A Phase II Trial of Osimertinib in the Second-Line Treatment of Non-small Cell Lung Cancer with the EGFR T790M Mutation, Detected from Circulating Tumor DNA: LiquidLung-O-Cohort 2

Abstract

Purpose: Administering the best treatment after failure of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy requires knowledge of resistance status. In this trial, treatment efficacy of osimertinib was assessed in patients with non-small cell lung carcinoma (NSCLC) harboring the T790M resistance mutation, detected from circulating tumor DNA (ctDNA) with unknown tumor mutation status.

Materials and methods: To extract ctDNA from plasma, 15 mL of peripheral blood was withdrawn and centrifuged immediately before storage. Cobas ver. 2 and PANA Mutyper were used for ctDNA genotyping. Patients with T790M, detected from ctDNA, were enrolled and they received a oncedaily administration of osimertinib 80 mg. The primary endpoint was objective response rate (ORR), and secondary endpoints were ctDNA test sensitivity, progression-free survival (PFS), duration of response (DoR), and safety.

Results: Eighty patients with acquired resistance to prior EGFR-TKI therapies were screened. ctDNA of 21 patients showed T790M positivity, and 19 patients were enrolled. In the responseevaluable population (n=15), ORR was 66.7% (10/15). Median PFS was 8.3 months (95% confidence interval [CI], 7.9 to 8.7) and median DoR was 6.8 months (95% CI, 5.3 to 8.3) in the intent-to-treat population (n=19). No subject experienced drug-related adverse event of grades ≥ 3 or required dose reduction. The sensitivity of the ctDNA tests was 56.8% using both methods and 45.9% with either method from the estimated T790M-positive cases.

Conclusion: Osimertinib has favorable efficacy in patients with NSCLC harboring T790M, detected from ctDNA with unknown tumor mutation status, in whom disease had progressed during prior EGFR-TKI therapy.

Keywords: Circulating tumor DNA; Non-small cell lung carcinoma; Osimertinib; T790M.

Fig. 1.

Study subjects screened and enrolled, diagnostic study assignments, and exclusions. NSCLC, non-small cell lung cancer; EGFR-TKIs, epidermal growth factor receptor–tyrosine kinase inhibitors; ctDNA, circulating tumor DNA; RE, response evaluable; NE, not evaluable. ^a)Must have experienced clinical benefit from prior EGFR-TKI, according to the Jackman criteria, followed by systemic objective progression (RECIST) while on continuous treatment with EGFR-TKI, ^b)Performance deterioration (n=1), expire (n=1), ^c)Tumor tissue (n=35), pleural fluid cytology (n=5), cerebrospinal fluid cytology (n=2), and fine needle aspiration cytology (n=1), ^d)Response not evaluable: poor adherence to treatment due to sepsis (n=1) and rapid deterioration leading to death (n=3), ^e)Negative (n=28), invalid or not requested for analysis (n=3).

Fig. 2.

Response to osimertinib. Waterfall plot (A) and spider plot (B) according to Response Evaluation Criteria in Solid Tumors in the response evaluable population (n=15). CR, complete response; PR, partial response; SD, stable disease.