. Author manuscript; available in PMC: 2017 Sep 26.

Published in final edited form as: Future Oncol. 2015;11(6):909–922. doi: 10.2217/fon.14.276

Table 1.

Registration trials resulting in US FDA approval of bevacizumab.

Study	Disease site	n	Eligibility criteria	Regimen studied	Outcome measure			AEs	Ref.
Study	Disease site	n	Eligibility criteria	Regimen studied	Visual acuity	Median PFS (months)	Median OS (months)	AEs	Ref.
*Ocular indication*
Martin et al.	AMD	1208	Visual acuity between 20/25 and 20/320	Ranibizumab monthly	8.0 letters gained			Equivalent rates of MI, death and stroke between arms	[25]
Martin et al.	AMD	1208	Visual acuity between 20/25 and 20/320	Bevacizumab monthly	8.5 letters gained			Equivalent rates of MI, death and stroke between arms	[25]

*Solid tumors*
Hurwitz et al.	Colorectal cancer	813	ECOG PS 0–1	ILF + placebo		6.2	15. 6	Leukopenia (37%); diarrhea (32%); HTN (11%); bleeding (3%); GI perforation (1.5%)	[26]
			First line	ILF + bev 5 mg/kg iv. Q2w		10.6	20.3
			Metastatic			(HR: 0.54; 95% CI: 0.45–0.66)	(HR: 0.66; 95% CI: 0.54–0.81)

Giantonio et al.	Colorectal cancer	829	Adv stage	FOLFOX-4 + placebo		4.7	10.8	HTN (6%); emesis (10%); bleeding (3%); neuropathy (16%); thromboembolism (3%)	[27]
			Metastatic	FOLFOX-4 + bev 10 mg/kg Q2w		7.3	13.0
				Bev 10 mg/kg Q2w		2.7	N/R
						(HR: 0.52; 95% CI: 0.42–0.65)^†	(HR: 0.75; 95% CI: 0.63–0.89)

Sandler et al.	Nonsquamous NSCLC	878	ECOG PS 0–1	Carbo/paclitaxel+ placebo		4.8	10.3	Leukopenia (25%); HTN (7%); proteinuria (3%); bleeding (4%)	[28]
			First line	Carbo/paclitaxel + bev 15 mg/kg		6.4	12.3
			Locally adv Metastatic Recurrent	Q3w		(HR: 0.65; 95% CI: 0.56–0.76)	(HR: 0.80; 95% CI: 0.69–0.93)

Miller et al.	Breast cancer	722	ECOG 0−1	Paclitaxel + placebo		5.8	24.8	Infection (9%); Fatigue (9%); HTN (15%); neuropathy (23%)	[29]
Miller et al.	Breast cancer	722	Locally recurrent Metastatic	Paclitaxel + bev 10 mg/kg Q2w		11.4 (HR: 0.42; 95% CI: 0.34–0.52)	26.5 (HR: 0.87; 95% CI: 0.72–1.05)^‡	Infection (9%); Fatigue (9%); HTN (15%); neuropathy (23%)	[29]

Friedman et al.	GBM	167	KPS >70%	Bev 10 mg/kg Q2w		42.6% (6 months PFS)	9.3	HTN (8%); thromboembolic disease (6%)	[30]
Friedman et al.	GBM	167	First or second recurrence	Bev 10 mg/kg Q2w + irinotecan		50.3% (6 months PFS)	8.8	HTN (8%); thromboembolic disease (6%)	[30]

Kreisl et al.	GBM	48	KPS >60%	Bev 10 mg/kg Q2w		16 weeks	31 weeks	Thromboembolism (12.5%); HTN (4%); hypophosphatemia (4%)	[31]
			Recurrent (no limit on number of prior therapies)	Transition to bev + irinotecan at progression		29% (6 months PFS)	57% (6 months survival)
						Arm closed early due to futility

Escudier et al.	Renal cell cancer	649	KPS >70%	IFN-α-2a + placebo		5.4^§	21.3	Fatigue (12%); asthenia (10%); proteinuria (7%); HTN (3%); bleeding (3%)	[32]
			First line	IFN-α-2a + bev 10 mg/kg Q2w		10.2^§	23.3
			Metastatic No CNS mets			(HR: 0.63; 95% CI: 0.52–0.75)	(HR: 0.91; 95% CI: 0.76 –1.10)

AURELIA	Ovarian cancer	361	ECOG PS 0–2	iv. paclitaxel or iv. topotecan or iv. PLD		3.4	13.3	HTN (20.1%); proteinuria (12.8%); fatigue (2.2%); GI perforation (1.7%); thromboembolic disease (3.4%)	[39]^¶
			Platinum-resistant recurrence	Chemo as above + bev 15 mg/kg Q3w		6.7	16.6
						(HR: 0.48; 95% CI: 0.36–0.60)	(HR: 0.85; 95% CI: 0.66 –1.08)

Tewari et al.	Cervical cancer	452	GOG PS 0–1	Chemotherapy + placebo		5.9	13.3	Fistula (3%); HTN (2%); neutropenia (35%); thromboembolism (8%); bleeding (5%)	[21]^¶
			Recurrent/ persistent or metastatic	Chemotherapy + bev 15 mg/kg Q3w		8.2	17.0
						(HR: 0.67; 95% CI: 0.54–0.82)	(HR: 0.71; 97% CI: 0.54–0.94)

^†

Diference between FOLFOX + placebo vs FOLFOX + bev.

^‡

Lack of a signifcant OS advantage resulted in the US FDA revoking initial approval of bevacizumab use in patients with metastatic/recurrent breast cancer.

^§

Signifcantly greater than historical controls for both treatment arms (p < 0.0001).

^¶

Regulatory approval granted by the US FDA on 14 August 2014 (recurrent/persistent and metastatic cervical cancer) and on 14 November 2014 (platinum-resistant ovarian cancer).

Adv: Advanced; AE: Grade 3 or 4 adverse events on bevacizumab; AMD: Age-related macular degeneration; Bev: Bevacizumab; Carbo: Carboplatin; Chemo: Paclitaxel + cisplatin vs paclitaxel + topotecan; ECOG: Eastern Cooperative Oncology Group; FOLFOX-4: Oxaliplatin + leucovorin + fuorouracil; GBM: Glioblastoma; GI: Gastrointestinal; GOG: Gynecologic Oncology Group; HR: Hazard ratio; HTN: Hypertension; ILF: Irinotecan + fuorouracil + leucovorin; iv.: Intravenous; KPS: Karnofsky performance score; Mets: Metastases; MI: Myocardial infarction; NSCLC: Non-small-cell lung cancer; OS: Overall survival; PFS: Progression-free survival; PLD: Pegylated liposomal doxorubicin; PS: Performance status; Q2w: Every 2 weeks; Q3w: Every 3 weeks.