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S. Ghiorghiu
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MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 3
- Moderators:G.J. Riely, M.C. Garassino
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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MINI16.06 - AZD9291 in Pre-Treated T790M Positive Advanced NSCLC: AURA Study Phase II Extension Cohort (ID 943)
16:45 - 18:15 | Author(s): S. Ghiorghiu
- Abstract
- Presentation
Background:
AZD9291 is an oral, potent, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selective for both EGFR-TKI-sensitizing (EGFRm) and T790M resistance mutations. The Phase I AURA study was a dose escalation/expansion study in patients with EGFRm positive advanced non-small cell lung cancer (NSCLC) who had progressed after EGFR‑TKI treatment. The 80 mg once daily (qd) dose was chosen for further evaluation in a Phase II extension cohort of the AURA study, and in an additional Phase II study (AURA2). Here we report efficacy and safety of AZD9291 from the AURA study Phase II extension cohort (NCT01802632) in patients pre-treated with EGFR-TKI and with centrally confirmed T790M positive advanced NSCLC.
Methods:
Eligible patients had measurable disease, World Health Organization performance status (WHO PS) 0 or 1, and acceptable organ function; stable brain metastases were allowed. A mandatory tumor sample was taken after disease progression on the most recent line of therapy, for prospective confirmation of T790M positive status by central laboratory testing (cobas™ EGFR Mutation Test). Patients received AZD9291 at 80 mg qd until disease progression. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 (assessed by independent central review, ICR). Secondary objectives included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), investigator-assessed ORR, and safety. Planned enrollment was 175 patients to give an estimate of the ORR with 95% CI within ±8%. Data cut-off was January 9, 2015 after all patients should have undergone the second tumor assessment.
Results:
201 patients were dosed in the extension cohort of the study; two patients without measurable disease at baseline by ICR were excluded from the evaluable-for-response set. By central testing, EGFR mutation subtypes were: T790M, 98%; Ex19del, 71%; L858R, 25%; other, 3%. Median age was 62 years; female, 66%; Asian, 57%; WHO PS 0/1/2, 34%/66%/1%; second/≥third-line, 30%/70%. At the data cut-off, median treatment exposure was 4.9 months and 168 patients remain on treatment. ORR by ICR was 58% (115/199; 95% CI 51, 65) and DCR was 92% (95% CI 87, 95). ORRs were similar across lines of therapy (second-line, 59.0% [36/61] vs ≥third-line, 57.2% [79/138]). Investigator-assessed ORR was 68% (137/201; 95% CI 61, 75). Median DoR and median PFS have not been reached (maturity 2% and 21%, respectively). The most common all-causality adverse events (AEs) were diarrhea, 41% (0.5% Gr≥3) and grouped rash terms 37% (0.5% Gr≥3); 42 (21%) patients experienced Gr≥3 AEs. Interstitial lung disease grouped terms were reported in five (2.5%) patients, one of which was fatal (0.5%) and considered possibly causally related to AZD9291 by the investigator. Eight patients (4%) discontinued treatment due to an AE. Updated results from a later data cut-off will be available for presentation.
Conclusion:
In the AURA study Phase II extension cohort, AZD9291 80 mg qd demonstrates clinical activity, manageable tolerability, and a low discontinuation rate in patients with centrally confirmed EGFR T790M positive advanced NSCLC that has progressed on or after EGFR‑TKI treatment. These data provide further validation of the results from the Phase I study cohorts.
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MINI16.07 - AZD9291 in Treatment-Naïve EGFRm Advanced NSCLC: AURA First-Line Cohort (ID 1232)
16:45 - 18:15 | Author(s): S. Ghiorghiu
- Abstract
- Presentation
Background:
AZD9291 is an oral, potent, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) selective for both EGFR-sensitizing (EGFRm) and T790M resistance mutations. It has shown anticancer activity and manageable tolerability in patients with EGFRm advanced NSCLC that had progressed after EGFR‑TKI treatment.
Methods:
In this first-line expansion cohort (AURA, NCT01802632), patients received AZD9291 at 80 or 160 mg/day, in sequential dose groups. EGFRm status was determined locally and/or by central testing using the cobas EGFR Mutation Test. Other inclusion criteria included measurable disease, World Health Organization performance status (WHO PS) 0 or 1, and acceptable organ function; stable brain metastases were allowed. Safety, tolerability, and anticancer activity were assessed in these cohorts, to evaluate AZD9291 in the first-line treatment setting. The data cut-off was December 2, 2014.
Results:
Sixty treatment-naïve patients were enrolled; 30 patients in each dose group (80 or 160 mg/day). By central testing, EGFR mutation subtypes were: L858R 40%; exon 19 deletion, 37%; other EGFR-sensitizing mutations, 3%; and T790M, 8%. Baseline median age was 63.5 years; 25% of patients were male; 57%/43% had WHO PS 0/1, respectively; 72% were Asian and 23% Caucasian. Median treatment exposure at the 80 and 160 mg dose levels was 260 and 171 days, respectively. Fifty-two out of 60 patients remained on treatment at the data cut-off. Anticancer activity of AZD9291 is shown in Table 1. One-third (33%) of patients experienced Grade ≥3 adverse events; two patients had Grade 3 diarrhea and one patient had Grade 3 skin rash. New data from a 2015 data cut of the AURA first-line expansion will be available for presentation.Table 1. Anticancer activity findings in AURA first-line expansion
Endpoint Finding Objective response rate: Overall 70% (95% CI 57, 81) AZD9291 80 mg/160 mg 60%/80% Disease control rate: Overall 97% (95% CI 89, 100) AZD9291 80 mg/160 mg 93%/100% Progression-free survival: Median Not yet reached 3-month/6-month 93%/87% Events to date 7/60 (12% mature)
Conclusion:
AZD9291 has a manageable tolerability profile and is associated with promising anticancer activity in treatment-naïve patients with EGFRm advanced NSCLC. A Phase III study (FLAURA, NCT02296125) has been initiated to assess the efficacy and safety of AZD9291 in comparison with a standard-of-care EGFR-TKI (gefitinib or erlotinib) in the first-line setting.
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MINI16.08 - AZD9291 in Pre-Treated T790M Positive Advanced NSCLC: AURA2 Phase II Study (ID 1406)
16:45 - 18:15 | Author(s): S. Ghiorghiu
- Abstract
- Presentation
Background:
The epidermal growth factor receptor (EGFR) T790M mutation is found in about half of patients who have developed resistance to EGFR-tyrosine kinase inhibitors (TKIs), gefitinib or erlotinib. AZD9291 is an oral, potent, irreversible EGFR-TKI selective for both EGFR-sensitizing (EGFRm) and T790M resistance mutations. In the Phase I AURA study, AZD9291 80 mg (dose selected for further evaluation) was found to be clinically active, with an acceptable tolerability profile. This ongoing AURA2 Phase II study (NCT02094261) investigates the efficacy and safety of AZD9291 80 mg once daily after previous EGFR-TKI treatment in patients with EGFRm and T790M positive advanced NSCLC.
Methods:
AURA2 (NCT02094261) is a global, open-label, single-arm Phase II study. To be eligible, all patients had a mandatory tumor sample taken after disease progression on the most recent line of therapy, for confirmation of T790M positive status by central laboratory testing using the cobas™ EGFR Mutation Test. Further inclusion criteria included measurable disease, World Health Organization performance status (WHO PS) 0 or 1, and acceptable organ function; stable brain metastases were allowed. Patients receive AZD9291 at 80 mg once daily until disease progression. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 (assessed by independent central review, ICR). Secondary objectives included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and safety. Planned enrollment was 175 patients to give an ORR with 95% confidence interval (CI) within ±8%. The data cut-off was January 9, 2015.
Results:
Recruitment is complete and 210 patients were enrolled; 12 patients did not have measurable disease at baseline by ICR and are excluded from the evaluable-for-response set. By central testing, in addition to T790M, patients had background EGFR mutation: Ex19del, 65%; L858R, 32%; other, 3%. Baseline characteristics: median age, 64 years; female, 70%; WHO PS 0/1, 40%/60%; Asian, 63%; second-/≥third-line, 32%/68%. Median treatment exposure was 4.0 months and 183 patients remain on treatment at the data cut-off. ORR by ICR was 64% (127/198; 95% CI 57, 71) and DCR was 90% (95% CI 85, 94). Investigator-assessed ORR was 64% (135/210; 95% CI 57, 71). Median DoR and median PFS have not been reached (maturity 6% and 20%, respectively). The estimated proportion of patients who are alive and progression free is 82% and 70% at 3 and 6 months, respectively. The most common all-causality adverse events (AEs) were diarrhea, 34% (1% Gr≥3) and grouped rash terms 40% (0.5% Gr≥3); 38 (18%) patients experienced Gr≥3 AEs. Interstitial lung disease grouped terms were reported in four (1.9%) patients, one of which was fatal (0.5%) and considered possibly causally related to AZD9291 by the investigator. Eight patients (4%) discontinued treatment due to an AE. Updated results from a later data cut-off will be available for presentation.
Conclusion:
AZD9291 80 mg once daily demonstrates clinical activity and manageable tolerability in patients with EGFRm, T790M mutation positive advanced NSCLC that has progressed on or after EGFR‑TKI treatment. AZD9291 is being investigated in the randomized AURA3 Phase III study (NCT02151981) in comparison with platinum-based doublet chemotherapy.
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