|Year : 2020 | Volume
| Issue : 1 | Page : 77-78
Osimertinib as an emerging therapeutic modality in nonsmall cell lung cancer: Opportunities and challenges in Indian scenario
Sayanta Thakur1, Dwaipayan Sarathi Chakraborty1, Sandeep Lahiry2, Shouvik Choudhury3
1 Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India
2 Department of Pharmacology, RG Kar Medical College, Kolkata, West Bengal, India
3 Department of Pharmacology, Burdwan Medical College, Burdwan, West Bengal, India
|Date of Submission||25-Jun-2019|
|Date of Acceptance||14-Sep-2019|
|Date of Web Publication||31-Dec-2019|
Dwaipayan Sarathi Chakraborty
Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Thakur S, Chakraborty DS, Lahiry S, Choudhury S. Osimertinib as an emerging therapeutic modality in nonsmall cell lung cancer: Opportunities and challenges in Indian scenario. Lung India 2020;37:77-8
|How to cite this URL:|
Thakur S, Chakraborty DS, Lahiry S, Choudhury S. Osimertinib as an emerging therapeutic modality in nonsmall cell lung cancer: Opportunities and challenges in Indian scenario. Lung India [serial online] 2020 [cited 2020 Jan 17];37:77-8. Available from: http://www.lungindia.com/text.asp?2020/37/1/77/274420
Osimertinib is a third-generation, central nervous system (CNS)-active epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), with selectivity against EGFR sensitizing as well as T790M mutation of EGFR. The mono-anilino-pyrimidine framework, developed by AstraZeneca, targets double-mutant (activating mutation + T790M) form of EGFR resistant to first- and second-generation TKIs  [Figure 1]. Besides being approved in other countries for the specified indication, on August 9, 2018, it was granted import and marketing permission by the DCGI, to be used in advanced nonsmall cell lung cancer (NSCLC) patients with EGFR exon 19 deletion or exon 21 (L858R) mutations. The commercially available form is distributed under the brand name Tagrisso© which is available at the strength of 40 or 80 mg.
|Figure 1: Epidermal growth factor receptor pathway and mechanism of action of osimertinib|
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Osimertinib binds irreversibly to the EGFR kinase, via the C797 amino acid covalent bond, accounting for its potent, highly selective inhibition. The salient pharmacokinetic properties, including large tissue distribution, slow absorption, and moderate clearance, with favorable pharmacodynamic parameters are in accordance with its surge in therapeutic purposes. It also demonstrated higher penetration into CNS compared to gefitinib, afatinib, or rociletinib in EGFR-mutated mouse brain metastasis model. Osimertinib was found to be 200 times more potent against L858R/T790M than wild-type EGFR in vitro. It possesses very low activity against additional kinases, such as ERBB2, ERBB4, ACK1, ALK1, BLK, BBK, MLK1, and MNK2.
Preliminary Phase III Trial (AURA III) indicated improvements in median progression-free survival (PFS) in osimertinib group (10.1 vs. 4.4 months, hazard ratio 0.30, P < 0.001), in patients of T790M-mutant advanced NSCLC in comparison with intravenous pemetrexed plus carboplatin or cisplatin for up to six cycles in 2:1 ratio. The median PFS was also significantly higher in patients with CNS metastasis (n = 144) in osimertinib group. However, Indian data on osimertinib are limited with one completed trial  and two trials on-going recently [Table 1]. Currently, a Phase III, randomized, double-blind multicenter clinical trial is being conducted in India (18 patients out of 200) as a subcenter. The safety profile of osimertinib is also being assessed in an observational Phase IV study.
In many ways, this necessitates the development of an appropriate diagnostic test to identify the mutational status, especially in India where the annual incidence of lung cancer is 6.9% with majority attributed to NSCLC variety (80%–85%). Interestingly, with the varying incidence of T790M mutation in India, a specific strategy adopted by AstraZeneca insists upon proper access to this diagnostic test. These include development of proper infrastructure, enlightening the medical and pathological experts of interest along with standardization of test quality through external quality assurance program.
Despite the impressive development of osimertinib, some pitfalls still persist. Detection of T790M mutation by serum-based circulating cell-free tumor DNA is a complex, costly procedure with high false-negative results. Advancement of diagnostic modalities to address further mechanism of resistance to osimertinib, i.e., C797S mutation in exon 20, needs to be accomplished. Finally, the price of Tagrisso© (INR 490,846 [$6998] for 30 tablets) might limit the significant patient pool affording this therapy with an impedance over further development of this molecule in India. A recent study suggested that the reduction of osimertinib price by 20%–25% can be favorable on the basis of cost-effectiveness profile in most of the countries around the globe. However, cost-sharing and risk-sharing approach may not be appropriate. Other measures such as managed entry agreement and compassionate access program can be adopted to ensure timely access to highly effective as well as an expensive drug like osimertinib.
As a new molecule, osimertinib holds promising esteem in future on account of its effectiveness and safety. A dilemma still persists as the paradigm of lung cancer treatment is shifted toward acquiring novelty in the context of a financial limitation faced in countries like India. Engaging multiple stakeholders may be rational to curb out pressure on the patients, payers, and also drug manufacturers.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al.
AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014;4:1046-61.
Santarpia M, Liguori A, Karachaliou N, Gonzalez-Cao M, Daffinà MG, D'Aveni A, et al.
Osimertinib in the treatment of non-small-cell lung cancer: Design, development and place in therapy. Lung Cancer (Auckl) 2017;8:109-25.
Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, et al.
Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res 2016;22:5130-40.
Noronha V, Majumdar S, Joshi A, Patil V, Trivedi V, Chougule A, et al.
Osimertinib in Indian patients with T790M-positive advanced nonsmall cell lung cancer. South Asian J Cancer 2017;6:143.
A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter, International Study of Osimertinib As Maintenance Therapy in Patients With Locally Advanced, Unresectable EGFR Mutation-Positive Non-Small Cell Lung Cancer (Stage III) Whose Disease Has Not Progressed Following Definitive Platinum-Based Chemoradiation Therapy (LAURA) (CTRI/2018/10/016042). Clinical Trials Registry-India. Available from: http://www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=28298&EncHid=&modid=& compid=%27,%2728298det%27
. [Last retrieved on 2019 Jun 05].
Will Financial Toxicity Weigh Down 1L NSCLC Win For Tagrisso In India. Cytecare Cancer Hospitals. Available from: https://www.cytecare.com/media/will-financial-toxicity-weigh-down-1l-nsclc-win-for-tagrisso-in-india. [Last retrieved on 2019 Jun 06].
Yoon S, Kang J, Lee DH. Osimertinib, the winner, but cannot yet take it all. Ann Transl Med 2018;6:61.
Ezeife DA, Kirk V, Chew DS, Nixon NA, Lee R, Le LW, et al.
Economic analysis of osimertinib in previously untreated EGFR-mutant advanced non-small cell lung cancer in Canada. Lung Cancer 2018;125:1-7.