Erlotinib: Package Insert and Label Information (Page 4 of 5)

14. CLINICAL STUDIES

14.1 Non-Small Cell Lung Cancer (NSCLC) – First-Line Treatment of Patients with EGFR Mutations

Study 1

The safety and efficacy of erlotinib tablets as monotherapy for the first-line treatment of patients with metastatic NSCLC containing EGFR exon 19 deletions or exon 21 (L858R) substitution mutations was demonstrated in Study 1, a randomized, open-label, clinical trial conducted in Europe. One hundred seventy-four (174) White patients were randomized 1:1 to receive erlotinib 150 mg once daily until disease progression (n=86) or four cycles of a standard platinum-based doublet chemotherapy (n=88); standard chemotherapy regimens were cisplatin plus gemcitabine, cisplatin plus docetaxel, carboplatin plus gemcitabine, and carboplatin plus docetaxel. The main efficacy outcome measure was progression-free survival (PFS) as assessed by the investigator. Randomization was stratified by EGFR mutation (exon 19 deletion or exon 21 (L858R) substitution) and Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 vs. 1 vs. 2). EGFR mutation status for screening and enrollment of patients was determined by a clinical trials assay (CTA). Tumor samples from 134 patients (69 patients from the erlotinib arm and 65 patients from the chemotherapy arm) were tested retrospectively by the FDA-approved companion diagnostic, the cobas^® EGFR Mutation Test.

Baseline demographics of the overall study population were: female (72%), White (99%), age ≥ 65 years (51%), ECOG PS 1 (53%), with ECOG PS 0 (33%), and ECOG PS 2 (14%), current smoker (11%), past-smoker (20%), and never smoker (69%). The disease characteristics were 93% Stage IV and 7% Stage IIIb with pleural effusion as classified by the American Joint Commission on Cancer (AJCC, 6^th edition), 93% adenocarcinoma, 66% exon 19 mutation deletions and 34% exon 21 (L858R) point mutation by a CTA.

A statistically significant improvement in investigator-determined PFS (based on RECIST 1.0 or clinical progression) was demonstrated for patients randomized to erlotinib compared to those randomized chemotherapy (see Table 6 and Figure 1). Similar results for PFS (based on RECIST 1.0) were observed for the subgroup evaluated by an independent-review committee (approximately 75% of patients evaluated in Study 1) and in the subgroup of 134 patients (77% of Study 1 population) with EGFR mutations confirmed by the cobas^® EGFR Mutation Test.

A protocol-specified analysis of overall survival (OS) conducted at the time of the final analysis of PFS showed no statistically significant difference between the erlotinib tablets and chemotherapy arms. At the time of the data cut-off, 84% of patients in the chemotherapy arm had received at least one subsequent treatment, of whom 97% received an EGFR-tyrosine kinase inhibitor. In the erlotinib tablets arm, 66% of patients had received at least one subsequent treatment.

Table 6: Efficacy Results (Study 1)

	Erlotinib(N = 86)	Chemotherapy(N = 88)
* Unstratified Cox regression model
Progression-Free Survival
Number of Progressions or Deaths	71 (83%)	63 (72%)
Median PFS in Months (95% CI)	10.4 (8.7, 12.9)	5.2 (4.6, 6.0)
Hazard Ratio (95% CI) *	0.34 (0.23, 0.49)
p-value (unstratified log-rank test)	<0.001
Overall Survival
Number of Deaths (%)	55 (64%)	54 (61%)
Median OS in Months (95% CI)	22.9 (17.0, 26.8)	19.5 (17.3, 28.4)
Hazard Ratio (95% CI)*	0.93 (0.64, 1.35)
Objective Response
Objective Response Rate (95% CI)	65% (54.1%, 75.1%)	16% (9.0%, 25.3%)

Figure 1: Kaplan-Meier Curves of Investigator-Assessed PFS in Study 1

In exploratory subgroup analyses based on EGFR mutation subtype, the hazard ratio (HR) for PFS was 0.27 (95% CI 0.17 to 0.43) in patients with exon 19 deletions and 0.52 (95% CI 0.29 to 0.95) in patients with exon 21 (L858R) substitution. The HR for OS was 0.94 (95% CI 0.57 to 1.54) in the exon 19 deletion subgroup and 0.99 (95% CI 0.56 to 1.76) in the exon 21 (L858R) substitution subgroup.

14.2 NSCLC — Lack of Efficacy of Erlotinib Tablets in Maintenance Treatment of Patients without EGFR Mutations

Lack of efficacy of erlotinib tablets for the maintenance treatment of patients with NSCLC without EGFR activating mutations was demonstrated in Study 2. Study 2 was a multicenter, placebo-controlled, randomized trial of 643 patients with advanced NSCLC without an EGFR exon 19 deletion or exon 21 L858R mutation who had not experienced disease progression after four cycles of platinum-based chemotherapy. Patients were randomized 1:1 to receive erlotinib tablets 150 mg or placebo orally once daily (322 erlotinib tablets, 321 placebo) until disease progression or unacceptable toxicity. Following progression on initial therapy, patients were eligible to enter an open-label phase. Baseline characteristics were as follows: median age 61 years (35% age ≥ 65 years), 75% male, 77% White, 21% Asian, 28% ECOG PS 0, 72% ECOG PS 1, 16% never smokers, 58% current smokers, 57% adenocarcinoma, 35% squamous cell carcinoma, 22% stage IIIB disease not amenable to combined modality treatment, and 78% stage IV disease. Fifty percent of patients randomized to erlotinib tablets entered the open-label phase and received chemotherapy, while 77% of patients randomized to placebo entered the open-label phase and received erlotinib tablets.

The main efficacy outcome was overall survival (OS). Median OS was 9.7 months in the erlotinib tablets arm and 9.5 months in the placebo arm; the hazard ratio for OS was 1.02 (95% CI 0.85, 1.22). Median PFS was 3.0 months in the erlotinib tablets arm and 2.8 months in the placebo arm; the hazard ratio for PFS was 0.94 (95% CI 0.80, 1.11).

14.3 NSCLC – Maintenance Treatment or Second/Third Line Treatment

Two randomized, double-blind, placebo-controlled trials, Studies 3 and 4, examined the efficacy and safety of erlotinib tablets administered to patients with metastatic NSCLC as maintenance therapy after initial treatment with chemotherapy (Study 3) or with disease progression following initial treatment with chemotherapy (Study 4). Determination of EGFR mutation status was not required for enrollment.

Study 3

The efficacy and safety of erlotinib tablets as maintenance treatment of NSCLC were demonstrated in Study 3, a randomized, double-blind, placebo-controlled trial conducted in 26 countries, in 889 patients with metastatic NSCLC whose disease did not progress during first-line platinum-based chemotherapy. Patients were randomized 1:1 to receive erlotinib tablets 150 mg or placebo orally once daily (438 erlotinib tablets, 451 placebo) until disease progression or unacceptable toxicity. The primary objective of the study was to determine if the administration of erlotinib tablets after standard platinum-based chemotherapy in the treatment of NSCLC resulted in improved progression-free survival (PFS) when compared with placebo, in all patients or in patients with EGFR immunohistochemistry (IHC) positive tumors.

Baseline demographics of the overall study population were as follows: male (74%), age < 65 years (66%), ECOG PS 1 (69%), ECOG PS 0 (31%), white (84%), Asian (15%), current smoker (55%), past-smoker (27%), and never smoker (17%). Disease characteristics were as follows: Stage IV (75%), Stage IIIb with effusion (25%) as classified by AJCC (6^th edition) with histologic subtypes of adenocarcinoma including bronchioalveolar (45%), squamous (40%) and large cell (5%); and EGFR IHC positive (70%), negative (14%), indeterminate (4%), and missing (12%).

Table 7: Efficacy Results (Study 3): (ITT Population)*

Efficacy Parameter	Erlotinib Tablets(N = 438)	Placebo(N = 451)
* Patients with PD prior to randomization were excluded from PFS and TTP analysis. † Univariate Cox regression model. ‡ Unstratified log-rank test.
Progression-Free Survival (PFS) based on investigator assessment
Number of Progression or Deaths (%)	349 (80%)	400 (89%)
Median PFS in Months (95% CI)	2.8 (2.8, 3.1)	2.6 (1.9, 2.7)
Hazard Ratio (95% CI) †	0.71 (0.62, 0.82)
p-value (stratified log-rank test) †,‡	p < 0.0001
Overall Survival (OS)
Number of Deaths	298 (68%)	350 (78%)
Median OS in Months (95% CI)	12.0 (10.6, 13.9)	11.0 (9.9, 12.1)
Hazard Ratio (95% CI) †	0.81 (0.70, 0.95)
p-value (stratified log-rank test) ‡	0.0088

Figure 2 depicts the Kaplan-Meier Curves for Overall Survival (ITT Population).

Figure 2: Kaplan — Meier Curves for Overall Survival of Patients by Treatment Group in Study 3

Note: HR is from a univariate Cox regression model.

Study 4

The efficacy and safety of single-agent erlotinib tablets was assessed in Study 4, a randomized, double blind, placebo-controlled trial in 731 patients with locally advanced or metastatic NSCLC after failure of at least one chemotherapy regimen. Patients were randomized 2:1 to receive erlotinib tablets 150 mg or placebo (488 erlotinib tablets, 243 placebo) orally once daily until disease progression or unacceptable toxicity. Efficacy outcome measures included overall survival, response rate, and progression-free survival (PFS). Duration of response was also examined. The primary endpoint was survival. The study was conducted in 17 countries.

Baseline demographics of the overall study population were as follows: male (65%), White (78%), Asian (12%), Black (4%), age < 65 years (62%), ECOG PS 1 (53%), ECOG PS 0 (13%), ECOG PS 2 (25%), ECOG PS 3 (9%), current or ex-smoker (75%), never smoker (20%), and exposure to prior platinum therapy (93%). Tumor characteristics were as follows: adenocarcinoma (50%), squamous (30%), undifferentiated large cell (9%), and mixed non-small cell (2%).

The results of the study are shown in Table 8.

Table 8: Efficacy Results (Study 4)

Efficacy Parameter	Erlotinib Tablets(N = 488)	Placebo(N = 243)
* Cox regression model with the following covariates: ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. † Two-sided log-rank test stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy
Overall Survival (OS)
Number of Deaths	378 (77%)	209 (86%)
Median OS in Months (95% CI)	6.7 (5.5, 7.8)	4.7 (4.1, 6.3)
Hazard Ratio (95% CI) *	0.73 (0.61, 0.86)
p-value (stratified log-rank test) †	p < 0.001
Progression-Free Survival (PFS)
Number of Progression or Deaths (%)	402 (82%)	211 (87%)
Median PFS in Months (95% CI)	2.3 (1.9, 3.3)	1.8 (1.8, 1.9)
Hazard Ratio (95% CI)*	0.59 (0.50, 0.70)
Objective Response
Objective Response Rate (95% CI)	8.9% (6.4, 12.0)	0.9% (0.1, 3.4)

Figure 3 depicts the Kaplan-Meier curves for overall survival.

Figure 3: Kaplan-Meier Curves for Overall Survival of Patients by Treatment Group in Study 4