Cetuximab: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Naoya Kitamura.

Cetuximab is a human/mouse chimeric monoclonal antibody targeting epidermal growth factor receptor (EGFR), first approved in the world.

  • Cetuximab

1. The History of Cetuximab

Cetuximab is used for the treatment of metastatic colon cancer, metastatic non-small cell lung cancer, and HNSCC. For colon cancer, cetuximab was first approved in Switzerland, USA, and EU from 2003 to 2004 as a second-line treatment for EGFR-positive unresectable advanced or recurrent colorectal cancer. In 2008, it was approved as a first-line treatment for EGFR-positive and KRAS wild-type colorectal cancer. On the other hand, for HNSCC, based on the results of the Bonner study in 2006, “cetuximab + RT” and “cetuximab single agent use after BRT” have been approved for LA-HNSCC [1]. In 2008, the results of the EXTREME study were published. For R/M-HNSCC, “Cetuximab + CDDP (or CBDCA) + 5-FU” was approved in many countries and was introduced to Japan in 2012 [2].[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]

2. Current Trends of Cetuximab in LA-HNSCC and R/M-HNSCC

Cetuximab has been proven to be useful in various clinical trials in combination with radiotherapy and chemotherapy such as CDDP. The Bonner study compared 424 LA-HNSCC patients with two groups, the combination group (radiotherapy plus cetuximab) and radio-monotherapy group [1]. As a result, the median local disease control period was 24.4 months in the combination group and 14.9 months in the radio-monotherapy group (p = 0.005), and the median overall survival (OS) was 49.0 months and 29.3 months, respectively (p = 0.03). Therefore, the cetuximab combination group was significantly superior in local control and survival.

The EXTREME study compared 442 R/M-HNSCC patients with two groups, the FP alone group (CDDP/CBDCA + 5-FU) and the combination group (FP plus cetuximab) [2]. As a result, the median OS was 10.1 months in the combination group versus 7.4 months in the FP alone group (p = 0.04), and the median progression-free survival was 5.6 months and 3.3 months, respectively (p = 0.001). Thus, a significantly prolonged survival was shown in the cetuximab combination group.

In addition to the EXTREME study, clinical trials for R/M-HNSCC include the GORTEC 2008-03 trial (CDDP + DTX + cetuximab) [13][3], Hitt trial (Weekly PTX + cetuximab) [14][4], CSPOR-HN02 trial (PCE regimen; PTX + CBDCA + cetuximab) [15][5], and any other widely applied regimens.

3. Future Prospects of Cetuximab in HNSCC

High EGFR expression is said to be found in 25–77% of colon cancers and 90% or more of HNSCC [16[6][7],17], when ligands such as EGF and transforming growth factor-α (TGF-α) bind to EGFR, they form a dimer with EGFR or other human epidermal growth factor receptor (HER) family members. Therefore, autophosphorylation of the intracellular tyrosine kinase domain, and activating further downstream Ras-Raf-MAPK and PI3K-Akt pathways are deeply involved in cancer growth and metastasis.

Initially, cetuximab was used exclusively in colon cancer cases in which EGFR expression was observed in tumor cells by immunostaining, but subsequent studies showed good response rates in colon cancer cases in which EGFR expression was negative [18][8]. Therefore, it was clarified that the intensity of EGFR expression did not correlate with the therapeutic effect of cetuximab [19][9]. Currently, EGFR immunostaining is not recommended for determining the indication of anti-EGFR antibody [20][10]. Anti-EGFR antibody therapy for unresectable colon cancer was found to be ineffective in cases with RAS (KRAS/NRAS) gene mutations (about 40% of colorectal cancers), and RAS genetic testing was established as a companion diagnostic tool [21][11]. Recently, other genetic abnormalities, such as gene mutation of BRAF [22][12], PIK3CA [23][13], and EGFR extracellular domain (ECD) [24][14], gene amplification of HER2 [25][15] and mesenchymal-epithelial transition factor (MET) [26][16], have been reported as acquisition resistance factors of anti-EGFR antibody [27][17].

Although a biomarker for predicting the therapeutic effect of cetuximab has not been established in HNSCC, it has been suggested to be associated with rash, which is a typical adverse event of cetuximab. In an additional report from the Bonner study, OS in BRT patients was 25.6 months in the group with Grade 1 or lower rash, whereas it was 68.8 months in the group with Grade 2 or higher [28][18], indicating that the OS of the severe rash group was significantly superior. Furthermore, in the report by Saltz L et al., the response rate and disease control rate of the cases with skin disorders, such as rash, tended to be higher than the cases without rash, when cetuximab was applied to R/M-HNSCC [29][19]. Rash, which is a typical adverse event of cetuximab, is the most clinically easy-to-understand index and is attracting attention as a clue for the development of biomarkers in the future.

References

  1. Bonner, J.A.; Harari, P.M.; Giralt, J.; Azarnia, N.; Shin, D.M.; Cohen, R.B.; Jones, C.U.; Sur, R.; Raben, D.; Jassem, J.; et al. Radiotherapy plus Cetuximab for Squamous-Cell Carcinoma of the Head and Neck. N. Engl. J. Med. 2006, 354, 567–578. [Google Scholar] [CrossRef] [PubMed]
  2. Vermorken, J.B.; Mesia, R.; Rivera, F.; Remenar, E.; Kawecki, A.; Rottey, S.; Erfan, J.; Zabolotnyy, D.; Kienzer, H.-R.; Cupissol, D.; et al. Platinum-Based Chemotherapy plus Cetuximab in Head and Neck Cancer. N. Engl. J. Med. 2008, 359, 1116–1127. [Google Scholar] [CrossRef] [PubMed]
  3. Guigay, J.; Fayette, J.; Dillies, A.F.; Sire, C.; Kerger, J.N.; Tennevet, I.; Machiels, J.P.; Zanetta, S.; Pointreau, Y.; Le Moal, L.B.; et al. Cetuximab, docetaxel, and cisplatin as first-line treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma: A multicenter, phase II GORTEC study. Ann. Oncol. 2015, 26, 1941–1947. [Google Scholar] [CrossRef] [PubMed]
  4. Hitt, R.; Irigoyen, A.; Cortes-Funes, H.; Grau, J.J.; García-Sáenz, J.A.; Cruz-Hernandez, J.J.; Spanish Head and Neck Cancer Cooperative Group (TTCC). Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Ann. Oncol. 2012, 23, 1016–1022. [Google Scholar] [CrossRef]
  5. Tahara, M.; Kiyota, N.; Yokota, T.; Hasegawa, Y.; Muro, K.; Takahashi, S.; Onoe, T.; Homma, A.; Taguchi, J.; Suzuki, M.; et al. Phase II trial of combination treatment with paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (CSPOR-HN02). Ann. Oncol. 2018, 29, 1004–1009. [Google Scholar] [CrossRef]
  6. Normanno, N.; Maiello, M.R.; De Luca, A. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs): Simple drugs with a complex mechanism of action? J. Cell. Physiol. 2002, 194, 13–19. [Google Scholar] [CrossRef]
  7. Chung, C.H.; Ely, K.; McGavran, L.; Varella-Garcia, M.; Parker, J.; Parker, N.; Jarrett, C.; Carter, J.; Murphy, B.A.; Netterville, J.; et al. Increased Epidermal Growth Factor Receptor Gene Copy Number Is Associated With Poor Prognosis in Head and Neck Squamous Cell Carcinomas. J. Clin. Oncol. 2006, 24, 4170–4176. [Google Scholar] [CrossRef]
  8. Chung, K.Y.; Shia, J.; Kemeny, N.E.; Shah, M.; Schwartz, G.K.; Tse, A.; Hamilton, A.; Pan, D.; Schrag, D.; Schwartz, L.; et al. Cetuximab Shows Activity in Colorectal Cancer Patients With Tumors That Do Not Express the Epidermal Growth Factor Receptor by Immunohistochemistry. J. Clin. Oncol. 2005, 23, 1803–1810. [Google Scholar] [CrossRef]
  9. Muro, K.; Yoshino, T.; Doi, T.; Shirao, K.; Takiuchi, H.; Hamamoto, Y.; Watanabe, H.; Yang, B.-B.; Asahi, D. A Phase 2 Clinical Trial of Panitumumab Monotherapy in Japanese Patients with Metastatic Colorectal Cancer. Jpn. J. Clin. Oncol. 2009, 39, 321–326. [Google Scholar] [CrossRef]
  10. National Comprehensive Cancer Network. NCCN Clinical Practical Guidelines in Oncology. Colon Cancer, version 4. 2019. Available online: https://www.nccn.org/professionals/physician_gls/default.aspx (accessed on 1 December 2020).
  11. Van Cutsem, E.; Lenz, H.-J.; Köhne, C.-H.; Heinemann, V.; Tejpar, S.; Melezínek, I.; Beier, F.; Stroh, C.; Rougier, P.; Van Krieken, J.H.; et al. Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Treatment and RAS Mutations in Colorectal Cancer. J. Clin. Oncol. 2015, 33, 692–700. [Google Scholar] [CrossRef]
  12. Rowland, A.; Dias, M.M.; Wiese, M.D.; Kichenadasse, G.; McKinnon, R.A.; Karapetis, C.S.; Sorich, M.J. Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br. J. Cancer 2015, 112, 1888–1894. [Google Scholar] [CrossRef] [PubMed]
  13. De Roock, W.; Claes, B.; Bernasconi, D.; De Schutter, J.; Biesmans, B.; Fountzilas, G.; Kalogeras, K.T.; Kotoula, V.; Papamichael, D.; Laurent-Puig, P.; et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: A retrospective consortium analysis. Lancet Oncol. 2010, 11, 753–762. [Google Scholar] [CrossRef]
  14. Montagut, C.; Dalmases, A.; Bellosillo, B.; Crespo, M.; Pairet, S.; Iglesias, M.; Salido, M.; Gallen, M.; Marsters, S.A.; Tsai, S.P.; et al. Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat. Med. 2012, 18, 221–223. [Google Scholar] [CrossRef] [PubMed]
  15. Bregni, G.; Sciallero, S.; Sobrero, A. HER2 Amplification and Anti-EGFR Sensitivity in Advanced Colorectal Cancer. JAMA Oncol. 2019, 5, 605–606. [Google Scholar] [CrossRef] [PubMed]
  16. Raghav, K.; Morris, V.; Tang, C.; Morelli, P.; Amin, H.M.; Chen, K.; Manyam, G.C.; Broom, B.; Overman, M.J.; Shaw, K.; et al. MET amplification in metastatic colorectal cancer: An acquired response to EGFR inhibition, not a de novo phenomenon. Oncotarget 2016, 7, 54627–54631. [Google Scholar] [CrossRef] [PubMed]
  17. Montagut, C.; Argilés, G.; Ciardiello, F.; Poulsen, T.T.; Dienstmann, R.; Kragh, M.; Kopetz, S.; Lindsted, T.; Ding, C.; Vidal, J.; et al. Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses. JAMA Oncol. 2018, 4, e175245. [Google Scholar] [CrossRef]
  18. Bonner, J.A.; Harari, P.M.; Giralt, J.; Cohen, R.B.; Jones, C.U.; Sur, R.K.; Raben, D.; Baselga, J.; Spencer, S.A.; Zhu, J.; et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010, 11, 21–28. [Google Scholar] [CrossRef]
  19. Saltz, L.; Kies, M.; Abbruzzese, J.L.; Azarnia, N.; Needle, M. The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies. Proc. Am. Soc. Clin. Oncol. 2003, 22, 204. [Google Scholar]
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ScholarVision Creations
Feedback