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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 184-185

Exploring novel combinations of targeted therapy in the journey of epidermal growth factor receptor-mutant lung cancers

1 Department of Medical Research, Bhaktivedanta Hospital and Research Institute, Mumbai, Maharashtra, India
2 Department of Medical Oncology, SDSOS, NMIMS, Mumbai, Maharashtra, India
3 Department of Biological Sciences, SDSOS, NMIMS, Mumbai, Maharashtra, India

Date of Submission27-Feb-2021
Date of Decision04-Mar-2021
Date of Acceptance06-Mar-2021
Date of Web Publication26-Mar-2021

Correspondence Address:
Veda Devakumar
Address- Bhaktivedanta Hospital and Research Institute, Thane, Mahrashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/crst.crst_51_21

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How to cite this article:
Devakumar V, Raut NV, Britto N. Exploring novel combinations of targeted therapy in the journey of epidermal growth factor receptor-mutant lung cancers. Cancer Res Stat Treat 2021;4:184-5

How to cite this URL:
Devakumar V, Raut NV, Britto N. Exploring novel combinations of targeted therapy in the journey of epidermal growth factor receptor-mutant lung cancers. Cancer Res Stat Treat [serial online] 2021 [cited 2021 May 12];4:184-5. Available from: https://www.crstonline.com/text.asp?2021/4/1/184/312111

We read the article titled, “Resistance mechanisms to epidermal growth factor receptor inhibitors in non-small-cell lung cancer” by Bondili et al.[1] We would like to congratulate the authors for sharing a rare case of on- and off-target resistance mechanisms (CTNNB1 along with epidermal growth factor receptor [EGFR] T790M/C797S mutations) post treatment with osimertinib. Given the higher incidence of EGFR mutations (EGFR) mutations in India than in the Western countries, it is important to study the resistance mechanisms to EGFR-directed therapies in our patient population.[2]

In the case presented by Bondili et al., in spite of finding targetable genetic alterations, the authors have used conventional chemotherapy alone. We propose a different approach as shown in [Figure 1]. The first step is finding the allelic context of T790M and C797S. If the mutations are present in the cis form, apart from EAI045 as mentioned by the authors, combination therapy with brigatinib and cetuximab,[3] and the other fourth-generation EGFR tyrosine kinase inhibitor (TKI), BLU945, could be used.[4]
Figure 1: Continuum of targeted therapy before chemotherapy

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However, if these mutations are present in trans, a combination therapy with gefitinib and osimertinib can be contemplated. The combination is quite safe to use as shown by Rotow et al. at the American Society of Clinical Oncology 2020 annual meeting.[5]

The next-generation sequencing (NGS) report in this case showed that the variant allele frequency for CTNNB1 was 23.2%, and the findings were also confirmed by immunohistochemistry. A recent analysis of 26 non-small-cell lung cancer (NSCLC) cases showed that CTNNB1 mutations are more likely to occur in TTF1-positive adenocarcinomas as well as in those harboring EGFR mutations and contribute to TKI resistance.[6] On similar lines, the patient in Bondili et al.'s article might have developed acquired resistance due to the CTNNB1 mutation. The authors have suggested the use of niclosamide to target the CTNNB1 mutation; however, this has only been shown to be efficacious in cell lines, and no case reports in NSCLC have been published in the literature. Nevertheless, this drug repurposing looks promising given its low cost and easy access. However, its safety in combination with EGFR TKIs is not known. The other drugs used to target CTNNB1 mutations are trametinib[7] and bevacizumab.[8] There is ample literature about the safety of combining bevacizumab with EGFR TKIs. The TATTON study presented at the American Association for Cancer Research 2020 meeting has shown a positive response and safety of osimertinib with a MEK inhibitor.

We prefer doing an NGS analysis on the tissue biopsy at every step of progression to better understand the tumor evolution. Using chemotherapy earlier, the authors have missed the chance to make use of the information obtained from NGS. Therefore, our suggestion is to exhaust all targeted treatment options before chemotherapy, as once the tumor progresses, we will not know what new mutations will be induced by chemotherapy and whether targeted therapy will remain a viable option.

In conclusion, this case report highlights the need to understand the resistance mechanisms to EGFR TKIs and plan novel combination approaches which will impact the overall survival of the patient.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Bondili SK, Nandhana R, Noronha V, Joshi A, Patil V, Menon N, et al. Resistance mechanisms to epidermal growth factor receptor inhibitors in non-small cell lung cancer. Cancer Res Stat Treat 2020;3:801-7.  Back to cited text no. 1
  [Full text]  
Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Prabhash K. Epidermal growth factor receptor-mutated non-small-cell lung cancer: A primer on contemporary management. Cancer Res Stat Treat 2019;2:36-53.  Back to cited text no. 2
  [Full text]  
Wang Y, Yang N, Zhang Y, Li L, Han R, Zhu M, et al. Effective treatment of lung adenocarcinoma harboring EGFR-activating mutation, T790M, and cis-C797S triple mutations by brigatinib and cetuximab combination therapy. J Thorac Oncol 2020;15:1369-75.  Back to cited text no. 3
Schalm S, Dineen T, Lim S, Park C, Hsieh J, Woessner R, et al. 1296P BLU-945, a highly potent and selective 4th generation EGFR TKI for the treatment of EGFR T790M/C797S resistant NSCLC. Ann Oncol 2020;31:S839.  Back to cited text no. 4
Rotow J, Costa D, Paweletz C, Awad M, Marcoux P, Rangachari D, et al. Concurrent osimertinib plus gefitinib for first-line treatment of EGFR-mutated non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38 Suppl 15:9507-7.  Back to cited text no. 5
Thomas de Montpréville V, Lacroix L, Rouleau E, Mamodaly M, Leclerc J, Tutuianu L, et al. Non-small cell lung carcinomas with CTNNB1 (beta-catenin) mutations: A clinicopathological study of 26 cases. Ann Diagn Pathol 2020;46:151522.  Back to cited text no. 6
Uitdehaag JC, de Roos JA, van Doornmalen AM, Prinsen MB, Spijkers-Hagelstein JA, de Vetter JR, et al. Selective targeting of CTNBB1-, KRAS- or MYC-driven cell growth by combinations of existing drugs. PLoS One 2015;10:e0125021.  Back to cited text no. 7
Berger A, Jelinic P, Levine D. Mechanisms of response to anti-angiogenesis therapy in CTNNB1-mutated endometrial cancers. Gynecologic Oncol 2019;154:50.  Back to cited text no. 8


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