|Year : 2018 | Volume
| Issue : 1 | Page : 43-45
Response to osimertinib in EGF816-resistant T790M-mutated lung cancer
James C Kuo, Natasha B Leighl
Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada
|Date of Web Publication||18-Jun-2018|
Dr. James C Kuo
Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON M5G 2M9
Source of Support: None, Conflict of Interest: None
A 75-year-old male with metastatic adenocarcinoma of the lung that harbored an epidermal growth factor receptor (EGFR) mutation had disease control for 16 months with EGF816, an investigational, third-generation EGFR tyrosine kinase inhibitor (TKI), in a phase I clinical trial. On disease progression, his treatment was switched to an earlier third-generation EGFR TKI, osimertinib. A rapid response occurred but was short-lived for only 10 weeks, before a rapid progression ensued. The mechanism of sequential resistance to EGF816, and subsequently, osimertinib in this male was indeterminant because of the absence of baseline genomic profiling of the tumor. Repeated molecular profiling demonstrated persistent EGFR mutations and a possibly emergent TP53 G266E mutation. This case highlighted the importance of serial biopsies for genomic analysis to understand emergent TKI resistance. As non-cross resistance may be present among the various EGFR TKI, the potential in the sequential approach in targeted therapy should be explored.
Keywords: Drug resistance, epidermal growth factor receptor mutation, nonsmall cell lung cancer, targeted therapy, tumor genomics
|How to cite this article:|
Kuo JC, Leighl NB. Response to osimertinib in EGF816-resistant T790M-mutated lung cancer. J Curr Oncol 2018;1:43-5
| Introduction|| |
The current treatment paradigm of advanced epidermal growth factor receptor (EGFR)-mutated lung cancer has been that of initial first- or second-generation EGFR tyrosine kinase inhibitors (TKIs), and subsequently, on disease progression, if due to acquired EGFR T790M resistance mutation, osimertinib, a third-generation EGFR TKI. There is now evidence to support the use of osimertinib upfront, given the favorable treatment outcome in comparison with first-generation TKI. However, overcoming resistance to osimertinib is an emerging challenge and remains an area of need for further research. Other third-generation TKI with activities against T790M are under active investigation, but the sequential use of TKI to overcome resistance beyond osimertinib remains indeterminate. Here, we report a case of rapid response to osimertinib, after disease progression on EGF816, a novel third-generation EGFR TKI. To the best of our knowledge, this is the first case in the literature of response to osimertinib in the third-line setting.
| Case Report|| |
A 75-year-old Korean male, an ex-smoker with metastatic EGFR L858R and T790M mutated lung adenocarcinoma, was treated in a phase I clinical trial with EGF816, a covalent irreversible third-generation EGFR TKI with activity against sensitizing and T790M mutations. Prior therapy before his EGFR status was known included surgical resection for early stage disease followed by adjuvant chemotherapy with vinorelbine/cisplatin, palliative chemotherapy with pemetrexed for relapse, which occurred within 12 months of completing adjuvant chemotherapy, and subsequently, erlotinib, with a durable disease control for 22 months. It was unknown whether the T790M mutation identified before commencing EGF816 was de novo or acquired. While receiving EGF816, he had a partial response with significant clinical benefit, sustained for 16 months, before a rapid disease progression ensued. A repeated tumor biopsy confirmed the persistence of L858R and T790M mutations. Next-generation sequencing was performed, using a focused sequencing panel with the TruSight Tumor 15 assay Illumina); this assay detects any variants in the DNA sequences of AKT1, BRAF, EGFR, ERBB2, FOXL2, GNA11, GNAQ, KIT, KRAS, MET, NRAS, PDGFRA, PIK3CA, RET, and TP53.). A mutation in TP53, G266E substitution, was detected; no other alterations were identified. He ceased EGF816 and commenced osimertinib through a compassionate access scheme. He reported marked symptom improvement at 2 weeks, with radiologic improvement by 4 weeks. Certainly, his disease progressed by week 10 of osimertinib and he died 4 weeks later.
| Discussion|| |
EGF816 is a novel TKI with activities against T790M and has an overall response rate of 48% in T790M-mutated patients in a phase I clinical trial. The IC50 for EGFR L858R/T790M- mutated lung cancer in the mouse model H1975 is comparable for EGF816 and osimertinib, at 9.0 × 10 − 9 mol/L  and 11.44 × 10 − 9 mol/L, respectively. As such, it is plausible that the acquired resistance to either EGF816 or osimertinib may have similar underlying mechanisms, which are yet fully elucidated. Emergence of C797S is considered the most common cause in osimertinib-resistant tumor. Tumor genomic analysis of nine patients with disease progression on EGF816 has identified several other potential mechanisms of resistance, including loss of T790M mutation and emergent mutations in TP53, RB1, mTOR, BRAF, or MET.
The sequential use of third-generation TKI has not been investigated. However, cases of osimertinib responses after rociletinib, another T790M-specific TKI, have been reported. Noncross resistance has been demonstrated in vitro with ASP8273, another third-generation, T790M-specific TKI, in cell line resistant to osimertinib and rocilectinib. A case series of nine patients who received osimertinib after developing resistance to rociletinib reported partial response in three patients with another four patients deriving a clinical benefit. This anecdotal evidence suggested the ability of third-generation TKI in overcoming tertiary resistance with a spectrum of activities on other secondary mutations beyond T790M also probable. Likewise, in ALK-rearranged lung cancer, resistance to later-generation TKI has been reported to be overcome by a less potent and less selective first-generation TKI. These isolated reports emphasized the importance of repeating tumor biopsies on disease progression in understanding the molecular basis of resistance, as well as supporting further investigation in the sequential use of third-generation EGFR TKI.
In our patient, the absence of longitudinal molecular profiling has limited the analysis of the underlying mechanisms for the pattern of resistance observed. Serial tumor genomic profiling may soon be clinically applicable with the advances in circulating tumor DNA (ctDNA) analyses. A case of the utility of ctDNA in assessing response and detecting emerging resistance mutation to osimertinib was recently described: treatment to overcome such resistance was directed by the observation of an increasing allelic fraction of a rarer mutation on serial ctDNA analysis and led to an objective response. In our patient, the use of serial ctDNA may detect changes preceding radiologic or clinical changes; this potential application of serial ctDNA has also been previously described. By the time our patient had a radiologic confirmation of disease progression, coinciding with sudden symptom deterioration, he was not fit for a conventional tumor biopsy, but a “liquid biopsy” for ctDNA analysis would have remained clinically feasible.
| Conclusion|| |
This case highlights the value in exploring the noncross resistance among the various third-generation EGFR TKI. Resistance to an initial T790M-specific TKI and the role of sequential TKI use need to be better understood. Serial tumor genomic profiling, with its application in detecting potentially reversible acquired resistance, may need to be incorporated into clinical practice as acquired resistance to T790M-specific TKI will inevitably become an emerging challenge.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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