Osimertinib (1) – Tagrisso®

• Clinical trials
  • AURAex is the Phase II extension arm of the open-label, single-arm, multicentre Phase I registration trial AURA of osimertinib and commenced in February 2013.
  • AURA2, which began in April 2014, is also an open-label, single-arm, multicentre Phase II trial that enrolled 210 patients with locally advanced or metastatic EGFR T790M-positive NSCLC who had experienced disease progression following treatment with an EGFR-TKI.
  • IMPRESS is a randomised, double-blind, placebo-controlled, multicentre Phase III-trial in which treatment with gefitinib in combination with platinum-based chemotherapy comprising pemetrexed and cisplatin was compared with pemetrexed and cisplatin chemotherapy alone (chemotherapy arm).
  • LUX-Lung 1 was a randomised, double-blind, placebo-controlled, multicentre Phase IIb/III-trial, which ran from April 2008 to October 2013 and enrolled 585 adult patients with locally advanced or metastatic NSCLC who had previously received one or two courses of chemotherapy and had experienced disease progression following at least 12-week course of EGFR TKI treatment, and who were treated with afatinib or placebo, both in addition to best supportive care (BSC).

a) Patients following prior treatment with an EGFR tyrosine kinase inhibitor – for patients for whom cytotoxic chemotherapy is considered appropriate at the clinician’s discretion

• For patients who have previously been treated with an EGFR tyrosine kinase inhibitor, an additional benefit over the appropriate comparator therapy is not proven.
• Side effects – severe adverse events (CTCAE grade ≥ 3)
  • Only in the time-to-event analyses of severe AEs (SAEs) with a Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 (both overall and for individual specific AEs) did statistically significant results emerge (e.g. overall rate of severe AEs for the second-line comparison in the AURA vs. IMPRESS studies: HR 0.26 [0.13; 0.53]; p < 0.001); however, this difference alone may also be due to systematic bias.
  • The study reports and protocols for the AURA studies differed in terms of the methodology used to record adverse events.
  • In particular, the AURA study reports recorded changes in laboratory values for neutrophil counts that occurred with a CTCAE severity grade of 3 or higher, although the total number of CTCAE Grade 3 events associated with the neutrophil count is not reflected in the overall rate of adverse events.
  • In contrast, in the IMPRESS study, all adverse events with a CTCAE grade of 3 or higher were included in the overall adverse event rate.

b) Patients following prior treatment with an EGFR tyrosine kinase inhibitor – for patients for whom cytotoxic chemotherapy is not an option

• For patients following prior treatment with an EGFR tyrosine kinase inhibitor for whom cytotoxic chemotherapy is not an option, an additional benefit over the appropriate comparator therapy is not proven.
• No data were presented for patients with a T790M mutation following prior treatment with an EGFR-TKI, for whom cytotoxic chemotherapy is not an option.

2) Previously untreated patients with a de novo T790M mutation

• For untreated patients with a de novo T790M mutation, additional benefit over the appropriate comparator therapy is not proven.
• The pharmaceutical manufacturer describes the data from four patients with a de novo T790M mutation from the dose-escalation phase of the Phase I AURA trial, without, however, carrying out a comparison with the appropriate comparator therapy; moreover, only two of these four patients are treatment-naïve and thus meet the criteria for the present sub-indication.

3) Patients following prior treatment with platinum-based chemotherapy and a de novo positive T790M mutation

• For patients who have previously received platinum-based chemotherapy and have a de novo T790M mutation, an additional benefit over the appropriate comparator therapy is not proven.
• The pharmaceutical manufacturer describes the data from four patients with a de novo T790M mutation from the dose-escalation phase of the Phase I AURA trial, without, however, carrying out a comparison with the appropriate comparator therapy; only two of these four patients had previously been treated with platinum-based chemotherapy and therefore meet the criteria for this specific indication.

Courtesy translation only, please refer to the German original.