Profile of bevacizumab in the treatment of platinum-resistant ovarian cancer: current perspectives

Figures & data

Table 1 Selected Phase II and III clinical trials evaluating bevacizumab for recurrent ovarian cancer

Study	Phase	N	Eligibility	Regimens	Response rate	Median PFS (months)	Median OS (months)	Comments
Burger et al^Citation31 (GOG 170D)	II	62	Recurrent (58% platinum resistant)	Bev 15 mg/kg every 3 weeks	21%	4.7	16.9
Cannistra et al^Citation32	II	44	Recurrent, platinum resistant	Bev 15 mg/kg every 3 weeks	15.9%	4.4	10.7	Terminated early due to high rate of GI perforation
Garcia et al^Citation33	II	70	Recurrent (40% platinum resistant)	Bev 10 mg/kg weekly for 3 weeks then every 2 weeks + cyclophosphamide 50 mg PO daily	24%	7.2	16.9
Matulonis et al^Citation34	II	20	Recurrent (70% platinum resistant)	Bev 15 mg/kg every 3 weeks + cyclophosphamide 50 mg daily added at disease progression	10%	8.4	22.7	– Disease control rate 75% – 13 patients received cyclophosphamide after PD on Bev alone
Wenham et al^Citation35	II	41	Recurrent <12 months after platinum (46% platinum resistant)	Bev 15 mg/kg every 3 weeks + docetaxel 40 mg/m^2 weekly	56.4%	5.2
Tillmanns et al^Citation36	II	48	Platinum resistant	Bev 10 mg/kg every 2 weeks + albumin bound paclitaxel 100 mg/m^2 weekly	50%	8.08	17.15
Verschraegen et al^Citation37	II	46	Platinum resistant	Bev 15 mg/kg + PLD 30 mg/m^2 every 3 weeks	30.2% (RECIST) 50% (GCIG)	7.8	33.2	– Clinical benefit rate 86.1% – High rate of decrease in cardiac function and dermatologic/mucosal toxicity of PLD. Concern for synergistic effect
Kudoh et al^Citation38	II	30	Recurrent (97% platinum resistant)	Bev 2 mg/kg + PLD 10 mg/m^2 weekly	33%	6	N/A	Clinical benefit rate 73%
McGonigle et al^Citation39	II	40	Platinum resistant	Bev 10 mg/kg every 2 weeks + topotecan 4 mg/m^2 days 1, 8, 15	25%	7.8	16.6	Patients with two prior regimens had greatest benefit
Hagemann et al^Citation40	II	34	Recurrent (35% platinum resistant)	Bev 15 mg/kg + pemetrexed 500 mg/m^2 every 3 weeks	41%	7.9	16.7
Ikeda et al^Citation42	II	19	Platinum resistant	B-GEMOX bev 2 mg/kg, gemcitabine 300 mg/m^2, oxaliplatin 30 mg/m^2 three weekly, 3 weeks on, 1 week off	34%	4.5		Clinical benefit rate 79%
Liu et al^Citation41	II	52	Platinum resistant	Bev 5 mg/kg every 2 weeks + irinotecan 60 mg/m^2 weekly	42%	8.0	13.8	Disease control rate 65.4%
Pujade-Lauraine et al^Citation9 (AURELIA)	III	361	Platinum resistant	Arm 1: Bev 10 mg every 2 weeks + chemotherapy (n=182)	30.2% (CT + Bev)	6.7 (CT + Bev)	16.6 (CT + Bev)	Patients were stratified by chemotherapy prior to randomization to bev, but chemotherapy selection was not randomized
				Arm 2: chemotherapy alone (n=179)	12.6% (CT) P<0.001	3.4 (CT) HR 0.42 (95% CI 0.32–0.53) P<0.001	13.3 (CT) HR 0.85 (95% CI 0.66–1.08) P<0.174
				CT = investigator choice, see subgroups below
Poveda et al^Citation92 (AURELIA subgroups)				Paclitaxel 80 mg/m^2 weekly + Bev (n=60)	53% (P + Bev) 30% (P)	10.4 (P + Bev) 3.9 (P)	22.4 (P + Bev) 13.2 (P)
				Paclitaxel alone (n=55)		HR 0.46 (95% CI 0.3–0.71)	HR 0.65 (95% CI 0.42–1.02)
				PLD 40 mg/m^2 every 4 weeks + Bev (n=62)	13.7% (PLD + Bev)	5.4 (PLD + Bev)	13.7 (PLD + Bev)
				PLD alone (n=64)	7.8% (PLD)	3.5 (PLD) HR 0.57 (95% CI 0.39–0.83)	14.1 (PLD) HR 0.91 (95% CI 0.62–1.36)
				Topotecan 4 mg/m^2 weekly or 1.25 mg/m^2 days 1–5 every 3 weeks + Bev (n=57)	17% (Topo + Bev)	5.8 (Topo + Bev)	13.8 (Topo + Bev)
				Topotecan alone (n=63)	0% (Topo)	2.1 (Topo) HR 0.32 (95% CI 0.21–0.49)	13.3 (Topo) HR 1.09 (95% CI 0.72–1.67)

Abbreviations: PFS, progression-free survival; OS, overall survival; Bev, bevacizumab; PO, orally; PLD, pegylated liposomal doxorubicin; N/A, not applicable; CT, chemotherapy; HR, hazard ratio; CI, confidence interval; P, paclitaxel; Topo, topotecan; AURELIA, Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer; GI, gastrointestinal; PD, progression of disease; RECIST, response evaluation criteria in solid tumors; GCIG, gynecologic cancer Intergroup; B-GEMOX, bevacizumab + gemcitabine + oxaliplatin; GOG, Gynecologic Oncology Group.

Table 2 Toxicity of bevacizumab in recurrent ovarian cancer

Study	Phase	N	Eligibility	Regimens	Grade 3–4 toxicities in patients receiving bevacizumab
Burger et al^Citation31 (GOG 170D)	II	62	Recurrent (58% platinum resistant)	Bev 15 mg/kg every 3 weeks	– GI perforation (0%) – HTN (9.7%) – VTE (1.6%) – GI (<5%) – GU (1.6%)
Cannistra et al^Citation32	II	44	Recurrent, platinum resistant	Bev 15 mg/kg every 3 weeks	– GI perforation (11%) – HTN (9%) – Dyspnea (4.5%) – Fatigue (4.5%) – GI (4.5%)
Garcia et al^Citation33	II	70	Recurrent (40% platinum resistant)	Bev 10 mg/kg weekly for 3 weeks then every 2 weeks + cyclophosphamide 50 mg PO daily	– GI perforation (2.9%) – GI fistula (1.4%) – Wound complication (1.4%) – GI bleeding (1.4%) – HTN (16%) – Hematologic (23%)
Matulonis et al^Citation34	II	20	Recurrent (70% platinum resistant)	Bev 15 mg/kg every 3 weeks + cyclophosphamide 50 mg daily added at PD	– GI perforation (5%) – MI (5%) – HTN (60%)
Wenham et al^Citation35	II	41	Recurrent <12 months after platinum (46% platinum resistant)	Bev 15 mg/kg every 3 weeks + docetaxel 40 mg/m^2 weekly	– GI perforation (2.4%) – GI fistula (2.4%) – Hematologic (14.6%) – Neuropathy (4.9%) – GI (9.8%)
Tillmanns et al^Citation36	II	48	Platinum resistant	Bev 10 mg/kg every 2 weeks + albumin bound paclitaxel 100 mg/m^2 weekly	– GI perforation (4.2%) – Hematologic (10.5%) – GI (26.3%) – HTN (6.3%) – VTE (4.2%)
Verschraegen et al^Citation37	II	46	Platinum resistant	Bev 15 mg/kg + PLD 30 mg/m^2 every 3 weeks	– GI perforation (0%) – HTN (30%) – Headache (11%) – Dermatologic (39%) – Mucositis (9%) – Hemolytic uremic syndrome (2%) – Wound dehiscence (2%) – Neurologic (2%) – Renal (2%) – Cardiac (2%)
Kudoh et al^Citation38	II	30	Recurrent (97% platinum resistant)	Bev 2 mg/kg + PLD 10 mg/m^2 weekly	– GI perforation (3%) – Hand foot syndrome (3%)
McGonigle et al^Citation39	II	40	Platinum resistant	Bev 10 mg/kg every 2 weeks + topotecan 4 mg/m^2 days 1, 8, and 15	– GI perforation (0%) – Neutropenia (18%) – HTN (20%) – GI (18%) – VTE (3%) – Proteinuria (3%)
Hagemann et al^Citation40	II	34	Recurrent (35% platinum resistant)	Bev 15 mg/kg + pemetrexed 500 mg/m^2 every 3 weeks	– Neutropenia (50%) – Thrombocytopenia (12) – Anemia (9%) – Febrile neutropenia (3%) – Impaired coagulation (6%) – Cardiac (3%) – GI (12%) – Pain (21%) – Neurologic (3%) – Metabolic (24%) – Hemorrhage (3%) – Renal (6%) – Secondary hematologic malignancy (6%) – VTE (3%)
Ikeda et al^Citation42	II	19	Platinum resistant	B-GEMOX bevacizumab 2 mg/kg, gemcitabine 300 mg/m^2, oxaliplatin 30 mg/m^2 3 weekly 3 weeks on, 1 week off	– GI perforation (0%) – Leukopenia (16%) – Neutropenia (10%) – Thrombocytopenia (5%) – Hand foot syndrome (5%)
Liu et al^Citation41	II	52	Platinum resistant	Bev 5 mg/kg every 2 weeks + irinotecan 60 mg/m^2 weekly	– GI perforation (0%) – HTN (3.8%) – VTE (3.8%) – Neutropenia (11.5%) – Thrombocytopenia (3.8%) – GI (3.8%)
Pujade-Lauraine et al^Citation9 (AURELIA)	III	361	Platinum resistant	Arm 1: Bev 10 mg every 2 weeks + chemotherapy	– GI perforation (2.2%) – HTN (7%) – Proteinuria (2%)
				Arm 2: chemotherapy alone	– VTE (5%) – Fistula (3%) – PRES (1%)
				CTa = investigator choice. Paclitaxel 80 mg/m^2 weekly, PLD 40 mg/m^2 every 4 weeks or topotecan 4 mg/m^2 weekly or 1.25 mg/m^2 days 1–5 every 3 weeks

Note:

a Due to the heterogeneity of the chemotherapy arm, rates of toxicity for the Aurelia study are those most likely to be attributable to bevacizumab exposure. A complete list of toxicities can be found in the original reference.

Abbreviations: Bev, bevacizumab; GI, gastrointestinal; HTN, hypertension; VTE, venous thromboembolism; GU, genitourinary; PO, orally; MI, myocardial infarction; PLD, pegylated liposomal doxorubicin; PRES, posterior reversible leukoencephalopathy syndrome; CT, chemotherapy; AURELIA, Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer; GOG, Gynecologic Oncology Group; PD, progression of disease; B-GEMOX, bevacizumab + gemcitabine + oxaliplatin.

Table 3 Selected trials of alternative antiangiogenic agents in recurrent ovarian cancer

Drug	Mechanism (target)	Study	Phase	N	Eligibility	Regimens	Response rate	Median PFS (months)	Median OS (months)	Grades 3–4 toxicity
Aflibercept	VEGF trap (VEGF-A)	Coleman et al^Citation69	I/II	46	Recurrent, measurable disease (33/46 platinum resistant)	Aflibercept 6 mg/kg + docetaxel 75 mg/m^2 every 3 weeks	54%	6.4	26.6	– GI perforation (0%) – Neutropenia (80%) – Fatigue (50%) – Dyspnea (22%) – Fistula (2%) – Neurologic (2%)
		Tew et al^Citation70	II	84	Recurrent, platinum resistant	Arm 1: aflibercept 2 mg/kg every 2 weeks Arm 2: aflibercept 4 mg/kg every 2 weeks	0.9% (arm 1) 4.6% (arm 2)	3 (arm 1) 3.1 (arm 2)	13.8 (arm 1) 11.5 (arm 2)	– GI perforation (1.4%) – HTN (arm 1, 25.5%, arm 2, 27.5%) – Fatigue (5.7%, 3.7%)
		Gotlieb et al^Citation71	II	55	Recurrent, symptomatic ascites	Aflibercept 4 mg/kg IV every 2 weeks vs placebo	No difference from placebo	6.3 (weeks, aflibercept) 7.3 (weeks, placebo)	12.9 (weeks, aflibercept) 16 (weeks, placebo)	(Aflibercept arm) – GI perforation (10%) – HTN (7%) – VTE (7%)
Sorafenib	TKI (VEGFR, PDGFR, Raf kinases)	Matei et al^Citation72	II	71	Recurrent	Sorafenib 400 mg twice daily	3.4%	2.1	16.3	– Rash (9.8%) – Hand foot syndrome (12) – Metabolic (14%) – GI (4%) – Cardiovascular (2.8%) – Pulmonary (2.8%)
		Bodnar et al^Citation73	II	11	Recurrent	Sorafenib 400 mg twice daily	0%	2	11.8	– Hematologic (9%) – Hand foot syndrome (9%)
		Ramasubbaiah et al^Citation74	II	14	Recurrent platinum resistant	Sorafenib 400 mg twice daily, topotecan 3.5 mg/m^2 days 1, 8, and 15	16.7%	3.7	14	– Neutropenia (23%) – Anemia (10%) – Thrombocytopenia (17%) – Fatigue (7%) – Nausea/vomiting (7%)
Sunitinib	TKI (VEGFR1–3, PDGFR, RET, Flt3, c-kit, CSF-1R)	Campos et al^Citation75	II	36	Recurrent (23/36 platinum resistant)	37.5 mg sunitinib PO daily	8.33%	2.3^a	N/A	– Hand foot syndrome (7%) reported by percentage events
		Baumann et al^Citation76	II	73	Recurrent, platinum resistant	Arm 1: sunitinib 50 mg PO daily followed by 14 days off drug Arm 2: sunitinib 37.5 mg PO daily	16.7% (arm 1), 5.4% (arm 2)	4.8 (arm 1), 2.9 (arm 2)	13.6 (arm 1), 13.7 (arm 2)	Reported by percentage events
		Biagi et al^Citation77	II	30	Recurrent	Sunitinib 50 mg daily ×4 weeks, changed midstudy to 37.5 mg daily due to rebound VEGF symptoms	3.3% (53% had SD)	4.1	N/A	– Hand foot (10%) – HTN (3%) – GI (10%) – Hematologic (10%–16.6%)
Cediranib	TKI (VEGFR1–3, c-kit)	Hirte et al^Citation80	II	74	Recurrent (35/74 platinum resistant)	Cediranib 45 mg daily, reduced to 30 mg daily after first 23 patients	12% (0% platinum resistant, 23% platinum sensitive)	4.9	18.9	– HTN (27%) – Fatigue (20%) – Diarrhea (14%)
		Matulonis et al^Citation81	II	46	Recurrent (30/46 platinum resistant)	Cediranib 45 mg daily reduced to 30 mg daily after first eleven patients	17%	5.2	N/A	– HTN (46%) – Fatigue (24%) – Diarrhea (13%) – Neurologic (2%) – GI perforation, fistula (0)
Pazopanib	TKI (VEGFR1–2, PDGFR, c-kit)	Friedlander et al^Citation83	II	36	Recurrent (9/36 platinum resistant or refractory)	Pazopanib 800 mg daily	18% (3/17 measurable disease) 31% (11/36 CA-125 response)	N/A	N/A	– Fatigue (11%) – HTN (3%) – Diarrhea (8%)
		Pignata et al^Citation84	II	74	Recurrent, platinum resistant	Arm 1: pazopanib 800 mg daily + paclitaxel 80 mg/m^2 weekly	56% (arm 1)	6.35 (arm 1) 3.49	19.1 (arm 1) 13.7	– GI perforation (3%) – Neutropenia (30%) – Fatigue (11%) – Diarrhea (5%) – ALT/AST elevation (5%)
						Arm 2: paclitaxel 80 mg/m^2 alone	25% (arm 2)	HR 0.42, 95% CI 0.25–0.69, P=0.0002	HR 0.60, 95% CI 0.32–1.13, P=0.056
Nintedanib (BIBF 1120)	TKI (VEGFR, PDGFR, FGFR)	Ledermann et al^Citation79	II	83	Recurrent	Nintedanib 250 mg twice daily vs placebo	Not reported	16% (nintedanib PFS at 36 weeks) 5% (placebo at 36 weeks)		Toxicity significantly increased from placebo: – Diarrhea – Nausea/vomiting – Fatigue – AST/ALT elevation

Abbreviations: PFS, progression-free survival; OS, overall survival; VEGF, vascular endothelial growth factor; GI, gastrointestinal; HTN, hypertension; IV, intravenously; VTE, venous thromboembolism; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; CSF-1R, colony-stimulating factor 1 receptor; PO, orally; N/A, not applicable; SD, stable disease; HR, hazard ratio; CI, confidence interval; ALT, alanine transaminase; AST, aspartate transaminase; FGFR, fibroblast growth factor receptor; Ca 125, cancer antigen 125.

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