TAGRISSO (Page 5 of 8)

14 CLINICAL STUDIES

14.1 Adjuvant Treatment of Early-Stage EGFR Mutation-Positive Non-Small Cell Lung Cancer (NSCLC)

The efficacy of TAGRISSO was demonstrated in a randomized, double-blind, placebo-controlled trial (ADAURA [NCT02511106]) for the adjuvant treatment of patients with EGFR exon 19 deletions or exon 21 L858R mutation-positive NSCLC who had complete tumor resection, with or without prior adjuvant chemotherapy. Eligible patients with resectable tumors (stage IB – IIIA according to American Joint Commission on Cancer [AJCC] 7th edition) were required to have predominantly non-squamous histology and EGFR exon 19 deletions or exon 21 L858R mutations identified prospectively from tumor tissue in a central laboratory by the cobas® EGFR Mutation Test. Patients with clinically significant uncontrolled cardiac disease, prior history of ILD/pneumonitis, or who received treatment with any EGFR kinase inhibitor were not eligible for the study.

Patients were randomized (1:1) to receive TAGRISSO 80 mg orally once daily or placebo following recovery from surgery and standard adjuvant chemotherapy if given. Patients who did not receive adjuvant chemotherapy were randomized within 10 weeks and patients who received adjuvant chemotherapy were randomized within 26 weeks following surgery. Randomization was stratified by mutation type (exon 19 deletions or exon 21 L858R mutations), race (Asian or non-Asian) and pTNM staging (IB or II or IIIA) according to AJCC 7th edition. Treatment was given for 3 years or until disease recurrence, or unacceptable toxicity.

The major efficacy outcome measure was disease-free survival (DFS, defined as reduction in the risk of disease recurrence or death) in patients with stage II – IIIA NSCLC determined by investigator assessment. Additional efficacy outcome measures included DFS in the overall population (patients with stage IB – IIIA NSCLC), and overall survival (OS) in patients with stage II – IIIA NSCLC and in the overall population.

A total of 682 patients were randomized to TAGRISSO (n=339) or placebo (n=343). The median age was 63 years (range 30-86 years); 70% were female; 64% were Asian and 72% were never smokers. Baseline WHO performance status was 0 (64%) or 1 (36%); 31% had stage IB, 35% II, and 34% IIIA. With regard to EGFR mutation status, 55% were exon 19 deletions and 45% were exon 21 L858R mutations. The majority (60%) of patients received adjuvant chemotherapy prior to randomization (27% IB; 70% II, 79% IIIA).

ADAURA demonstrated a statistically significant and clinically meaningful difference in DFS for patients treated with TAGRISSO compared to patients treated with placebo. Overall survival (OS) data were not mature at the time of the DFS analysis with 27% of the 94 deaths required for the final analysis of OS in patients with stage II-IIIA disease. Efficacy results from ADAURA are summarized in Table 8 and Figure 1, respectively.

Table 8. Efficacy Results in ADAURA according to Investigator Assessment
*
Stratified by race (Asian vs non-Asian), mutation status (Ex19del vs L858R), and pTNM staging
Pike estimator
Stratified log-rank test

STAGE II-IIIA POPULATION

STAGE IB-IIIA POPULATION

Efficacy Parameter

TAGRISSO(N=233)

PLACEBO(N=237)

TAGRISSO(N=339)

PLACEBO(N=343)

DFS events (%)

26 (11)

130 (55)

37 (11)

159 (46)

Recurrent disease (%)

26 (11)

129 (54)

37 (11)

157 (46)

Deaths (%)

0

1 (0.4)

0

2 (0.6)

Median DFS, months (95% CI)

NR (38.8, NE)

19.6 (16.6, 24.5)

NR (NE, NE)

27.5 (22.0, 35.0)

Hazard ratio (95% CI)*

0.17 (0.12, 0.23)

0.20 (0.15, 0.27)

p-value *

<0.0001

<0.0001

DFS results based on investigator assessment

CI=Confidence Interval; NE=Not Estimable; NR=Not Reached

Figure 1. Kaplan-Meier curve of disease-free survival (overall population) by Investigator Assessment in ADAURA

Figure 1
(click image for full-size original)

In an exploratory analysis of site(s) of relapse, the proportion of patients with CNS involvement at the time of disease recurrence was 5 patients (1.5%) on the TAGRISSO arm and 34 patients (10%) on the placebo arm.

14.2 Previously Untreated EGFR Mutation-Positive Metastatic NSCLC

The efficacy of TAGRISSO was demonstrated in a randomized, multicenter, double-blind, active-controlled trial (FLAURA [NCT02296125]) in patients with EGFR exon 19 deletions or exon 21 L858R mutation-positive, metastatic NSCLC, who had not received previous systemic treatment for metastatic disease. Patients were required to have measurable disease per RECIST v1.1, a WHO performance status of 0-1, and EGFR exon 19 deletions or exon 21 L858R mutation in tumor prospectively identified by the cobas® EGFR Mutation Test in a central laboratory or by an investigational assay at a CLIA-certified or accredited laboratory. Patients with CNS metastases not requiring steroids and with stable neurologic status for at least two weeks after completion of definitive surgery or radiotherapy were eligible. Patients were assessed at the investigator’s discretion for CNS metastases if they had a history of, or suspected, CNS metastases at study entry.

Patients were randomized (1:1) to receive TAGRISSO 80 mg orally once daily or to receive gefitinib 250 mg orally once daily or erlotinib 150 mg orally once daily until disease progression or unacceptable toxicity. Randomization was stratified by EGFR mutation type (exon 19 deletions or exon 21 L858R mutation) and ethnicity (Asian or non-Asian). Patients randomized to the control arm were offered TAGRISSO at the time of disease progression if tumor samples tested positive for the EGFR T790M mutation. The major efficacy outcome measure was progression-free survival (PFS), as assessed by investigator. Additional efficacy outcome measures included overall survival (OS) and overall response rate (ORR).

A total of 556 patients were randomized to TAGRISSO (n=279) or to control (gefitinib n=183; erlotinib n=94). The median age was 64 years (range 26-93 years); 54% were <65 years of age; 63% were female; 62% were Asian and 64% were never smokers. Baseline WHO performance status was 0 (41%) or 1 (59%); 5% had Stage IIIb and 95% had Stage IV; and 7% received prior systemic cytotoxic chemotherapy as neoadjuvant or adjuvant therapy. With regard to EGFR tumor testing, 63% were exon 19 deletions and 37% were exon 21 L858R; 5 patients (<1%) also had a concomitant de novo T790M mutation. EGFR mutation status was confirmed centrally using the cobas® EGFR Mutation Test in 90% of patients. At the time of the final data cut-off, of those randomized to TAGRISSO and to investigator’s choice erlotinib or gefitinib arm, 133 (48%) and 180 (65%) patients had received at least one subsequent treatment, respectively. Out of the 180 patients randomized to erlotinib or gefitinib who received subsequent treatment, 85 (47%) patients received TAGRISSO as first subsequent therapy.

FLAURA demonstrated a statistically significant improvement in PFS for patients randomized to TAGRISSO as compared to erlotinib or gefitinib (see Table 9 and Figure 2). The final analysis of overall survival demonstrated a statistically significant improvement in overall survival in patients randomized to TAGRISSO compared to erlotinib or gefitinib. (see Table 9 and Figure 3).

Table 9. Efficacy Results in FLAURA according to Investigator Assessment
Efficacy Parameter TAGRISSO (N=279) EGFR TKI (gefitinib or erlotinib) (N=277)
*
Without documented radiological disease progression
Stratified by ethnicity (Asian vs non-Asian) and mutation status (Ex19del vs L858R)
Pike estimator
§
Stratified log-rank test
Confirmed responses

Progression-Free Survival (PFS)

PFS events (%)

136 (49)

206 (74)

Progressive disease (%)

125 (45)

192 (69)

Death * (%)

11 (4)

14 (5)

Median PFS in months (95% CI)

18.9 (15.2, 21.4)

10.2 (9.6, 11.1)

Hazard Ratio (95% CI)

0.46 (0.37, 0.57)

p-value §

<0.0001

Overall Survival (OS)

Number of deaths (%)

155 (56)

166 (60)

Median OS in months (95% CI)

38.6 (34.5, 41.8)

31.8 (26.6, 36.0)

Hazard Ratio (95% CI)

0.80 (0.64, 1.00)

p-value §

0.0462

Overall Response Rate (ORR)

ORR, % (95% CI)

77 (71, 82)

69 (63, 74)

Complete response, %

2

1

Partial response, %

75

68

Duration of Response (DoR)

Median in months (95% CI)

17.6 (13.8, 22.0)

9.6 (8.3, 11.1)

Figure 2. Kaplan-Meier Curves of PFS by Investigator Assessment in FLAURA

Figure 2
(click image for full-size original)

In a supportive analysis of PFS according to blinded independent central review, median PFS was 17.7 months in the TAGRISSO arm compared to 9.7 months in the EGFR TKI comparator arm (HR=0.45; 95% CI: 0.36, 0.57).

Figure 3. Kaplan-Meier Curves of Overall Survival in FLAURA

Figure__3
(click image for full-size original)

Of 556 patients, 200 patients (36%) had baseline brain scans reviewed by BICR; this included 106 patients in the TAGRISSO arm and 94 patients in the investigator choice of EGFR TKI arm. Of these 200 patients, 41 had measurable CNS lesions per RECIST v1.1. Results of pre-specified exploratory analyses of CNS ORR and DoR by BICR in the subset of patients with measurable CNS lesions at baseline are summarized in Table 10.

Table 10. CNS ORR and DOR by BICR in Patients with Measurable CNS Lesions at Baseline in FLAURA
*
According to RECIST v1.1.
Based on confirmed response.
Based on patients with response only; DoR defined as the time from the date of first documented response (complete response or partial response) until progression or death event.

TAGRISSO

N=22

EGFR TKI

(gefitinib or erlotinib)

N=19

CNS Tumor Response Assessment *

CNS ORR, % (95% CI)

77 (55, 92)

63 (38, 84)

Complete response, %

18

0

Duration of CNS Response

Number of responders

17

12

Response Duration ≥6 months, %

88

50

Response Duration ≥12 months, %

47

33

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