T790M mutation and clinical outcomes with osimertinib in patients with epidermal growth factor receptor-mutant nonsmall cell lung cancer

• Published in: Indian journal of medical and paediatric oncology Vol. 40; no. 1; pp. 73 - 78
• Main Authors: Jaiswal, Ravi, Pinninti, Rakesh, Mohan, MVT Krishna, Santa, A, Boyella, Pavan Kumar, Nambaru, Lavanya, Murthy, Sudha S, Chowdary, K Veeriah, Rajappa, Senthil
• Format: Journal Article
• Language: English
• Published: A-12, 2nd Floor, Sector 2, Noida-201301 UP, India Thieme Medical and Scientific Publishers Pvt. Ltd 01-01-2019; Wolters Kluwer India Pvt. Ltd; Medknow Publications and Media Pvt. Ltd; Medknow Publications & Media Pvt. Ltd
• Subjects: Analysis; Biopsy; Chemotherapy; Clinical outcomes; Drug resistance; Drug therapy; Epidermal growth factor; Genetic aspects; Histology; Lung cancer; Lung cancer, Non-small cell; Mutation; Original Article; Response rates; Statistical analysis; Studies; Targeted cancer therapy; Treatment outcome; lung cancer; T790M; Epidermal growth factor receptor; liquid biopsy; osimertinib; re-biopsy
• ISSN: 0971-5851; 0975-2129
• DOI: 10.4103/ijmpo.ijmpo_215_18

Abstract
Introduction:
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors TKIs) are highly effective in EGFR-mutant advanced lung cancer. The most common resistance mechanism to EGFR-TKI is the development of T790M mutation in Exon 20. Osimertinib, a highly selective EGFR-TKI, has been approved for use in patients who progress on the first-line TKI and harbor the T790M mutation.
Objective:
The primary objective is to prospectively study the incidence of T790M mutation in patients who progress on the first-line EGFR-TKI. Secondary objectives include clinical characteristics that predict for T790M mutation and outcomes with osimertinib.
Materials and Methods:
This single-center, prospective observational study included 90 patients who progressed on first-line EGFR TKI. All patients had DNA extracted from tissue re-biopsy or plasma circulating tumor DNA (re-biopsy was not feasible or inadequate). T790M mutation was detected using amplification refractory mutation system-polymerase chain reaction, and patients harboring T790M mutation were started on osimertinib (80 mg once daily) until progression or unacceptable side effects.
Results:
At progression, T790M mutation was detected in 47/90 patients (52.2%). On binary logistic regression model analysis, variables that were independently predictive of the development of T790M were younger age (odds ratio [OR] 4.3, 95% confidence interval [CI] 1.14–16.6,
P
= 0.031); nonerlotinib TKI use (OR 8.3, 95% CI 1.24–55.8,
P
= 0.029); and pure adenocarcinoma histology (OR 6.2, 95% CI 1.60–24.7,
P
= 0.008). Forty-six patients were started on osimertinib. The overall response rate and median progression-free survival were 65.21% and 12.45 months (standard deviation [SD] 1.03, 95% CI 10.41–14.48), respectively. Osimertinib was well tolerated with most toxicities being Grade 1 and 2 diarrhea and skin rash.
Conclusions:
In our prospective cohort, half of all patients had a T790M mutation at progression on the first-line EGFR TKI. Tissue biopsy is feasible in the majority of patients. Clinical outcomes with osimertinib were consistent with those reported.