EGFR mutation analysis for prospective patient selection in AURA3 phase III trial of osimertinib versus platinum-pemetrexed in patients with EGFR T790M-positive advanced non-small-cell lung cancer.

In AURA3 (NCT02151981), osimertinib treatment provided significant clinical benefit compared with platinum-pemetrexed in patients with epidermal growth factor receptor (EGFR) T790M-positive advanced non-small-cell lung cancer (NSCLC), whose tumors had progressed on previous EGFR-tyrosine kinase inhibitor therapy. This retrospective analysis investigated detection rates for T790M, common (exon 19 deletion and L858R), and rare EGFR mutations in tissue samples from the screened population of AURA3. In AURA3, eligible patients were randomized 2:1 to receive oral osimertinib 80 mg once daily or intravenous platinum-pemetrexed every 3 weeks for up to six cycles. Tumor tissue samples were centrally tested for EGFR mutations using the cobas® EGFR Mutation Test (Version 2). T790M-positive status was a key inclusion criteria. A total of 820 screened patients had a valid EGFR mutation test result, of whom 452 (55%) were T790M-positive. Detection rates were similar by ethnicity (Asian versus non-Asian) for T790M (53% versus 58%) and exon 19 deletions (56% versus 63%). Conversely, the L858R rate was higher among Asian patients versus non-Asian patients (39% versus 28%; p = 0.0017). In the overall population, a higher proportion of patients had T790M detected against a background of exon 19 deletion versus L858R mutations (64% versus 47%; p < 0.0001). Rare EGFR mutations were detected in 28 (3%) patients, including G719X (2%), exon 20 insertion (1%), and S768I (<1%). Among AURA3 screened patients with EGFR mutation-positive advanced NSCLC, approximately half had detectable T790M in their tumor tissue, a rate unaffected by ethnicity. Results are consistent with previous reports of T790M detection rate in this patient population.

John T ，Akamatsu H ，Delmonte A ，Su WC ，Lee JS ，Chang GC ，Huang X ，Jenkins S ，Wu YL ... -  《-》

Epidermal growth factor receptor mutation analysis in tissue and plasma from the AURA3 trial: Osimertinib versus platinum-pemetrexed for T790M mutation-positive advanced non-small cell lung cancer.

This study assesses different technologies for detecting epidermal growth factor receptor (EGFR) mutations from circulating tumor DNA in patients with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) from the AURA3 study (NCT02151981), and it evaluates clinical responses to osimertinib and platinum-pemetrexed according to the plasma T790M status. Tumor tissue biopsy samples were tested for T790M during screening with the cobas EGFR Mutation Test (cobas tissue). Plasma samples were collected at screening and at the baseline and were retrospectively analyzed for EGFR mutations with the cobas EGFR Mutation Test v2 (cobas plasma), droplet digital polymerase chain reaction (ddPCR; Biodesix), and next-generation sequencing (NGS; Guardant360, Guardant Health). With cobas tissue test results as a reference, the plasma T790M positive percent agreement (PPA) was 51% (110 of 215 samples) by cobas plasma, 58% (110 of 189) by ddPCR, and 66% (136 of 207) by NGS. Plasma T790M detection was associated with a larger median baseline tumor size (56 mm for T790M-positive vs 39 mm for T790M-negative; P < .0001) and the presence of extrathoracic disease (58% for M1b-positive vs 39% for M0-1a-positive; P = .002). Progression-free survival (PFS) was prolonged in randomized patients (tissue T790M-positive) with a T790M-negative cobas plasma result in comparison with those with a T790M-positive plasma result in both osimertinib (median, 12.5 vs 8.3 months) and platinum-pemetrexed groups (median, 5.6 vs 4.2 months). PPA was similar between ddPCR and NGS assays; both were more sensitive than cobas plasma. All 3 test platforms are suitable for routine clinical practice. In patients with tissue T790M-positive NSCLC, an absence of detectable plasma T790M at the baseline is associated with longer PFS, which may be attributed to a lower disease burden.

Papadimitrakopoulou VA ，Han JY ，Ahn MJ ，Ramalingam SS ，Delmonte A ，Hsia TC ，Laskin J ，Kim SW ，He Y ，Tsai CM ，Hida T ，Maemondo M ，Kato T ，Jenkins S ，Patel S ，Huang X ，Laus G ，Markovets A ，Thress KS ，Wu YL ，Mok T ... -  《-》

Osimertinib in Japanese patients with EGFR T790M mutation-positive advanced non-small-cell lung cancer: AURA3 trial.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the first-line treatment for patients with EGFR mutant non-small-cell lung cancer (NSCLC). However, most patients become resistant to these drugs, so their disease progresses. Osimertinib, a third-generation EGFR-TKI that can inhibit the kinase even when the common resistance-conferring Thr790Met (T790M) mutation is present, is a promising therapeutic option for patients whose disease has progressed after first-line EGFR-TKI treatment. AURA3 was a randomized (2:1), open-label, phase III study comparing the efficacy of osimertinib (80 mg/d) with platinum-based therapy plus pemetrexed (500 mg/m2 ) in 419 patients with advanced NSCLC with the EGFR T790M mutation in whom disease had progressed after first-line EGFR-TKI treatment. This subanalysis evaluated the safety and efficacy of osimertinib specifically in 63 Japanese patients enrolled in AURA3. The primary end-point was progression-free survival (PFS) based on investigator assessment. Improvement in PFS was clinically meaningful in the osimertinib group (n = 41) vs the platinum-pemetrexed group (n = 22; hazard ratio 0.27; 95% confidence interval, 0.13-0.56). The median PFS was 12.5 and 4.3 months in the osimertinib and platinum-pemetrexed groups, respectively. Grade ≥3 adverse events determined to be related to treatment occurred in 5 patients (12.2%) treated with osimertinib and 12 patients (54.5%) treated with platinum-pemetrexed. The safety and efficacy results in this subanalysis are consistent with the results of the overall AURA3 study, and support the use of osimertinib in Japanese patients with EGFR T790M mutation-positive NSCLC whose disease has progressed following first-line EGFR-TKI treatment. (ClinicalTrials.gov trial registration no. NCT02151981.).

Akamatsu H ，Katakami N ，Okamoto I ，Kato T ，Kim YH ，Imamura F ，Shinkai M ，Hodge RA ，Uchida H ，Hida T ... -  《-》

Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis.

In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis. Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points. A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm. In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib. ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981.

Papadimitrakopoulou VA ，Mok TS ，Han JY ，Ahn MJ ，Delmonte A ，Ramalingam SS ，Kim SW ，Shepherd FA ，Laskin J ，He Y ，Akamatsu H ，Theelen WSME ，Su WC ，John T ，Sebastian M ，Mann H ，Miranda M ，Laus G ，Rukazenkov Y ，Wu YL ... -  《-》

Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer.

Mok TS ，Wu Y-L ，Ahn M-J ，Garassino MC ，Kim HR ，Ramalingam SS ，Shepherd FA ，He Y ，Akamatsu H ，Theelen WS ，Lee CK ，Sebastian M ，Templeton A ，Mann H ，Marotti M ，Ghiorghiu S ，Papadimitrakopoulou VA ，AURA3 Investigators ... -  《-》