STAGE 1: DATA EXTRACTION — ADAURA TRIAL

Trial Name: ADAURA
Cancer Type: Non-Small Cell Lung Cancer (NSCLC), EGFR mutation-positive
Citation: Wu Y-L, Tsuboi M, et al. N Engl J Med. 2020;383:1711-1723

1. TRIAL DESIGN & METHODS

Design: Phase 3, double-blind, placebo-controlled, randomized, international trial

Sponsor: AstraZeneca

ClinicalTrials.gov: NCT02511106

Randomization: 1:1 ratio

• Stratification factors: Disease stage (IB, II, or IIIA), EGFR mutation type (Ex19del or L858R), Race (Asian or non-Asian)

Treatment Arms:

• Osimertinib: 80 mg orally once daily for 3 years (or until disease recurrence or discontinuation criteria met)

• Placebo: Once daily for 3 years

Study Period: November 2015 to February 2019 (enrollment)

Data Cutoff Date: January 17, 2020 (unplanned interim analysis)

Follow-up: Median 22.1 months (osimertinib), 14.9 months (placebo)

Analysis Triggered: Independent data monitoring committee recommended early unblinding 2 years ahead of planned February 2022 analysis due to efficacy benefit (April 2020 review)

2. ELIGIBILITY CRITERIA

Inclusion:

• Age ≥18 years (≥20 years in Japan and Taiwan)

• WHO performance status 0 or 1

• Primary nonsquamous NSCLC

• Postsurgical pathological stage IB, II, or IIIA (per AJCC 7th edition)

• Centrally confirmed EGFR mutation (Ex19del or L858R, alone or with other EGFR mutations)

• Complete resection of primary NSCLC (mandatory)

• Adjuvant platinum-based chemotherapy allowed but not mandatory (decision made by physician and patient before enrollment)

Exclusion:

• Preoperative, postoperative, or planned radiation therapy not allowed

3. PATIENT CHARACTERISTICS (BASELINE)

Total Enrolled: 682 patients

• Osimertinib: 339 patients

• Placebo: 343 patients

Demographics

Characteristic

Osimertinib (N=339)

Placebo (N=343)

Sex

Male

32%

28%

Female

68%

72%

Age (median)

64 years

62 years

Age range

30–86 years

31–82 years

Smoking History

Yes

32%

25%

No

68%

75%

Former

31%

24%

Never

68%

75%

Current

1%

1%

Pack-years (median)

22

18

Pack-years range

0–360

0–130

Race

Asian

64%

64%

Non-Asian

36%

36%

WHO Performance Status

0

64%

64%

1

36%

36%

Disease Characteristics

Characteristic

Osimertinib (N=339)

Placebo (N=343)

AJCC Stage

IB

32%

32%

II

34%

34%

IIIA

35%

34%

Histologic Type

Adenocarcinoma

96%

97%

Acinar adenocarcinoma

25%

24%

Malignant papillary adenocarcinoma

13%

13%

Malignant adenocarcinoma

54%

55%

Bronchioloalveolar adenocarcinoma

3%

4%

Solid adenocarcinoma with mucus formation

1%

1%

Non-adenocarcinoma

4%

3%

Lung Resection Type

Lobectomy

97%

94%

Other

4%

6%

Sleeve resection

1%

1%

Bilobectomy

2%

2%

Pneumonectomy

1%

3%

Regional Lymph Nodes

N0

41%

42%

N1

29%

28%

N2

31%

30%

EGFR Mutation Type

Ex19del

55%

55%

L858R

45%

45%

p.Thr790Met

1%

1%

Adjuvant Chemotherapy

Yes

60%

60%

No

40%

40%

Note: 76% of patients with stage II–IIIA disease received adjuvant platinum-based chemotherapy; 26% of patients with stage IB disease received adjuvant chemotherapy

4. TREATMENT EXPOSURE & DISCONTINUATION

Treatment Duration:

• Osimertinib: Median 22.5 months (range 0–38)

• Placebo: Median 18.7 months (range 0–36)

Patients Continuing Treatment at Data Cutoff:

• Osimertinib: 205/337 (61%)

• Placebo: 136/343 (40%)

Discontinuations:

• Osimertinib: 92/339 (27%)

• Placebo: 174/343 (51%)

Dose Reductions (Safety Analysis):

• Osimertinib: 49/337 (15%)

• Placebo: 3/343 (1%)

Dose Interruptions:

• Osimertinib: 80/337 (24%)

• Placebo: 37/343 (11%)

Discontinuation Due to Adverse Events:

• Osimertinib: 37/337 (11%)

• Placebo: 10/343 (3%)

Patients on Treatment at Disease Recurrence:

• Osimertinib: 24/37 (65%)

• Placebo: 149/159 (94%)

5. PRIMARY ENDPOINT — DISEASE-FREE SURVIVAL (STAGE II–IIIA)

Population: 470 patients with stage II–IIIA disease

Events:

• Total: 156 events (33% maturity)

• Osimertinib: 26 events (11% maturity)

• Placebo: 130 events (55% maturity)

24-Month DFS Rate:

• Osimertinib: 90% (95% CI: 84–93)

• Placebo: 44% (95% CI: 37–51)

Median DFS:

• Osimertinib: Not reached (95% CI: 38.8–not calculable)

• Placebo: 19.6 months (95% CI: 16.6–24.5)

Hazard Ratio: 0.17 (99.06% CI: 0.11–0.26; P<0.001)

• Risk reduction: 83%

Statistical Significance Threshold: P<0.0094 (two-sided) at this interim analysis

6. SECONDARY ENDPOINTS

A. Disease-Free Survival (Overall Population: Stage IB–IIIA)

Population: 682 patients

Events:

• Total: 196 events (29% maturity)

• Osimertinib: 37/339 (11%)

• Placebo: 159/343 (46%)

24-Month DFS Rate:

• Osimertinib: 89% (95% CI: 85–92)

• Placebo: 52% (95% CI: 46–58)

Median DFS:

• Osimertinib: Not reached (95% CI: not calculable–not calculable)

• Placebo: 27.5 months (95% CI: 22.0–35.0)

Hazard Ratio: 0.20 (99.12% CI: 0.14–0.30; P<0.001)

• Risk reduction: 80%

Statistical Significance Threshold: P<0.0088 (two-sided) at this interim analysis

B. Overall Survival

Status: Immature at data cutoff

Deaths:

• Osimertinib: 9/339

• Placebo: 20/343

• Total: 29 patients

Note: Trial was not powered for overall survival; hierarchical testing planned after DFS; follow-up ongoing

7. SUBGROUP ANALYSES (OVERALL POPULATION)

All subgroups favored osimertinib. Key HR (95% CI):

Subgroup

N

HR (95% CI)

Overall

682

0.20 (0.15–0.27)

Sex

Male

204

0.19 (0.13–0.27)

Female

478

0.19 (0.10–0.33)

Age

<65 years

380

0.18 (0.11–0.28)

≥65 years

302

0.16 (0.09–0.26)

Smoking History

Yes

194

0.22 (0.13–0.36)

No

488

0.10 (0.04–0.22)

Race

Asian

434

0.23 (0.15–0.34)

Non-Asian

248

0.21 (0.13–0.31)

Stage

IB

212

0.39 (0.18–0.76)

II

236

0.17 (0.08–0.31)

IIIA

234

0.12 (0.07–0.20)

EGFR Mutation

Ex19del

378

0.12 (0.07–0.20)

L858R

304

0.31 (0.18–0.49)

Adjuvant Chemotherapy

Yes

410

0.16 (0.10–0.26)

No

272

0.23 (0.13–0.40)

DFS by Stage (24-Month Rates)

Stage IB:

• Osimertinib: 88% (95% CI: 78–94)

• Placebo: 71% (95% CI: 60–80)

• HR: 0.39 (95% CI: 0.18–0.76)

Stage II:

• Osimertinib: 91% (95% CI: 82–95)

• Placebo: 56% (95% CI: 45–65)

• HR: 0.17 (95% CI: 0.08–0.31)

Stage IIIA:

• Osimertinib: 88% (95% CI: 79–94)

• Placebo: 32% (95% CI: 23–41)

• HR: 0.12 (95% CI: 0.07–0.20)

DFS by Adjuvant Chemotherapy Use (24-Month Rates)

Received Adjuvant Chemotherapy:

• Osimertinib: 89% (95% CI: 83–93)

• Placebo: 49% (95% CI: 41–56)

• HR: 0.16 (95% CI: 0.10–0.26)

Did Not Receive Adjuvant Chemotherapy:

• Osimertinib: 89% (95% CI: 81–94)

• Placebo: 58% (95% CI: 49–67)

• HR: 0.23 (95% CI: 0.13–0.40)

8. EXPLORATORY ENDPOINTS — SITES OF RECURRENCE

Recurrence Patterns (Overall Population)

Recurrence Type

Osimertinib (N=339)

Placebo (N=343)

Locoregional-only

23 (7%)

61 (18%)

Distant (with or without locoregional)

14 (4%)

96 (28%)

Death without recurrence

0

2 (1%)

CNS recurrence

4 (1%)

33 (10%)

CNS-related disease or death

6 (2%)

39 (11%)

CNS Disease-Free Survival

24-Month CNS Disease-Free Rate:

• Osimertinib: 98% (95% CI: 95–99)

• Placebo: 85% (95% CI: 80–89)

Median CNS Disease-Free Survival:

• Osimertinib: Not reached (95% CI: 39.0–not calculable)

• Placebo: 48.2 months (95% CI: not calculable–not calculable)

Hazard Ratio: 0.18 (95% CI: 0.10–0.33)

• Risk reduction: 82% for CNS disease recurrence or death

9. SAFETY & TOLERABILITY

Safety Population: 680 patients (osimertinib N=337; placebo N=343)

Any Adverse Events

• Osimertinib: 329/337 (98%)

• Placebo: 306/343 (89%)

Grade ≥3 Adverse Events

• Osimertinib: 68/337 (20%)

• Placebo: 46/343 (13%)

Serious Adverse Events

• Osimertinib: 54/337 (16%)

• Placebo: 42/343 (12%)

Fatal Adverse Events

• Osimertinib: 0

• Placebo: 1 (pulmonary embolism)

Common Adverse Events (Any Grade, ≥10% in Either Arm)

Adverse Event

Osimertinib (N=337)

Placebo (N=343)

Any Grade

Grade 1

Diarrhea

46%

34%

Paronychia

25%

9%

Dry skin

23%

22%

Pruritus

19%

15%

Cough

18%

13%

Stomatitis

18%

10%

Nasopharyngitis

14%

9%

Upper respiratory tract infection

13%

7%

Decreased appetite

13%

9%

Mouth ulceration

12%

9%

Dermatitis acneiform

11%

9%

Interstitial Lung Disease (Grouped Terms)

• Osimertinib: 10/337 (3%) — all mild or moderate severity; all patients recovered

• Placebo: 0

Note: No new safety concerns were noted. ILD events were considered less clinically severe than those observed in advanced disease setting.

10. STATISTICAL CONSIDERATIONS

Original Trial Design:

• Primary analysis planned: February 2022

• Target events: 247 disease recurrence/deaths in stage II–IIIA patients

• Power: 80% to detect HR 0.70 at two-sided alpha 0.05

• Hierarchical testing: DFS (stage II–IIIA) → DFS (overall) → OS

Interim Analysis (Actual):

• Alpha adjustment: Required due to unplanned efficacy reviews

• Alpha for stage II–IIIA DFS: P<0.0094 (two-sided)

• Alpha for overall DFS: P<0.0088 (two-sided)

• Analysis method: Log-rank test stratified by disease stage, mutation type, race; Breslow approach for tied events

11. KEY CONCLUSIONS FROM AUTHORS

1. Adjuvant osimertinib resulted in significantly longer disease-free survival than placebo in patients with stage IB–IIIA EGFR mutation-positive NSCLC

2. 83% risk reduction in disease recurrence or death in stage II–IIIA patients (primary endpoint)

3. 80% risk reduction in overall population

4. Benefit observed consistently across all predefined subgroups including all disease stages and regardless of adjuvant chemotherapy use

5. 82% reduction in CNS disease recurrence or death

6. No new safety concerns; adverse events manageable

7. Overall survival data immature; follow-up ongoing

12. CONTEXT & PRIOR THERAPY

Adjuvant Chemotherapy (Pre-Randomization):

• Platinum-based chemotherapy allowed but not mandatory

• Decision made by physician and patient before trial enrollment

• Balanced across both arms (60% received; 40% did not)

Historical Context:

• Standard adjuvant cisplatin-based chemotherapy provides only 16% decrease in risk of recurrence/death at 5 years

• Recurrence rates remain high after surgery: 45% (stage IB) to 76% (stage III) despite adjuvant chemotherapy

• Previous first-generation EGFR-TKI adjuvant trials (RADIANT, ADJUVANT/CTONG1104, EVAN) showed DFS benefit but did not translate to OS or change clinical practice

• High rate of CNS recurrence with first-generation TKIs (37% in RADIANT)

END OF STAGE 1 DATA EXTRACTION

✅ Trial name identified: ADAURA
✅ All numbers copied exactly as reported
✅ All HRs include confidence intervals
✅ All subgroup analyses extracted
✅ Safety data extracted with specific toxicity rates
✅ Line of therapy and prior exposures documented
✅ Em dashes (—) used for unreported data where applicable