Osimertinib in poor performance status patients with T790M-positive advanced non-small-cell lung cancer after progression of first- and second-generation EGFR-TKI treatments (NEJ032B)

Abstract

Background: Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown.

Methods: Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2-4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety.

Results: Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3-5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations.

Conclusion: Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.

Keywords: EGFR T790M; Non-small-cell lung cancer; Osimertinib; Phase II; Poor performance status.

Fig. 1

Waterfall plot of the best percentage change in target lesion size. CR complete response, NE non-evaluable, PD progressive disease, PR partial response, SD stable disease

Fig. 2

Kaplan–Meier curves for progression-free survival (PFS) and overall survival (OS). a PFS, median observation period: 4.8 months, events occurred in 25/33 patients. b OS, median observation period: 10.0 months, events occurred in 24/33 patients. CI, confidence interval

Fig. 3

Change in the performance status of each patient during treatment. Each line shows the change in performance status (PS) of a patient from baseline to their best status during the treatment (lowest observed PS from the day of the first dose to the day treatment was stopped). A clinically significant improvement was observed in 54.5% (95% CI 36.4–71.9) of patients. ECOG PS, Eastern Cooperative Oncology Group performance status

Fig. 4

EGFR mutation status at different time points of osimertinib treatment. This figure depicts the percentage of each mutation at each time point of osimertinib treatment (P0, P1, and P2). The horizontal axis shows the number of patients. P0: plasma samples before the start of the study treatment, P1: plasma samples 8 weeks after the start of the study treatment, P2: plasma samples after disease progression

Fig. 5

Swimmer plot of progression-free survival (PFS) between patients with clearance and non-clearance of the activating EGFR mutations. Each histogram shows PFS. Gray histograms show the PFS of patients who experienced plasma clearance of activating mutations. Orange histograms show the PFS of patients with sustained plasma-activating mutations. P0: plasma samples before the start of the study treatment, P1: plasma samples 8 weeks after the start of the study treatment. (+): positive for plasma EGFR mutations, (−): negative for plasma EGFR mutations