ERLOTINIB HYDROCHLORIDE (Page 5 of 7)

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

Lack of efficacy of erlotinib 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 150 mg or placebo orally once daily (322 erlotinib, 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 entered the open-label phase and received chemotherapy, while 77% of patients randomized to placebo entered the open-label phase and received erlotinib.

The main efficacy outcome was overall survival (OS). Median OS was 9.7 months in the erlotinib 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 months in the erlotinib arm and 2.8 months in the placebo arm; the hazard ratio for PFS was 0.94 (95% CI 0.8, 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 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 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 150 mg or placebo orally once daily (438 erlotinib, 451 placebo) until disease progression or unacceptable toxicity. The primary objective of the study was to determine if the administration of erlotinib 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 (6th 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)1

Efficacy Parameter Erlotinib (N = 438) Placebo (N = 451)
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)(2) 0.71 (0.62, 0.82)
p-value (stratified log-rank test) (2,3) p < 0.0001
Overall Survival (OS)
Number of Deaths298 (68%)350 (78%)
Median OS in Months (95% CI)12 (10.6, 13.9)11 (9.9, 12.1)
Hazard Ratio (95% CI) (2) 0.81 (0.7, 0.95)
p-value (stratified log-rank test) (3) 0.0088

(1) Patients with PD prior to randomization were excluded from PFS and TTP analysis.

(2) Univariate Cox regression model.

(3) Unstratified log-rank test.

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

Figure 2
(click image for full-size original)

Note: HR is from a univariate Cox regression model.

Study 4

The efficacy and safety of single-agent erlotinib 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 150 mg or placebo (488 erlotinib, 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 (N = 488) Placebo (N = 243)
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) (1) 0.73 (0.61, 0.86)
p-value (stratified log-rank test) (2) 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) 1 0.59 (0.5, 0.7)
Objective Response
Objective Response Rate (95% CI) 8.9% (6.4, 12) 0.9% (0.1, 3.4)

(1) Cox regression model with the following covariates: ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy.
(2) Two-sided log-rank test stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy.

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

Figure 3
(click image for full-size original)

Figure 2Figure 3

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