AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer
Open accessAbstract
BACKGROUND: The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation (EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. METHODS: We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included dose-escalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy. RESULTS: A total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M-negative patients. CONCLUSIONS: AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01802632.).
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?
Osimertinib is being studied in combination with other targeted therapies for NSCLC, such as inhibitors of the Met, Bcl-2, and MAPK pathways.
“In addition to being used alone, osimertinib is also being studied in combination with other targeted therapies for NSCLC, such as inhibitors of the Met, Bcl-2, and MAPK pathways.138–140”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [139]
In Janne's clinical trial of AZD9291, the overall objective tumor response rate was 51%, indicating that AZD9291 was highly effective in patients with EGFR T790M mutant lung cancer whose disease had progressed during previous EGFR tyrosine kinase inhibitor treatment.
“The overall objective tumor response rate was 51%, indicating that AZD9291 was highly effective in patients with EGFR (T790M) mutant lung cancer whose disease had progressed during previous treatment with EGFR tyrosine kinase inhibitors [71, 72].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [72]
Third-generation EGFR inhibitors that inhibit mutant EGFR with T790M produce responses in nearly two-thirds of patients.
“Third generation EGFR inhibitors capable of inhibiting mutant EGFR with T790M produce responses in nearly two thirds of patients.”
Several other molecules targeting T790M are in development.
“although several other molecules are in development.11”
From Rociletinib in <i>EGFR</i>-Mutated Non–Small-Cell Lung Cancer (2015) · cites this paper as [11]
AZ5104 demonstrated potent activity and could potentially contribute to the overall efficacy of osimertinib, although its clinical relevance remains unclear because it exists at about 10% of parental levels.
“The circulating metabolite AZ5104 also demonstrated potent activity, suggesting it could potentially contribute to the overall efficacy of osimertinib, although the clinical relevance remains unclear since the metabolite only exists at ~10% of parental levels (19).”
From Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions (2018) · cites this paper as [19]
CO-1686 and AZD9291 cause substantially less skin toxicity than typical EGFR TKIs.
“In addition, both agents are associated with substantially less skin toxicity than typically observed for EGFR TKIs (17, 18).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [17]
Phase I studies of CO-1686 or AZD9291 have produced response rates above 50% in EGFR-mutant T790M NSCLC patients who progressed on gefitinib or erlotinib.
“In phase I studies to date, treatment with either CO-1686 or AZD9291, has resulted in a RR > 50% in EGFR mutant EGFR T790M NSCLC patients that have developed resistance to gefitinib or erlotinib (17, 18).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [17]
Mutant-selective EGFR kinase inhibitors including WZ4002, CO-1686, and AZD9291 have demonstrated encouraging efficacy in preclinical models and in EGFR mutant NSCLC patients with EGFR T790M-mediated drug resistance.
“These include the development of mutant selective EGFR kinase inhibitors, including WZ4002, CO-1686 and AZD9291, which to date have demonstrated encouraging efficacy in both preclinical models and in EGFR mutant NSCLC patients with EGFR T790M mediated drug resistance (14–18).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [17]
AZD9291 demonstrated promising activity in a phase I study in patients with EGFR-TKI resistant NSCLC with an ORR of 51% and an ORR of 62% in patients T790M-positive, with no dose-limiting toxicities and a maximum tolerated dose not defined.
“AZD9291 demonstrated promising activity in a phase I study in patients with EGFR-TKI resistant NSCLC with an ORR of 51% and an impressive ORR of 62% in patients T790M-positive, with no dose-limiting toxicities and a maximum tolerated dose not defined [89].”
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 [89]
Osimertinib response rate for EGFR T790M positive patients was 61% and progression free survival was 9.6 months.
“Osimertinib showed a promising safety and efficacy, the response rate and progression free survival for EGFR T790M positive patients was 61% and 9.6 months, respectively [38].”
No dose-limiting toxicity was observed during the 28-day evaluation period at any dose levels.
“No dose-limiting toxicity was observed during the 28-day evaluation period at any dose levels.”
In human clinical trials, osimertinib and rociletinib showed promising safety and efficacy, even though some hyperglycemia was observed in patients treated with rociletinib.
“In human clinical trials, osimertinib and rociletinib showed promising safety and efficacy, even though some hyperglycemia was observed in patients treated with rociletinib [38, 39].”
The maximum serum concentrations were 106.3, 305.1, 635.4, 1006, and 1510 nM for 20, 40, 80, 160, and 240 mg dose levels, respectively.
“The maximum serum concentrations were 106.3, 305.1, 635.4, 1006, and 1510 nM for 20, 40, 80, 160, and 240 mg dose levels, respectively.”
In the phase I study, patients were assigned to once-daily dosing from 20 mg to 240 mg.
“The patients were assigned to once-daily dosing from 20 mg to 240 mg.”
Osimertinib has been approved for T790M tumors based on a high objective response rate of approximately 60% for tumors with T790M mutations as a resistance mechanism of first-generation TKIs.
“Osimertinib has been approved for T790M tumors based on the high ORR of approximately 60% for tumors with T790M mutations as a resistance mechanism of 1G‐TKI.38”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [38]
The number of patients with Del19+T790M tumors enrolled in phase I/II trials for osimertinib and rociletinib was approximately twice as large as the number with L858R+T790M.
“The number of patients with Del19 + T790M tumors who enrolled in phase I/II trials for osimertinib38 and rociletinib39 was approximately twice as large as the number of patients with L858R+T790M.”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [38]
The AURA3 outcomes with osimertinib (median PFS 10.1 months, response rate 71%) were in line with results from phase 1/2 AURA and AURA2 studies.
“Among patients receiving osimertinib, the AURA3 outcomes (median progression-free survival duration of 10.1 months and response rate of 71%) were in line with results of the phase 1/2 AURA and AURA2 studies.22,23”
From Osimertinib or Platinum–Pemetrexed in <i>EGFR</i> T790M–Positive Lung Cancer (2017) · cites this paper as [22]
In previously published data from the AURA study, osimertinib exhibited a better confirmed ORR (61% v 21%) and median PFS (9.6 months v 2.8 months) in patients with T790M-positive versus T790M-negative tumor genotyping.
“In previously published data from the AURA study, osimertinib exhibited a better response rate (confirmed ORR, 61% v 21%) and median progression-free survival (PFS; 9.6 months v 2.8 months) in patients with T790M-positive versus T790M-negative tumor genotyping.12”
From Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non–Small-Cell Lung Cancer (2016) · cites this paper as [12]
At least five third-generation EGFR-TKIs are in clinical development, and all have reported objective response rates exceeding 45% in patients with EGFR-mutant NSCLC and T790M-positive resistance.
“At least five third-generation EGFR-TKIs are in clinical development (rociletinib, osimertinib, HM61713/BI1482694, ASP8273, and EGF816) and all have reported objective response rates (ORRs) that exceed 45% in patients with EGFR-mutant NSCLC and T790M-positive resistance.12-16”
From Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non–Small-Cell Lung Cancer (2016) · cites this paper as [12]
Next-generation EGFR TKIs designed to target T790M produce high and durable responses in advanced EGFR-mutant NSCLC that has progressed after first- or second-generation EGFR TKIs.
“Next-generation EGFR TKIs have since been developed specifically to target the T790M mutation, 17,18 and they have demonstrated high and durable responses in patients with advanced EGFRmutant NSCLC who have been previously treated and in whom firstor second-generation EGFR TKIs have failed.”
Third-generation EGFR TKIs have shown a median progression-free survival of 9.6 months in patients without central nervous system metastases.
“with the recent approval of third-generation EGFR TKIs that demonstrated a median PFS of 9.6 months (for patients without central nervous system [CNS] metastases).18”
In the AURA study, osimertinib produced an objective response rate up to 51% in patients with T790M mutations confirmed by repeat tumor biopsy and 21% in T790M-negative tumors.
“In the setting of clinical resistance to EGFR TKI, the extended phase I study (AURA) of the thirdgeneration inhibitor osimertinib (AZD9291) confers an objective response rate (ORR) of up to 51% in patients with T790M mutations confirmed in repeat tumor biopsies and 21% in T790M-negative tumors.18”
Cites
Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040938 · Cited by 11,486 · see citing works
<i>EGFR</i> Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
Paez, J. G., Jänne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F. J., Lindeman, N., Boggon, T. J., et al. (2004) · Science · doi:10.1126/science.1099314 · Cited by 9,368 · see citing works
Self-citationGefitinib 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-citation<i>MET</i> Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
Engelman, J. A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J. O., Lindeman, N., Gale, C.-M., Zhao, X., Christensen, J., et al. (2007) · Science · doi:10.1126/science.1141478 · Cited by 4,496 · see citing works
Self-citationSequist, 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-citationCross, 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
Self-citationThe T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP
Yun, C.-H., Mengwasser, K. E., Toms, A. V., Woo, M. S., Greulich, H., Wong, K.-K., Meyerson, M., & Eck, M. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709662105 · Cited by 2,118 · cited 3× · see citing works
“Any grade 0 6 (10) 11 (12) 9 (14) 2 (10) 28 (11)”
Miller, V. A., Hirsh, V., Cadranel, J., Chen, Y.-M., Park, K., Kim, S.-W., Zhou, C., Su, W.-C., Wang, M., Sun, Y., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70087-6 · Cited by 961 · see citing works
Self-citationOncogenic Transformation by Inhibitor-Sensitive and -Resistant EGFR Mutants
Greulich, H., Chen, T.-H., Feng, W., Jänne, P. A., Alvarez, J. V., Zappaterra, M., Bulmer, S. E., Frank, D. A., Hahn, W. C., Sellers, W. R., et al. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020313 · Cited by 677 · see citing works
Yap, 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
Jänne, P. A., Boss, D. S., Camidge, D. R., Britten, C. D., Engelman, J. A., Garon, E. B., Guo, F., Wong, S., Liang, J., Letrent, S., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-1220 · Cited by 181 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Herbst, R. S., Baas, P., Kim, D.-W., Felip, E., Pérez-Gracia, J. L., Han, J.-Y., Molina, J., Kim, J.-H., Arvis, C. D., Ahn, M.-J., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(15)01281-7 · Cited by 6,449 · see citing works
Self-citationThe biology and management of non-small cell lung cancer
Herbst, R. S., Morgensztern, D., & Boshoff, C. (2018) · Nature · doi:10.1038/nature25183 · Cited by 4,891 · see citing works
Osimertinib or Platinum–Pemetrexed in <i>EGFR</i> T790M–Positive Lung Cancer
Mok, T. S., Wu, Y.-L., Ahn, M.-J., Garassino, M. C., Kim, H. R., Ramalingam, S. S., Shepherd, F. A., He, Y., Akamatsu, H., Theelen, W. S. M. E., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1612674 · Cited by 3,379 · see citing works
Self-citationNovello, S., Barlesi, F., Califano, R., Cufer, T., Ekman, S., Levra, M. G., Kerr, K., Popat, S., Reck, M., Senan, S., et al. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw326 · Cited by 2,631 · see citing works
Thress, K. S., Paweletz, C. P., Felip, E., Cho, B. C., Stetson, D., Dougherty, B., Lai, Z., Markovets, A., Vivancos, A., Kuang, Y., et al. (2015) · Nature Medicine · doi:10.1038/nm.3854 · Cited by 1,589 · see citing works
Self-citationPark, 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-citationMechanisms of receptor tyrosine kinase activation in cancer
Du, Z., & Lovly, C. M. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0782-4 · Cited by 1,066 · see citing works
Hata, A. N., Niederst, M. J., Archibald, H. L., Gomez-Caraballo, M., Siddiqui, F. M., Mulvey, H. E., Maruvka, Y. E., Ji, F., Bhang, H.-E. C., Krishnamurthy Radhakrishna, V., et al. (2016) · Nature Medicine · doi:10.1038/nm.4040 · Cited by 985 · 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
Oxnard, G. R., Thress, K. S., Alden, R. S., Lawrance, R., Paweletz, C. P., Cantarini, M., Yang, J. C.-H., Barrett, J. C., & Jänne, P. A. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2016.66.7162 · Cited by 850 · see citing works
Self-citationCheckpoint inhibitors in metastatic EGFR-mutated non–small cell lung cancer-a meta-analysis
Lee, C. K., Man, J., Lord, S., Links, M., Gebski, V., Mok, T., & Yang, J. C.-H. (2017) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.10.007 · Cited by 839 · see citing works
Self-citationAdvances in covalent drug discovery
Boike, L., Henning, N. J., & Nomura, D. K. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00542-z · Cited by 823 · see citing works
Cell death-based treatment of lung adenocarcinoma
Denisenko, T. V., Budkevich, I. N., & Zhivotovsky, B. (2018) · Cell Death & Disease · doi:10.1038/s41419-017-0063-y · Cited by 768 · see citing works
Ballard, P., Yates, J. W. T., Yang, Z., Kim, D.-W., Yang, J. C.-H., Cantarini, M., Pickup, K., Jordan, A., Hickey, M., Grist, M., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0399 · Cited by 718 · see citing works
Self-citationOxnard, G. R., Hu, Y., Mileham, K. F., Husain, H., Costa, D. B., Tracy, P., Feeney, N., Sholl, L. M., Dahlberg, S. E., Redig, A. J., et al. (2018) · JAMA Oncology · doi:10.1001/jamaoncol.2018.2969 · Cited by 686 · see citing works
Self-citationRociletinib 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
ESMO-magnitude of clinical benefit scale version 1.1
Cherny, N. I., Dafni, U., Bogaerts, J., Latino, N. J., Pentheroudakis, G., Douillard, J.-Y., Tabernero, J., Zielinski, C., Piccart, M. J., & de Vries, E. G. E. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx310 · Cited by 641 · see citing works
EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance
Uribe, M. L., Marrocco, I., & Yarden, Y. (2021) · Cancers · doi:10.3390/cancers13112748 · Cited by 604 · 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
Yang, Z., Yang, N., Ou, Q., Xiang, Y., Jiang, T., Wu, X., Bao, H., Tong, X., Wang, X., Shao, Y. W., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2310 · Cited by 542 · 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-citationKobayashi, Y., & Mitsudomi, T. (2016) · Cancer Science · doi:10.1111/cas.12996 · Cited by 413 · see citing works
Yang, J. C. H., Kim, S.-W., Kim, D.-W., Lee, J.-S., Cho, B. C., Ahn, J.-S., Lee, D. H., Kim, T. M., Goldman, J. W., Natale, R. B., et al. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.19.00457 · Cited by 395 · see citing works
Self-citationSevere immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib
Schoenfeld, A. J., Arbour, K. C., Rizvi, H., Iqbal, A. N., Gadgeel, S. M., Girshman, J., Kris, M. G., Riely, G. J., Yu, H. A., & Hellmann, M. D. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz077 · Cited by 406 · see citing works
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
Le, X., Puri, S., Negrao, M. V., Nilsson, M. B., Robichaux, J., Boyle, T., Hicks, J. K., Lovinger, K. L., Roarty, E., Rinsurongkawong, W., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-1542 · Cited by 387 · 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
Sundaresan, T. K., Sequist, L. V., Heymach, J. V., Riely, G. J., Jänne, P. A., Koch, W. H., Sullivan, J. P., Fox, D. B., Maher, R., Muzikansky, A., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1031 · Cited by 347 · see citing works
Self-citationYoda, S., Lin, J. J., Lawrence, M. S., Burke, B. J., Friboulet, L., Langenbucher, A., Dardaei, L., Prutisto-Chang, K., Dagogo-Jack, I., Timofeevski, S., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-1256 · Cited by 322 · see citing works
Shah, K. N., Bhatt, R., Rotow, J., Rohrberg, J., Olivas, V., Wang, V. E., Hemmati, G., Martins, M. M., Maynard, A., Kuhn, J., et al. (2019) · Nature Medicine · doi:10.1038/s41591-018-0264-7 · Cited by 286 · see citing works
Biomarkers for the Clinical Use of PD-1/PD-L1 Inhibitors in Non–Small-Cell Lung Cancer: A Review
Sacher, A. G., & Gandhi, L. (2016) · JAMA Oncology · doi:10.1001/jamaoncol.2016.0639 · Cited by 255 · 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-citationTargeting KRAS mutant cancers: from druggable therapy to drug resistance
Zhu, C., Guan, X., Zhang, X., Luan, X., Song, Z., Cheng, X., Zhang, W., & Qin, J.-J. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01629-2 · Cited by 231 · see citing works
Nagasaka, M., Zhu, V. W., Lim, S. M., Greco, M., Wu, F., & Ou, S.-H. I. (2021) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2020.11.028 · Cited by 219 · see citing works
Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer
Raoof, S., Mulford, I. J., Frisco-Cabanos, H., Nangia, V., Timonina, D., Labrot, E., Hafeez, N., Bilton, S. J., Drier, Y., Ji, F., et al. (2019) · Oncogene · doi:10.1038/s41388-019-0887-2 · Cited by 216 · see citing works
Tan, D. S. W., Yom, S. S., Tsao, M. S., Pass, H. I., Kelly, K., Peled, N., Yung, R. C., Wistuba, I. I., Yatabe, Y., Unger, M., et al. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.05.008 · Cited by 201 · 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
Combinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling
Liu, C., Lu, H., Wang, H., Loo, A., Zhang, X., Yang, G., Kowal, C., Delach, S., Wang, Y., Goldoni, S., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-2718 · Cited by 167 · see citing works
Lu, X., Yu, L., Zhang, Z., Ren, X., Smaill, J. B., & Ding, K. (2018) · Medicinal Research Reviews · doi:10.1002/med.21488 · Cited by 173 · see citing works
Yang, J. C.-H., Camidge, D. R., Yang, C.-T., Zhou, J., Guo, R., Chiu, C.-H., Chang, G.-C., Shiah, H.-S., Chen, Y., Wang, C.-C., et al. (2020) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2020.09.001 · Cited by 165 · see citing works
Self-citationHirano, 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
Nilsson, M. B., Sun, H., Diao, L., Tong, P., Liu, D., Li, L., Fan, Y., Poteete, A., Lim, S.-O., Howells, K., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aao4307 · Cited by 146 · see citing works
Self-citationKim, S.-Y., Kim, S.-M., Lim, S., Lee, J. Y., Choi, S.-J., Yang, S.-D., Yun, M. R., Kim, C. G., Gu, S. R., Park, C., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-5026 · Cited by 151 · see citing works
Self-citationOu, S.-H. I., Agarwal, N., & Ali, S. M. (2016) · Lung Cancer · doi:10.1016/j.lungcan.2016.05.015 · Cited by 149 · see citing works
Lin, C.-C., Shih, J.-Y., Yu, C.-J., Ho, C.-C., Liao, W.-Y., Lee, J.-H., Tsai, T.-H., Su, K.-Y., Hsieh, M.-S., Chang, Y.-L., et al. (2018) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(17)30480-0 · Cited by 145 · see citing works
Self-citationWang, M., Yang, J. C.-H., Mitchell, P. L., Fang, J., Camidge, D. R., Nian, W., Chiu, C.-H., Zhou, J., Zhao, Y., Su, W.-C., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1615 · Cited by 133 · see citing works
Self-citationFloc'h, N., Martin, M. J., Riess, J. W., Orme, J. P., Staniszewska, A. D., Ménard, L., Cuomo, M. E., O'Neill, D. J., Ward, R. A., Finlay, M. R. V., et al. (2018) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0758 · Cited by 115 · see citing works
Targeting EGFR in Lung Cancer: Current Standards and Developments
Díaz-Serrano, A., Gella, P., Jiménez, E., Zugazagoitia, J., & Paz-Ares Rodríguez, L. (2018) · Drugs · doi:10.1007/s40265-018-0916-4 · Cited by 108 · see citing works
Tan, C.-S., Cho, B.-C., & Soo, R. A. (2016) · Lung Cancer · doi:10.1016/j.lungcan.2016.01.003 · Cited by 105 · see citing works
Girard, N. (2018) · Future Oncology · doi:10.2217/fon-2017-0636 · Cited by 103 · see citing works
Minari, R., Bordi, P., Del Re, M., Facchinetti, F., Mazzoni, F., Barbieri, F., Camerini, A., Comin, C. E., Gnetti, L., Azzoni, C., et al. (2018) · Lung Cancer · doi:10.1016/j.lungcan.2017.11.011 · Cited by 105 · see citing works
Resistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma
Neel, D. S., & Bivona, T. G. (2017) · npj Precision Oncology · doi:10.1038/s41698-017-0007-0 · Cited by 98 · see citing works
Lelais, G., Epple, R., Marsilje, T. H., Long, Y. O., McNeill, M., Chen, B., Lu, W., Anumolu, J., Badiger, S., Bursulaya, B., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01985 · Cited by 95 · see citing works
Chen, K., Zhou, F., Shen, W., Jiang, T., Wu, X., Tong, X., Shao, Y. W., Qin, S., & Zhou, C. (2017) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.12.024 · Cited by 89 · see citing works
Xu, X., Mao, L., Xu, W., Tang, W., Zhang, X., Xi, B., Xu, R., Fang, X., Liu, J., Fang, C., et al. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0281 · Cited by 87 · see citing works
Banno, E., Togashi, Y., Nakamura, Y., Chiba, M., Kobayashi, Y., Hayashi, H., Terashima, M., de Velasco, M. A., Sakai, K., Fujita, Y., et al. (2016) · Cancer Science · doi:10.1111/cas.12980 · Cited by 87 · see citing works
Santana-Codina, N., Chandhoke, A. S., Yu, Q., Małachowska, B., Kuljanin, M., Gikandi, A., Stańczak, M., Gableske, S., Jedrychowski, M. P., Scott, D. A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.03.021 · Cited by 77 · see citing works
Theard, P. L., Sheffels, E., Sealover, N. E., Linke, A. J., Pratico, D. J., & Kortum, R. L. (2020) · eLife · doi:10.7554/elife.58204 · Cited by 69 · see citing works
Genome-wide CRISPR screening reveals genetic modifiers of mutant EGFR dependence in human NSCLC
Zeng, H., Castillo-Cabrera, J., Manser, M., Lu, B., Yang, Z., Strande, V., Begue, D., Zamponi, R., Qiu, S., Sigoillot, F., et al. (2019) · eLife · doi:10.7554/elife.50223 · Cited by 57 · see citing works
Lou, Y., Song, F., Cheng, M., Hu, Y., Chai, Y., Hu, Q., Wang, Q., Zhou, H., Bao, M., Gu, J., et al. (2023) · PeerJ · doi:10.7717/peerj.15844 · Cited by 55 · see citing works
Jenkins, S., Chih-Hsin Yang, J., Jänne, P. A., Thress, K. S., Yu, K., Hodge, R., Weston, S., Dearden, S., Patel, S., Cantarini, M., et al. (2017) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2017.05.002 · Cited by 53 · see citing works
Self-citationStructural basis of mutant-selectivity and drug-resistance related to CO-1686
Yan, X.-E., Zhu, S.-J., Liang, L., Zhao, P., Choi, H. G., & Yun, C.-H. (2017) · Oncotarget · doi:10.18632/oncotarget.18588 · Cited by 43 · see citing works
Continuing EGFR inhibition beyond progression in advanced non-small cell lung cancer
Yap, T. A., Macklin-Doherty, A., & Popat, S. (2017) · European Journal of Cancer · doi:10.1016/j.ejca.2016.10.014 · Cited by 38 · see citing works
Lee, J. Y., Sun, J.-M., Lim, S. H., Kim, H. S., Yoo, K. H., Jung, K. S., Song, H.-N., Ku, B. M., Koh, J., Bae, Y.-H., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1653 · Cited by 36 · see citing works
“Recently, third-generation EGFR TKI, AZD9291 and rociletinib demonstrated robust and durable response in both T790M-positive and -negative patients (43, 44).”
BackgroundSelf-citationAZD9291 in <i>EGFR</i> -Mutant Advanced Non-Small-Cell Lung Cancer Patients
Remon, J., & Planchard, D. (2015) · Future Oncology · doi:10.2217/fon.15.250 · Cited by 33 · see citing works
Self-citationHan, L., Zhang, X., Wang, Z., Zhang, X., Zhao, L., Fu, W., Liang, X., Zhang, Z., & Wang, Y. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.665253 · Cited by 31 · see citing works
Ou, S.-H., & Soo, R. (2015) · Drug Design, Development and Therapy · doi:10.2147/dddt.s52787 · Cited by 28 · see citing works
Ni, J., Weng, L., Liu, Y., Sun, Z., Bai, C., & Wang, Y. (2017) · Oncology Letters · doi:10.3892/ol.2017.6022 · Cited by 23 · see citing works
Overcoming Resistance to AC0010, a Third Generation of EGFR Inhibitor, by Targeting c-MET and BCL-2
Xu, W., Tang, W., Li, T., Zhang, X., & Sun, Y. (2019) · Neoplasia · doi:10.1016/j.neo.2018.11.004 · Cited by 23 · see citing works
Xiong, A., Ren, S., Liu, H., Miao, L., Wang, L., Chen, J., Li, W., Li, R., Wang, X., Lu, Z., et al. (2022) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2022.06.013 · Cited by 20 · see citing works
Murakami, H., Nokihara, H., Hayashi, H., Seto, T., Park, K., Azuma, K., Tsai, C., Yang, J. C., Nishio, M., Kim, S., et al. (2018) · Cancer Science · doi:10.1111/cas.13724 · Cited by 17 · see citing works
Self-citationShi, Y., Wu, L., Ji, Y., Chen, G., Li, B., Bi, M., Yang, R., Miao, L., Zhang, G., Gao, H., et al. (2025) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(25)00121-3 · Cited by 16 · see citing works
Yanagisawa, A., Kinehara, Y., Kijima, R., Tanaka, M., Ninomiya, R., Jokoji, R., & Tachibana, I. (2023) · Internal Medicine · doi:10.2169/internalmedicine.0002-22 · Cited by 7 · see citing works
Zheng, J., Shen, L., Jiang, N., Zhu, Y., Wu, L., Cao, H., Sun, W., Zhou, J., & Zhou, J. (2020) · Clinical Lung Cancer · doi:10.1016/j.cllc.2020.07.001 · Cited by 6 · see citing works
- Authors
- 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., Haggstrom, D., Felip, E., Kim, J.-H., Frewer, P., Cantarini, M., Brown, K. H., Dickinson, P. A., Ghiorghiu, S., & Ranson, M.
- Affiliations
- National Taiwan University (TW)
- Seoul National University Hospital (KR)
- Institut Gustave Roussy (FR)
- National Cancer Center Hospital (JP)
- Winship Cancer Institute (US)
- Samsung Medical Center (KR)
- Asan Medical Center (KR)
- National Cheng Kung University Hospital (TW)
- Vanderbilt University (US)
- Carolinas Healthcare System (US)
- Vall d'Hebron Hospital Universitari (ES)
- Yonsei University Health System (KR)
- AstraZeneca (United Kingdom) (GB)
- University of Manchester (GB)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2015-04-30
- Volume
- 372
- Issue
- 18
- Pages
- 1689-1699
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2076178766
- Semantic Scholar
- f9314c8da8733e870b830f3af40dae87a2f7eaa2
- Cited by
- 2,116
- References
- 11
- Citations by year
- 2026: 67 · 2025: 97 · 2024: 105 · 2023: 129 · 2022: 153 · 2021: 164 · 2020: 172 · 2019: 214 · 2018: 269 · 2017: 348 · 2016: 289 · 2015: 107 · 2014: 1 · 2013: 1
- FWCI
- 268.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Ariad Pharmaceuticals
- Celgene
- Clovis Oncology
- Astellas Pharma
- Genentech
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- osimertinib, T790M mutation, EGFR tyrosine kinase inhibitors, drug resistance, non-small cell lung cancer, EGFR-mutant lung cancer, targeted therapy, progression-free survival, objective response, dose escalation, pharmacokinetics, adverse events
- MeSH terms
- Acrylamides, Adult, Aged, Aged, 80 and over, Aniline Compounds, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Dose-Response Relationship, Drug, Female, Humans, Indoles, Lung Neoplasms, Male, Middle Aged, Mutation, Pyrimidines, Disease-Free Survival, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, ErbB Receptors
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
