by ecancer reporter Janet Fricker

Osimertinib (Tagrisso™) showed significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small cell lung (NSCL) cancers, found the AURA3 study published in The England Journal of Medicine.

Among advanced NSCL patients with a mutant epidermal growth factor receptor (EGFR), EGFR tyrosine kinas inhibitors (TKIs) are standard first line therapy.

Despite high tumour response rates, however, in the majority of cases the disease progresses after nine to 13 months.

At time of progression, 60% of patients are found to have a p.Thr790Met point mutation (T790M) in the gene encoding EGFR, with the mutation reducing EGFR-TKI binding to the ATP binding pocket of EGFR.

Osimertinib is an oral, irreversible EGFR-TKI that is selective for both EGFR and T790M resistance mutations with activity in the central nervous system (CNS).

Between August 2014 and September 2015, 103 patients with locally advanced or metastatic NSCL cancer and disease progression after first line EGFR-TKI therapy were screened for both EGFR mutations and T790M variants.

For the phase 3 study, 419 eligible patients were identified and randomly assigned 2:1 to oral osimertinib (80 mg once daily) (n=279) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve 5) or cisplatin (75mg per square metre) every three weeks for up to six cycles (n=140).

Study participants were stratified according to Asian or non-Asian race.

Results show that median duration of progression-free survival was 10.1 months for osimertinib versus 4.4 months for pemetrexed-platinum therapy (HR 0.30; 95% CI 0.23 to 0.41; P<0.001).

Furthermore, the objective response rate was 71% for osimertinib versus 31% for pemetrexed- platinum therapy (OR 5.39; 95% CI 3.47 to 8.48; P<0.0001).

Among 144 patients with CNS metastases, the median duration of progression-free survival was 8.5 months for osimertinib versus 4.2 months for pemetrexed-platinum therapy (HR 0.32; 95% CI, 0.21 to 0.49).

Progression free survival benefits for osimertinib were observed across all pre-defined subgroups including race, sex, age, CNS metastases and smoking history.

Overall, adverse events tended to be more severe in the-pemetrexed-platinum group, despite longer osimertinib treatment durations.

“In conclusion, osimertinib was more effective than combination platinum-based chemotherapy in patients with T790M-positive non-small-cell lung cancer, including those with CNS metastases after disease progression with first-line EGFR-TKI therapy,” write the authors, led by Tony Mok, from the Chinese University of Hong Kong.

“The findings of AURA3 support the feasibility of detecting EGFRT790M from plasma ctDNA samples,” write the authors.

Due to high false negative rates with plasma ctDNA T790M testing analysis, they add, biopsy samples are recommended for patients with a plasma T790-M-negative result who have disease progression after first-line EGFR-TKI.

Reference
Mok T, Wu Y, Ahn M, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. Doi: 10.1056/NEJMoa1612674