa, K., Pirazzoli, V., Arcila, M. E., Nebhan, C. A., Song, X., de Stanchina, E., Ohashi, K., Janjigian, Y. Y., Spitzler, P. J., Melnick, M. A., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0108 · Cited by 710 · see citing works
Self-citationThe emerging treatment landscape of targeted therapy in non-small-cell lung cancer
Yuan, M., Huang, L., Chen, J., Wu, J., & Xu, Q. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0099-9 · Cited by 678 · see citing works
Rociletinib in <i>EGFR</i>-Mutated Non–Small-Cell Lung Cancer
Sequist, L. V., Soria, J.-C., Goldman, J. W., Wakelee, H. A., Gadgeel, S. M., Varga, A., Papadimitrakopoulou, V., Solomon, B. J., Oxnard, G. R., Dziadziuszko, R., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1413654 · Cited by 665 · see citing works
Chabon, J. J., Simmons, A. D., Lovejoy, A. F., Esfahani, M. S., Newman, A. M., Haringsma, H. J., Kurtz, D. M., Stehr, H., Scherer, F., Karlovich, C., et al. (2016) · Nature Communications · doi:10.1038/ncomms11815 · Cited by 647 · see citing works
Goss, G. D., Tsai, C., Shepherd, F. A., Bazhenova, L. A., Lee, J. S., Chang, G., Crinò, L., Satouchi, M., Chu, Q. S.-C., Hida, T., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30508-3 · Cited by 647 · see citing works
Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer
Harrison, P. T., Vyse, S., & Huang, P. H. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.09.015 · Cited by 625 · see citing works
Walter, A. O., Sjin, R. T. T., Haringsma, H. J., Ohashi, K., Sun, J., Lee, K., Dubrovskiy, A., Labenski, M., Zhu, Z., Wang, Z., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0314 · Cited by 620 · see citing works
Jackson, P. A., Widen, J. C., Harki, D. A., & Brummond, K. M. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00788 · Cited by 588 · see citing works
Niederst, M. J., Hu, H., Mulvey, H. E., Lockerman, E. L., Garcia, A. R., Piotrowska, Z., Sequist, L. V., & Engelman, J. A. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0560 · Cited by 583 · see citing works
Paz-Ares, L., Tan, E.-H., O’Byrne, K., Zhang, L., Hirsh, V., Boyer, M., Yang, J. C.-H., Mok, T., Lee, K. H., Lu, S., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdw611 · Cited by 524 · see citing works
Self-citationThird-generation EGFR and ALK inhibitors: mechanisms of resistance and management
Cooper, A. J., Sequist, L. V. D., & Lin, J. J. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00639-9 · Cited by 525 · see citing works
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor–Resistant Disease
Ohashi, K., Maruvka, Y. E., Michor, F., & Pao, W. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.43.3912 · Cited by 467 · see citing works
Challenges and Opportunities in Cancer Drug Resistance
Ward, R. A., Fawell, S. E., Floc’h, N., Flemington, V., McKerrecher, D., & Smith, P. D. (2020) · Chemical Reviews · doi:10.1021/acs.chemrev.0c00383 · Cited by 454 · see citing works
Soria, J.-C., Felip, E., Cobo, M., Lu, S., Syrigos, K., Lee, K. H., Göker, E., Georgoulias, V., Li, W., Isla, D., et al. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00006-6 · Cited by 433 · see citing works
Uchibori, K., Inase, N., Araki, M., Kamada, M., Sato, S., Okuno, Y., Fujita, N., & Katayama, R. (2017) · Nature Communications · doi:10.1038/ncomms14768 · Cited by 424 · see citing works
Yang, J. C., Shih, J., Su, W., Hsia, T., Tsai, C., Ou, S. I., Yu, C., Chang, G., Ho, C., Sequist, L. V. D., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70086-4 · Cited by 410 · see citing works
Self-citationOverview of current systemic management of EGFR-mutant NSCLC
Hsu, W.-H., Yang, J. C., Mok, T. S. K., & Loong, H. H.-F. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx702 · Cited by 390 · see citing works
Self-citationTreatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer
Tan, C., Gilligan, D., & Pacey, S. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00246-6 · Cited by 390 · see citing works
EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors
Ercan, D., Choi, H. G., Yun, C.-H., Capelletti, M., Xie, T., Eck, M. J., Gray, N. S., & Jänne, P. A. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2789 · Cited by 368 · see citing works
Janjigian, Y. Y., Smit, E. F., Groen, H. J. M., Horn, L., Gettinger, S., Camidge, D. R., Riely, G. J., Wang, B., Fu, Y., Chand, V. K., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0326 · Cited by 362 · see citing works
Self-citationEmerging Paradigms in the Development of Resistance to Tyrosine Kinase Inhibitors in Lung Cancer
Gainor, J. F., & Shaw, A. T. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.45.2029 · Cited by 349 · see citing works
Afatinib: First Global Approval
Dungo, R. T., & Keating, G. M. (2013) · Drugs · doi:10.1007/s40265-013-0111-6 · Cited by 340 · see citing works
Katakami, N., Atagi, S., Goto, K., Hida, T., Horai, T., Inoue, A., Ichinose, Y., Koboyashi, K., Takeda, K., Kiura, K., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.45.0981 · Cited by 326 · see citing works
Self-citationHe, J., Huang, Z., Han, L., Gong, Y. Q., & Xie, C. (2021) · International Journal of Oncology · doi:10.3892/ijo.2021.5270 · Cited by 321 · see citing works
Stewart, E., Tan, S. Z., Liu, G., & Tsao, M. (2015) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2218-6751.2014.11.06 · Cited by 311 · see citing works
Ward, R. A., Anderton, M. J., Ashton, S., Bethel, P. A., Box, M., Butterworth, S., Colclough, N., Chorley, C. G., Chuaqui, C., Cross, D. A. E., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400822z · Cited by 279 · see citing works
Molecular Pathways: Resistance to Kinase Inhibitors and Implications for Therapeutic Strategies
Lovly, C. M., & Shaw, A. T. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-1610 · Cited by 276 · see citing works
Afatinib for the Treatment of NSCLC Harboring Uncommon EGFR Mutations: A Database of 693 Cases
Yang, J. C., Schüler, M., Popat, S., Miura, S., Heeke, S., Park, K., Märten, A., & Kim, E. S. (2020) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2019.12.126 · Cited by 277 · see citing works
Self-citationLin, A., Wei, T., Meng, H., Luo, P., & Zhang, J. (2019) · Molecular Cancer · doi:10.1186/s12943-019-1062-7 · Cited by 263 · see citing works
Hoffknecht, P., Tufman, A., Wehler, T., Pelzer, T., Wiewrodt, R. G., Schütz, M., Serke, M. H., Stöhlmacher-Williams, J., Märten, A., Huber, R. M., et al. (2014) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000380 · Cited by 255 · see citing works
Besse, B., Adjei, A., Baas, P., Meldgaard, P., Nicolson, M. C., Paz-Ares, L. G., Reck, M., Smit, E. F., Syrigos, K., Stahel, R. A., et al. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu123 · Cited by 244 · see citing works
Hunter, J. C., Gurbani, D., Ficarro, S. B., Carrasco, M. A., Lim, S. M., Choi, H. G., Xie, T., Marto, J. A., Chen, Z., Gray, N. S., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1404639111 · Cited by 242 · see citing works
The Cysteinome of Protein Kinases as a Target in Drug Development
Chaikuad, A., Koch, P., Laufer, S., & Knapp, S. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201707875 · Cited by 237 · see citing works
Personalized Cancer Medicine: Molecular Diagnostics, Predictive biomarkers, and Drug Resistance
de Castro, D. G., Clarke, P. A., Al‐Lazikani, B., & Workman, P. (2012) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2012.237 · Cited by 234 · see citing works
Epidermal growth factor receptor mutations in lung adenocarcinoma
Siegelin, M. D., & Borczuk, A. (2013) · Laboratory Investigation · doi:10.1038/labinvest.2013.147 · Cited by 233 · see citing works
Wu, S.-G., Liu, Y.-N., Tsai, M.-F., Chang, Y.-L., Yu, C.-J., Yang, P.-C., Yang, J. C.-H., Wen, Y.-F., & Shih, J.-Y. (2016) · Oncotarget · doi:10.18632/oncotarget.7189 · Cited by 234 · see citing works
Self-citationMurtuza, A., Bulbul, A., Shen, J. P., Keshavarzian, P., Woodward, B. D., Lopez-Diaz, F. J., Lippman, S. M., & Husain, H. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-1281 · Cited by 226 · see citing works
Gan, G. N., Weickhardt, A. J., Scheier, B. Y., Doebele, R. C., Gaspar, L. E., Kavanagh, B. D., & Camidge, D. R. (2014) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2013.11.010 · Cited by 222 · see citing works
Gelatti, A., Drilon, A. E. D. C., & Santini, F. C. (2019) · Lung Cancer · doi:10.1016/j.lungcan.2019.09.017 · Cited by 220 · see citing works
The Ascension of Targeted Covalent Inhibitors
Singh, J. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c02134 · Cited by 210 · see citing works
Makinoshima, H., Takita, M., Matsumoto, S., Yagishita, A., Owada, S., Esumi, H., & Tsuchihara, K. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.575464 · Cited by 204 · see citing works
Clinical Pharmacokinetics and Pharmacodynamics of Afatinib
Wind, S., Schnell, D., Ebner, T., Freiwald, M., & Stopfer, P. (2017) · Clinical Pharmacokinetics · doi:10.1007/s40262-016-0440-1 · Cited by 206 · see citing works
“0, NSCLC non-small cell lung cancer, TKI tyrosine kinase inhibitor a TKI-naı̈ve patients in LUX-Lung 2 [59] and LUX-Lung 3 [19] who received an afatinib starting dose of 40 mg b TKI-resistant NSCLC patients in LUX-Lung 1 [60] and LUX-Lung 4 [61, 62] who received an afatinib starting dose of 50 mg c Both NSCLC patient…”
BackgroundZhou, C., Li, X., Wang, Q., Gao, G., Zhang, Y., Chen, J., Shu, Y., Hu, Y., Fan, Y., Fang, J., et al. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.20.00297 · Cited by 206 · see citing works
Self-citationBlakely, C. M., Pazarentzos, E., Olivas, V., Asthana, S., Yan, J. J., Tan, I., Hrustanovic, G., Chan, E., Lin, L., Neel, D. S., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.03.012 · Cited by 204 · see citing works
Watanabe, S., Minegishi, Y., Yoshizawa, H., Maemondo, M., Inoue, A., Sugawara, S., Isobe, H., Harada, M., Ishii, Y., Gemma, A., et al. (2014) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000048 · Cited by 204 · see citing works
Kim, S. M., Kwon, O.-J., Hong, Y. K., Kim, J. H., Solca, F., Ha, S., Soo, R. A., Christensen, J. G., Lee, J. H., & Cho, B. C. (2012) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-0311 · Cited by 202 · see citing works
Self-citationProgress with covalent small-molecule kinase inhibitors
Zhao, Z., & Bourne, P. E. (2018) · Drug Discovery Today · doi:10.1016/j.drudis.2018.01.035 · Cited by 200 · see citing works
Zhang, L., Zhang, Z., & Yu, Z. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-02173-2 · Cited by 201 · see citing works
Chia, P. L., John, T., Dobrovic, A., & Mitchell, P. L. R. (2014) · Clinical Epidemiology · doi:10.2147/clep.s69718 · Cited by 200 · see citing works
EGFR-TKI resistance in NSCLC patients: mechanisms and strategies.
Lin, Y., Wang, X., & Jin, H. (2014) · Europe PMC (PubMed Central) · Cited by 198 · see citing works
Minguet, J., Smith, K. H., & Bramlage, P. (2015) · International Journal of Cancer · doi:10.1002/ijc.29915 · Cited by 195 · see citing works
Reardon, D. A., Nabors, B., Mason, W. P., Perry, J., Shapiro, W., Kavan, P., Mathieu, D., Phuphanich, S., Cseh, A., Fu, Y., et al. (2014) · Neuro-Oncology · doi:10.1093/neuonc/nou160 · Cited by 192 · see citing works
El‐Metwally, S. A., Saied, K. F., Eissa, I. H., & Elkaeed, E. B. (2019) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2019.102944 · Cited by 191 · see citing works
Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors
Vigarios, É., Epstein, J. B., & Sibaud, V. (2017) · Supportive Care in Cancer · doi:10.1007/s00520-017-3629-4 · Cited by 190 · see citing works
Costa, R. L. B., Shah, A. N., Santa-Maria, C. A., Cruz, M. R. D. S., Mahalingam, D., Carneiro, B. A., Chae, Y. K., Cristofanilli, M., Gradishar, W. J., & Giles, F. J. (2017) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2016.12.010 · Cited by 176 · see citing works
Nukaga, S., Yasuda, H., Tsuchihara, K., Hamamoto, J., Masuzawa, K., Kawada, I., Naoki, K., Matsumoto, S., Mimaki, S., Ikemura, S., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2359 · Cited by 179 · see citing works
Russo, A., Franchina, T., Rita Ricciardi, G. R., Picone, A., Ferraro, G., Zanghì, M., Toscano, G., Giordano, A., & Adamo, V. (2015) · Oncotarget · doi:10.18632/oncotarget.4254 · Cited by 173 · see citing works
Cheng, Y., He, Y., Li, W., Zhang, H., Zhou, Q. H., Wang, B., Liu, C., Walding, A., Saggese, M., Huang, X., et al. (2021) · Targeted Oncology · doi:10.1007/s11523-021-00794-6 · Cited by 167 · see citing works
Patel, H., Pawara, R., Ansari, A., & Surana, S. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.05.027 · Cited by 170 · see citing works
Hirano, T., Yasuda, H., Tani, T., Hamamoto, J., Oashi, A., Ishioka, K., Arai, D., Nukaga, S., Miyawaki, M., Kawada, I., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.5887 · Cited by 165 · see citing works
Molecular histology of lung cancer: From targets to treatments
Wood, S. L., Pernemalm, M., Crosbie, P. A. J., & Whetton, A. D. (2015) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2015.02.008 · Cited by 161 · see citing works
Burotto, M., Manasanch, E. E., Wilkerson, J., & Fojo, T. (2015) · The Oncologist · doi:10.1634/theoncologist.2014-0154 · Cited by 156 · see citing works
Peters, S., Zimmermann, S., & Adjei, A. A. (2014) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2014.06.010 · Cited by 155 · see citing works
Molecular-Targeted Therapies for Epidermal Growth Factor Receptor and Its Resistance Mechanisms
Yamaoka, T., Ohba, M., & Ohmori, T. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18112420 · Cited by 152 · see citing works
Uncommon EGFR mutations in advanced non-small cell lung cancer
O'Kane, G. M., Bradbury, P. A., Feld, R. D., Leighl, N. B., Liu, G., Pisters, K.-M., Kamel‐Reid, S., Tsao, M., & Shepherd, F. A. (2017) · Lung Cancer · doi:10.1016/j.lungcan.2017.04.016 · Cited by 152 · see citing works
Liao, B.-C., Lin, C., & Yang, J. C. (2015) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000164 · Cited by 147 · see citing works
Self-citationWang, J., Wang, B., Chu, H., & Yao, Y. (2016) · OncoTargets and Therapy · doi:10.2147/ott.s106399 · Cited by 141 · see citing works
Lee, K. H. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.001 · Cited by 142 · see citing works
Oncogenic alterations in advanced NSCLC: a molecular super-highway
Friedlaender, A., Pérol, M., Banna, G. L., Parikh, K., & Addeo, A. (2024) · Biomarker Research · doi:10.1186/s40364-024-00566-0 · Cited by 144 · see citing works
Molecular targeted therapy in the treatment of advanced stage non‐small cell lung cancer ( NSCLC )
Kumarakulasinghe, N. B., van Zanwijk, N., & Soo, R. A. (2015) · Respirology · doi:10.1111/resp.12490 · Cited by 141 · see citing works
Molecularly Targeted Therapies in Non–Small-Cell Lung Cancer Annual Update 2014
Morgensztern, D., Campo, M. J., Dahlberg, S. E., Doebele, R. C., Garon, E. B., Gerber, D. E., Goldberg, S. B., Hammerman, P. S., Heist, R. S., Hensing, T. A., et al. (2015) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000405 · Cited by 137 · see citing works
Remón, J., Morán, T., Majem, M., Reguart, N., Dalmau, E., Márquez-Medina, D., & LIANES, P. (2013) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2013.06.002 · Cited by 135 · see citing works
Liang, W., Wu, X., Fang, W., Zhao, Y., Yang, Y., Hu, Z., Xue, C., Zhang, J., Zhang, J., Ma, Y., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0085245 · Cited by 133 · see citing works
Ellis, P. M., Shepherd, F. A., Millward, M. J., Perrone, F., Seymour, L., Liu, G., Sun, S. B., Cho, B. C., Morabito, A., Leighl, N. B., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70472-3 · Cited by 132 · see citing works
Schüler, M., Yang, J. C., Park, K., Kim, J., Bennouna, J., Chen, Y.-M., CHOUAID, C., de Marinis, F., Feng, J., Grossi, F., et al. (2015) · Annals of Oncology · doi:10.1093/annonc/mdv597 · Cited by 132 · see citing works
Self-citationChallenge and countermeasures for EGFR targeted therapy in non-small cell lung cancer
Tian, X., Gu, T., Lee, M., & Dong, Z. (2021) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2021.188645 · Cited by 133 · see citing works
The Evolution of Therapies in Non-Small Cell Lung Cancer
Boolell, V., Alamgeer, M., Watkins, D. N., & Ganju, V. (2015) · Cancers · doi:10.3390/cancers7030864 · Cited by 126 · see citing works
Jänne, P. A., Ou, S.-H. I., Kim, D.-W., Oxnard, G. R., Martins, R., Kris, M. G., Dunphy, F., Nishio, M., O'Connell, J., Paweletz, C., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70461-9 · Cited by 127 · see citing works
Monotherapy Administration of Sorafenib in Patients With Non–Small Cell Lung Cancer (MISSION) Trial
Paz-Ares, L. G., Hirsh, V., Zhang, L., de Marinis, F., Yang, J. C., Wakelee, H. A., Seto, T., Wu, Y.-L. L. C., Novello, S., Juhász, É., et al. (2015) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000693 · Cited by 127 · see citing works
Self-citationTargeted Therapy and Immunotherapy for Lung Cancer
Naylor, E. C., Desani, J., & Chung, P. K. (2016) · Surgical Oncology Clinics of North America · doi:10.1016/j.soc.2016.02.011 · Cited by 125 · see citing works
EGFR-Targeted Therapy for Non-Small Cell Lung Cancer: Focus on EGFR Oncogenic Mutation
Antonicelli, A., Cafarotti, S., Indini, A., Galli, A., Russo, A., Cesario, A., Lococo, F., Russo, P., Mainini, A. F., Bonifati, L. G., et al. (2013) · International Journal of Medical Sciences · doi:10.7150/ijms.4609 · Cited by 129 · see citing works
EGFR first- and second-generation TKIs—there is still place for them in EGFR-mutant NSCLC patients
Karachaliou, N., Fernández-Bruno, M., Bracht, J. W. P., & Rosell, R. (2018) · Translational Cancer Research · doi:10.21037/tcr.2018.10.06 · Cited by 127 · see citing works
Fighting cancer drug resistance: Opportunities and challenges for mutation-specific EGFR inhibitors
Juchum, M., Günther, M., & Laufer, S. (2015) · Drug Resistance Updates · doi:10.1016/j.drup.2015.05.002 · Cited by 123 · see citing works
Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data
Jorge, S. E., Kobayashi, S. S., & Costa, D. B. (2014) · Brazilian Journal of Medical and Biological Research · doi:10.1590/1414-431x20144099 · Cited by 124 · see citing works
Solassol, I., Pinguet, F., & Quantin, X. (2019) · Biomolecules · doi:10.3390/biom9110668 · Cited by 123 · see citing works
Buettner, R., Wolf, J., & Thomas, R. K. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.45.9867 · Cited by 121 · see citing works
Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC
Agulnik, M., Nelson, Ziehr, & Johnson, J. R. (2013) · OncoTargets and Therapy · doi:10.2147/ott.s23165 · Cited by 119 · see citing works
Renal effects of targeted anticancer therapies
Porta, C., Cosmai, L., Gallieni, M. A., Pedrazzoli, P., & Malberti, F. (2015) · Nature Reviews Nephrology · doi:10.1038/nrneph.2015.15 · Cited by 119 · see citing works
- Authors
- Miller, V. A., Hirsh, V., Cadranel, J., Chen, Y.-M., Park, K., Kim, S.-W., Zhou, C., Su, W.-C., Wang, M., Sun, Y., Heo, D. S., Crino, L., Tan, E.-H., Chao, T.-Y., Shahidi, M., Cong, X. J., Lorence, R. M., & Yang, J. C.-H.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- McGill University Health Centre (CA)
- Assistance Publique – Hôpitaux de Paris (FR)
- Taipei Veterans General Hospital (TW)
- Samsung Medical Center (KR)
- Asan Medical Center (KR)
- Tongji University (CN)
- National Cheng Kung University Hospital (TW)
- Peking Union Medical College Hospital (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Seoul National University Hospital (KR)
- National Cancer Centre Singapore (SG)
- Taipei Medical University-Shuang Ho Hospital (TW)
- Boehringer Ingelheim (United Kingdom) (GB)
- Boehringer Ingelheim (United States) (US)
- National Taiwan University (TW)
- Corresponding author
- Yang, James Chih-Hsin
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2012-05
- Volume
- 13
- Issue
- 5
- Pages
- 528-538
- ISSN
- 1470-2045 (ISSN-L)
- OpenAlex
- W2152905269
- Cited by
- 961
- References
- 29
- Citations by year
- 2026: 14 · 2025: 14 · 2024: 28 · 2023: 38 · 2022: 33 · 2021: 46 · 2020: 50 · 2019: 57 · 2018: 70 · 2017: 103 · 2016: 99 · 2015: 125 · 2014: 139 · 2013: 107 · 2012: 37
- FWCI
- 105.26
- Type
- journal article
- Language
- en
- Update notices
- erratum (2012-05-01)
- Open access
- closed
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- afatinib, non-small cell lung cancer, lung adenocarcinoma, EGFR tyrosine kinase inhibitors, erlotinib, gefitinib, EGFR mutation, EGFR inhibitor resistance, second-line therapy, overall survival, progression-free survival, best supportive care, targeted therapy
- MeSH terms
- Erlotinib Hydrochloride, Gefitinib, Afatinib, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Double-Blind Method, Female, Humans, Lung Neoplasms, Male, Middle Aged, Quinazolines, Protein Kinase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
