Clinical Trial Result Information

Protocol number
BO17704

Title of Study
A randomized double-blind multicenter phase III study of bevacizumab in combination with cisplatin and gemcitabine versus placebo, cisplatin and gemcitabine in patients with advanced or recurrent non-squamous non-small cell lung cancer, who have not received prior chemotherapy.

Sponsor
Hoffmann-La Roche Ltd/Inc/AG/Roche Global Development

Company division
Pharmaceutical

Product name
Avastin

Generic name
bevacizumab

Therapeutic area
Non-Small Cell Lung Cancer

Clinical study summary
This was a multi-center, randomized, double-blind study to investigate the effect of adding two different doses of Avastin (bevacizumab) to cisplatin and gemcitabine on progression-free survival in patients with advanced or recurrent non-squamous non-small cell lung cancer.

Study center(s)
150 centers in Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Czech Republic, France, Great Britain, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Poland, Russia, Spain, Taiwan and Thailand.

Phase of development
III

Objectives
Primary: To demonstrate superiority in progression-free survival (PFS), when Avastin  (bevacizumab, Bv) was added to cisplatin (C) and gemcitabine (G) (Bv7.5+CG, Bv15+CG) compared to placebo plus cisplatin/gemcitabine (Pl+CG).
Secondary: To compare overall survival (OS); to compare response rate and assess duration of response; to evaluate and compare the safety profile of patients treated with 2 different doses of Bv+CG versus Pl+CG; to characterize the pharmacokinetics (PK) of the combination of bevacizumab, cisplatin and gemcitabine; to assess quality of life (QoL).

Methodology
Eligible patients were randomized to receive one of 3 treatments:
1) cisplatin + gemcitabine + placebo, 2) cisplatin + gemcitabine + Avastin 7.5mg/kg/q3w or 3) cisplatin + gemcitabine + Avastin 15mg/kg/q3w. Cisplatin + gemcitabine were administered in combination with blinded Avastin/placebo cycles of 21 days duration until disease progression or unacceptable toxicity, or for a maximum of 6 cycles. If patients had not progressed after the chemotherapy combination phase, they were allowed to receive Avastin/placebo to disease progression.

Number of patients (planned/analyzed)
Planned: 1050. Enrolled: 1043.

Diagnosis and main criteria for inclusion
Patients ≥18 years of age with histologically or cytologically documented inoperable, locally advanced (stage IIIB with supraclavicular lymph node metastases or with malignant pleural or pericardial effusion), metastatic (stage IV) or recurrent non-squamous NSCLC were eligible.

Test product, dose and mode of administration or test procedure
Avastin (bevacizumab) 7.5mg or 15mg q3w iv, day 1.
Cisplatin 80mg/m² iv, day 1.
Gemcitabine 1250mg/m² iv, days 1 and 8.

Duration of treatment
Avastin + cisplatin/gemcitabine or placebo + cisplatin/gemcitabine were administered every 3 weeks for a maximum of 6 cycles, followed by Avastin as a single agent until disease progression.

Reference therapy, dose and mode of administration or reference procedure
Placebo iv, day 1.
Cisplatin 80m/m² iv, day 1.
Gemcitabine 1250mg/m² iv, days 1 and 8.

Criteria for evaluation (efficacy, safety)
Efficacy: Progression-free survival (primary endpoint), overall survival, response rate, duration of response, QoL (FACT-L, FACT-G, TOI, LCS).
Safety: Adverse events, vital signs, laboratory parameters.
Pharmacokinetics: AUC_0-∞, AUC_0-last, C_max, T_max, CL, Vd and t½ of cisplatin (total platinum) and gemcitabine.

Statistical methods
Efficacy: 2-sided log rank test at the 5% alpha level, Kaplan Meier curves, Cox regression analyses; difference in overall response rate was tested using a chi-square test with Schouten correction and 95% Hauck-Anderson confidence intervals for the difference in response rate between treatment arms.
Pharmacokinetics: The geometric mean ratio of AUC_0-last or AUC_0-∞ when appropriate were analyzed by an ANOVA with fixed effect for treatment, day and random effect for patients.

Summary (efficacy, safety, other results)
The addition of Avastin (at either dose level) to cisplatin/gemcitabine chemotherapy resulted in a clinically meaningful and statistically significant improvement in both PFS (the primary efficacy parameter) and objective response rate. The duration of response was also improved by the addition of Avastin to cisplatin/gemcitabine as compared to placebo + cisplatin/gemcitabine.

Table 1: Summary of Overall Efficacy (Clinical Cut-Off October 7, 2006; ITT)

Parameter	Pl+CG N=347	Bv7.5+CG N=345	Bv15+CG N=351
PFS HR (95% CI)		0.75 (0.62; 0.91) p=0.0026	0.82 (0.68;0.98) p=0.0301
Overall Survival* HR (95% CI)		0.88 (0.68; 1.14)	1.02 (0.79; 1.31)
Overall Response Rate	20.1%	34.1%	30.4%
Complete Response	0%	0.9%	1.2%
Partial Response	20.1%	33.1%	29.2%
Stable Disease	49.7%	46.4%	40.4%
Progressive Disease	13.0%	4.6%	12.0%
Missing**	17.3%	14.9%	17.2%
Duration of Response (KM estimate – months)	4.7	6.1	6.1

* Exploratory analysis
** Missing: Includes pts with no post-baseline tumor assessments, pts who received antineoplastic therapy not defined in the protocol before first tumor assessment, and pts whose first tumor assessment occurred >56 days after last dose of last component of study medication.

None of the FACT-L, FACT-G, TOI, or LCS scores appeared to change meaningfully after baseline in any of the treatment arms, suggesting that the addition of Avastin to cisplatin/gemcitabine chemotherapy did not lead to a deterioration of QoL during trial treatment. The QoL data collected during the course of the study were limited, and these data should therefore be viewed with caution.

Pharmacokinetics: The results from the drug-drug interaction substudy indicated no effect of bevacizumab on the disposition of cisplatin, as measured by total platinum but did not allow firm conclusion to be drawn on the impact of bevacizumab on gemcitabine disposition.

Safety: A higher incidence of adverse events of special interest was observed in the Avastin arms, with a numerically higher incidence in the Avastin 15mg arm. However, no clinically significant differences between the two Avastin arms were apparent. The overall higher incidence of events of special interest in the Avastin arms was mostly driven by hypertension (all Grades) and certain bleeding events (e.g. epistaxis).
Overall, Avastin did not seem to increase the known toxicities of cisplatin/gemcitabine and no new safety signal related to Avastin appeared.

	Pl+CG N=327	Bv7.5+CG N=330	Bv15+CG N=329
	Number of Patients (%)
Any AE	322 (98%)	326 (99%)	326 (99%)
Grade 3, 4, 5 AE	246 (75%)	252 (76%)	265 (81%)
Serious AE	116 (35%)	116 (35%)	145 (44%)
AE leading to Death	14 (4%)	13 (4%)	16 (5%)
AE leading to any other component withdrawal	74 (23%)	86 (26%)	98 (30%)
AE of Special Interest	135 (41%)	189 (57%)	207 (63%)
Grade 3, 4, 5	48 (15%)	65 (20%)	76 (23%)
Bleeding	6 (2%)	14 (4%)	14 (4%)
Hypertension	6 (2%)	21 (6%)	29 (9%)
Venous Thromboembolic events	21 (6%)	24 (7%)	23 (7%)
Arterial Thromboembolic events	15 (5%)	8 (2%)	10 (3%)
Congestive Heart Failure	2 (<1%)	4 (1%)	3 (<1%)
Gastrointestinal Perforations	2 (<1%)	0	1 (<1%)
Proteinuria	0	1 (<1%)	4 (1%)
Wound Complication	2 (<1%)	0	0

Conclusions
The combination of Avastin with cisplatin and gemcitabine for the treatment of NSCLC resulted in a clinically relevant and statistically significant improvement in both progression-free survival and objective response rate. The duration of response was also improved by the addition of Avastin. In addition, Avastin could be safely administered in combination with cisplatin/gemcitabine and the safety profile was consistent with prior Avastin studies in lung cancer.

Date of report
6/1/2007

Click here for the protocol registry listing of this trial.