Dual Inhibition of EGFR with Afatinib and Cetuximab in Kinase Inhibitor–Resistant EGFR -Mutant Lung Cancer with and without T790M Mutations

Janjigian, Yelena Y.; Smit, Egbert F.; Groen, Harry J.M.; Horn, Leora; Gettinger, Scott; Camidge, D. Ross; Riely, Gregory J.; Wang, Bushi; Fu, Yali; Chand, Vikram K.; Miller, Vincent A.; Pao, William

doi:10.1158/2159-8290.cd-14-0326

Cited by 362Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchLung Cancer Diagnosis and Treatment

Dual Inhibition of EGFR with Afatinib and Cetuximab in Kinase Inhibitor–Resistant EGFR -Mutant Lung Cancer with and without T790M Mutations

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Janjigian, Yelena Y., Smit, Egbert F., Groen, Harry J.M., Horn, Leora, Gettinger, Scott, Camidge, D. Ross, Riely, Gregory J., Wang, Bushi +4 more·2014·Cancer Discovery

DOI 10.1158/2159-8290.cd-14-0326PMC PMC4155006

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Abstract

UNLABELLED: EGFR-mutant lung cancers responsive to reversible EGFR inhibitors (gefitinib/erlotinib) develop acquired resistance, mediated by second-site EGFR T790M mutation in >50% of cases. Preclinically, afatinib (irreversible ErbB family blocker) plus cetuximab (anti-EGFR monoclonal antibody) overcomes T790M-mediated resistance. This phase Ib study combining afatinib and cetuximab enrolled heavily pretreated patients with advanced EGFR-mutant lung cancer and acquired resistance to erlotinib/gefitinib. Patients provided post-acquired-resistance tumor samples for profiling EGFR mutations. Among 126 patients, objective response rate (overall 29%) was comparable in T790M-positive and T790M-negative tumors (32% vs. 25%; P = 0.341). Median progression-free survival was 4.7 months (95% confidence interval, 4.3-6.4), and the median duration of confirmed objective response was 5.7 months (range, 1.8-24.4). Therapy-related grade 3/4 adverse events occurred in 44%/2% of patients. Afatinib-cetuximab demonstrated robust clinical activity and a manageable safety profile in EGFR-mutant lung cancers with acquired resistance to gefitinib or erlotinib, both with and without T790M mutations, warranting further investigation. SIGNIFICANCE: This article reports the results of a trial combining afatinib and cetuximab in patients with acquired resistance and details the first clinical proof-of-concept for the preclinical hypothesis that a significant proportion of tumors in patients with acquired resistance to gefitinib/erlotinib remain dependent on EGFR signaling for survival.

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The combination of afatinib with EGFR antibodies or bevacizumab has shown promise but some may be associated with considerable treatment-related toxicities.
“Other approaches include the combination of afatinib with EGFR antibodies or bevacizumab, which have shown promise but some may be associated with considerable treatment-related toxicities.”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [107]
The Discussion reports a 29% response rate for afatinib plus the EGFR antibody cetuximab. The Results (Tolerability and Adverse Event Profile) report grade 3/4 treatment-related adverse events in 44%/2% of patients. The paper does not report a combination of afatinib with bevacizumab, so it supports only the cetuximab part of the claim. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Afatinib plus cetuximab caused substantial skin toxicity, with 18% grade 3+ rash.
“However, this combination has substantial skin toxicity with 18% of patients reporting CTCAE grade 3 or higher rash (33).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [33]
Afatinib plus cetuximab produced a 32% unconfirmed response rate in a phase IB trial of EGFRm+ lung cancer with acquired erlotinib resistance.
“One regimen that showed potential activity is afatinib plus the anti-EGFR antibody, cetuximab, which induced a 32% unconfirmed response rate in a phase IB trial for patients with EGFRm+ lung cancer and acquired resistance to erlotinib (33).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [33]
Treatment with EGFR monoclonal antibodies based on EGFR amplification and overexpression has modestly improved clinical outcomes of squamous NSCLC, and cetuximab added to afatinib appears to increase response rates compared with afatinib alone in patients with EGFR exon 19 deletion or L858R.
“Treatment with EGFR monoclonal antibodies based on EGFR amplification and overexpression has modestly improved clinical outcomes of squamous NSCLC, and cetuximab added to afatinib appears to increase response rates compared to afatinib alone in patients with EGFR exon 19 deletion or L858R”
From Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC (2018) · cites this paper as [22]
The afatinib-cetuximab combination carries substantial skin and gastrointestinal toxicity that may restrict its use.
“However, this combination is associated with substantial skin and gastrointestinal toxic effects, which may limit its use.”
From Rociletinib in EGFR-Mutated Non–Small-Cell Lung Cancer (2015) · cites this paper as [16]

The best therapy so far for acquired resistance has been daily afatinib plus cetuximab every other week, yielding a 30% response rate and median progression-free survival of 4.7 months.
“The most successful therapy to date for acquired resistance has been a combination of daily afatinib and the EGFR monoclonal antibody cetuximab every other week, with a response rate of 30% and a median progression-free survival of 4.7 months.16”
From Rociletinib in EGFR-Mutated Non–Small-Cell Lung Cancer (2015) · cites this paper as [16]
Some EGFR mutant proteins, including L858R/T790M, do not require dimerization for oncogenic transformation.
“Prior studies have demonstrated that some EGFR mutant proteins, including L858R/T790M, do not require dimerization for oncogenic transformation (35).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [35]
Other EGFR mutants, including EGFR L858R, require dimerization and are sensitive to cetuximab, which disrupts EGFR dimerization.
“In contrast, other mutants, including EGFR L858R, require dimerization and are sensitive to the anti-EGFR antibody cetuximab which disrupts EGFR dimerization (35).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [35]
Combining second-generation EGFR TKIs with other targeted agents, such as Afatinib plus Cetuximab and Neratinib plus Temsirolimus, has recently reported promising results, albeit toxicity profile could limit clinical implementation.
“However, the role of second generation EGFR TKIs in acquired resistance is not definitely thrown over, since combining these agents with other targeted agents, such as the dual combination Afatinib plus Cetuxumab [82] and Neratinib plus Temsirolimus [83], has recently reported promising results, albeit toxicity profile of these combinations could limit their clinical implementation.”
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 [82]
The afatinib-cetuximab combination has shown early evidence of efficacy in EGFR TKI-resistant NSCLC.
“Another strategy with anti-EGFR antibodies is the combination of afatinib-cetuximab, which has demonstrated early evidence of efficacy in EGFR TKI-resistant NSCLC.67”
From The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation–Positive Non–Small Cell Lung Cancer: Status in 2016 (2016) · cites this paper as [67]

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[43]Ranson M Pao W Kim D-W Kim S-W Ohe Y Felip E AZD9291: an irreversible, potent and selective tyrosine kinase inhibitor (TKI) of activating (EGFRm+) and resistance (T790M) mutations in advanced NSCLC 2013 15th World Conference on Lung Cancer (WCLC), Sydney Australia Abstract MO21.12.
[44]Soria JC Sequist LV Gadgeel SM Goldman J Wakelee H Varga A First-in-human evaluation of CO-1686, an irreversible, highly, selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M) 2013 15th World Conference on Lung Cancer (WCLC), Sydney Australia Abstract O03.06.

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Nastiuk, K. L., & Krolewski, J. J. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.12.005 · Cited by 85 · see citing works
Development of Dual Inhibitors Targeting Epidermal Growth Factor Receptor in Cancer Therapy
Tan, L., Zhang, J., Wang, Y., Wang, X., Wang, Y., Zhang, Z., Shuai, W., Wang, G., Chen, J., Wang, C., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01714 · Cited by 88 · see citing works
EGFR-targeted therapy results in dramatic early lung tumor regression accompanied by imaging response and immune infiltration in EGFR mutant transgenic mouse models
Venugopalan, A., Lee, M.-J., Niu, G., Medina-Echeverz, J., Tomita, Y., Lizak, M. J., Cultraro, C. M., Simpson, R. M., Chen, X., Trepel, J. B., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.11021 · Cited by 40 · see citing works
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, 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
“This combination regimen has demonstrated an augmented response rate of 29% for TKI-resistant EGFR mutant NSCLC patients in a recent clinical trial (20).”
BackgroundResult
AZD9291 in EGFR -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

Authors: 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., Miller, V. A., & Pao, W.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Vrije Universiteit Amsterdam (NL)
University Medical Center Groningen (NL)
Vanderbilt University (US)
Yale Cancer Center (US)
University of Colorado Cancer Center (US)
Boehringer Ingelheim (United States) (US)
Corresponding author: Janjigian, Yelena Y.
ORCID: Janjigian, Yelena Y.
Smit, Egbert F.
Groen, Harry J.M.
Horn, Leora
Gettinger, Scott
Camidge, D. Ross
Riely, Gregory J.
Wang, Bushi
Fu, Yali
Miller, Vincent A.
Pao, William
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2014-09-01
Volume: 4
Issue: 9
Pages: 1036-1045
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-14-0326
PMC: PMC4155006
OpenAlex: W2129656399
Cited by: 362
References: 35
Citations by year: 2026: 9 · 2025: 6 · 2024: 4 · 2023: 16 · 2022: 16 · 2021: 18 · 2020: 22 · 2019: 29 · 2018: 50 · 2017: 57 · 2016: 50 · 2015: 68 · 2014: 17
FWCI: 51.24
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Cancer Discovery (publishedVersion)
PubMed (publishedVersion)
Pure Amsterdam UMC (publishedVersion)
Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
PubMed Central (acceptedVersion)
University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Funders: Eli Lilly and Company
American Society of Clinical Oncology
National Institutes of Health (UL1TR000445)
National Cancer Institute (R01CA121210, P01CA129243, L30 CA162361, U54CA143798, P30CA008748)
National Center for Research Resources (UL1RR024975)
National Center for Advancing Translational Sciences
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: EGFR-mutant lung cancer, afatinib, cetuximab, T790M mutation, acquired drug resistance, gefitinib resistance, erlotinib resistance, irreversible EGFR inhibitors, combination therapy, progression-free survival
MeSH terms: Cetuximab, Afatinib, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Quinazolines, Treatment Outcome, Drug Resistance, Neoplasm, Amino Acid Substitution, Protein Kinase Inhibitors, ErbB Receptors

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Dual Inhibition of EGFR with Afatinib and Cetuximab in Kinase Inhibitor–Resistant EGFR -Mutant Lung Cancer with and without T790M Mutations

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