Osimertinib in patients with T790M mutation‐positive, advanced non–small cell lung cancer: Long‐term follow‐up from a pooled analysis of 2 phase 2 studies

Abstract

BACKGROUND:Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is selective for both EGFR-TKI-sensitizing and T790M (threonine-to-methionine substitution at codon 790)-resistance mutations. The authors present long-term follow-up data from a preplanned, pooled analysis of phase 2 studies, the AZD9291 First Time in Patients Ascending Dose Study (AURA) extension trial (clincialtrials.gov identifier NCT01802632) and the AURA2 trial (NCT02094261). METHODS: Patients with centrally confirmed, T790M mutation-positive, advanced non-small cell lung cancer received osimertinib 80 mg once daily until disease progression or study discontinuation. Response was assessed by a blinded, independent, central review using Response Evaluation Criteria in Solid Tumors, version 1.1. The primary endpoint was the objective response rate. RESULTS: In total, 411 patients received osimertinib (second line, 129 patients; third line or later, 282 patients). At the data cutoff date of November 1, 2016, the median treatment exposure was 16.4 months (range, 0-29.7 months), the objective response rate was 66% (95% confidence interval [CI], 61%-70%), the median response duration was 12.3 months (95% CI, 11.1-13.8 months), and the median progression-free survival was 9.9 months (95% CI, 9.5-12.3 months). At the data cutoff date of May 1, 2018, 271 patients (66%) had died, and 140 patients (34%) had discontinued before death. The median overall survival was 26.8 months (95% CI, 24.0-29.1 months); and the 12-month, 24-month, and 36-month survival rates were 80%, 55%, and 37%, respectively. Grade ≥3 possibly causally related (investigator assessed) adverse events were reported in 65 patients (16%), and the most common were rash (grouped terms; 42%; grade ≥3, 1%) and diarrhea (39%; <1%). CONCLUSIONS: This pooled analysis represents the most mature clinical trial data for osimertinib in patients with pretreated, T790M-positive, advanced non-small cell lung cancer, further establishing osimertinib as a standard of care for this patient population. Cancer 2019;125:892-901.

Osimertinib Plus Durvalumab versus Osimertinib Monotherapy in EGFR T790M–Positive NSCLC following Previous EGFR TKI Therapy: CAURAL Brief Report

“…However, we observed no trends suggesting the combination therapy to be superior to osimertinib alone; the response to osimertinib monotherapy was consistent with the existing efficacy profile seen in phase II/III trials of osimertinib in patients with T790Mpositive advanced NSCLC. 8,9 There were no new safety signals for osimertinib in combination with durvalumab or as monotherapy.…”

“…10 The incidence of ILD with osimertinib is in line with that for first-generation EGFR-TKIs, with rates of 2% to 4% in large phase II/III trials. 8,9,11 An unexpectedly high incidence of ILD-like events (in 13 of 34 patients [38%]) was reported in the osimertinib plus durvalumab arm of TATTON. 7 In CAURAL, only one ILD event was reported in 12 patients who received Figure 3.…”

Abivertinib in patients with T790M‐positive advanced NSCLC and its subsequent treatment with osimertinib

“…In two patients who experienced grade 3 ILD and skin rash because of abivertinib, no similar SAEs recurred during osimertinib therapy. The median total treatment duration with abivertinib and osimertinib was as long as 15.9 months, while the median response duration with osimertinib treatment alone was 12.3 months in NSCLC patients with T790M mutations according to a long‐term follow‐up of a pooled analysis of two phase II studies …”

“…The median total treatment duration with abivertinib and osimertinib was as long as 15.9 months, while the median response duration with osimertinib treatment alone was 12.3 months in NSCLC patients with T790M mutations according to a long-term follow-up of a pooled analysis of two phase II studies. 22 To our knowledge, there is no evidence that the sequential use of different first generation TKIs (gefitinib, erlotinib, icotinib) could bring more benefits to patients, because all first-generation TKIs target the same EGFRsensitive mutation. With regard to the effectiveness of osimertinib as a subsequent therapy after abivertinib, despite both being third-generation EGFR TKIs, we supposed that it may be due to the unique structure of abivertinib, which differs from osimertinib.…”

Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer

“…In a larger study of 1,217 patients (ASTRIS, NCT02474355), the investigator-assessed response rate was 64% at 4 months and safety parameters reflected the original study (15). Pooled analysis has demonstrated a median survival of 26.8 months with second-line osimertinib (16). The success of the compound in the second line prompted evaluation in the firstline therapy for EGFR-mutant disease (11).…”