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
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Abstract
Purpose: In this phase Ib/II study, we aimed to assess the safety and efficacy of afatinib plus nimotuzumab (N) in advanced non–small 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. Clin Cancer Res; 22(9); 2139–45. ©2015 AACR.
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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 <i>EGFR</i> mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [108]
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MethodEpidermal Growth Factor Receptor Tyrosine Kinase Inhibitor–Resistant Disease
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“NSCLC patients who progressed during prior treatment with gefitinib or erlotinib was disappointing with only 7% to 8% (18, 40).”
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“confirmed the minimal toxicity of nimotuzumab in combination with thoracic radiation, and also demonstrated favorable results compared with historical controls in a NSCLC (25-27).”
ResultNimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin
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“13 extremely rare with nimotuzumab in other solid tumors (34-36).”
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“Fewer side effects of nimotuzumab compared with other anti-EGFR mAbs may be attributed to unique binding affinity in the range of 10 M - 10 M to maximize tumor cell targeting while minimizing normal cell toxicity (37, 38).”
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“Several retrospective studies regarding gefitinib readministration have shown that a prolonged gefitinib-free interval was a predictive factor for a favorable clinical result (41, 42), suggesting that cytotoxic chemotherapy modify the heterogeneous tissue distribution in sensitive or resistant cells.”
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“EGFR (exon 18–21)mutations were analyzed by directional sequencing or the peptide nucleic acid-locked nucleic acid PCR clampmethod especially for detection of T790 M (28, 29).”
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“confirmed the minimal toxicity of nimotuzumab in combination with thoracic radiation, and also demonstrated favorable results compared with historical controls in a NSCLC (25-27).”
ResultTomizawa, Y., Fujita, Y., Tamura, A., Shirai, M., Shibata, S., Kawabata, T., Shibayama, T., Fukai, S., Kawahra, M., & Saito, R. (2009) · Lung Cancer · doi:10.1016/j.lungcan.2009.06.025 · Cited by 59 · cited 1× · see citing works
“Several retrospective studies regarding gefitinib readministration have shown that a prolonged gefitinib-free interval was a predictive factor for a favorable clinical result (41, 42), suggesting that cytotoxic chemotherapy modify the heterogeneous tissue distribution in sensitive or resistant cells.”
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“13 extremely rare with nimotuzumab in other solid tumors (34-36).”
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“Recently, third-generation EGFR TKI, AZD9291 and rociletinib demonstrated robust and durable response in both T790M-positive and -negative patients (43, 44).”
BackgroundEffect of weekly or daily dosing regimen of Gefitinib in mouse models of lung cancer
Zhang, Q., Li, R., Chen, X., Lee, S. B., Pan, J., Xiong, D.-H., Hu, J., Miller, M. S., Szabo, E., Lubet, R., et al. (2017) · OncoTarget · doi:10.18632/oncotarget.19785 · Cited by 28
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“According the toxicity profiles of afatinib (40mg per day), rash and diarrhea occurred in 76% of patients, with 4% grade 3 rash and 7% grade 3 diarrhea (33).”
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“Predicated on the results of afatinib under a Named Patient Use(30), we presumed H0 to be less than 20% of the ORR andH1 to bemore than 40%, yielding a sample size of 33 with 80% power and a two-sided significance level set as a¼ 0.1.”
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“In this context, there is an urgent need to elucidate the mechanisms of erlotinib resistance and to discover reliable biological targets that play important role in erlotinib resistance([105]).”
BackgroundEffect of weekly or daily dosing regimen of Gefitinib in mouse models of lung cancer
Zhang, Q., Li, R., Chen, X., Lee, S. B., Pan, J., Xiong, D.-H., Hu, J., Miller, M. S., Szabo, E., Lubet, R., et al. (2017) · OncoTarget · doi:10.18632/oncotarget.19785 · Cited by 28
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BackgroundSelf-citationNovel Approaches for Efficient Delivery of Tyrosine Kinase Inhibitors.
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Novel EGFR Inhibitors in Non-small Cell Lung Cancer: Current Status of Afatinib
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The Position of EGF Deprivation in the Management of Advanced Non-Small Cell Lung Cancer
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Detection of Rare Mutations in EGFR-ARMS-PCR-Negative Lung Adenocarcinoma by Sanger Sequencing
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BackgroundA Review of Monoclonal Antibody-Based Treatments in Non-small Cell Lung Cancer
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- Authors
- 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., Lee, S.-H., Ahn, J. S., Park, K., & Ahn, M.-J.
- Affiliations
- Samsung Medical Center (KR)
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2016-05-01
- Volume
- 22
- Issue
- 9
- Pages
- 2139-2145
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2199174919
- Cited by
- 36
- References
- 55
- Citations by year
- 2026: 2 · 2023: 2 · 2022: 1 · 2021: 6 · 2020: 3 · 2019: 7 · 2018: 4 · 2017: 8 · 2016: 3
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Boehringer Ingelheim (GE1-B3-081-1)
- 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, nimotuzumab, non-small cell lung cancer, gefitinib resistance, erlotinib resistance, anti-EGFR therapy, combination therapy, dose-limiting toxicity, recommended phase 2 dose, anticancer activity
- MeSH terms
- Erlotinib Hydrochloride, Antineoplastic Agents, Immunological, Gefitinib, Afatinib, Adult, Aged, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Quinazolines, Radiation-Sensitizing Agents, Disease-Free Survival, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, Antibodies, Monoclonal, Humanized, ErbB Receptors
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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.
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