TABLE 1

FDA–approved targeted therapies with specific FDA-labeled indications

This table gives an overview of clinical trials that led to approval of each drug and extension of the FDA label for particular indications following initial approval. Important key trials were added at the discretion of the authors. Accelerated approval of drugs for particular indications is highlighted in the indications column.

Drug, U.S. FDA-Labeled Approval(s)	Study Name	Phase	Study Population, Size	Intervention(s)	Primary Outcome(s)	Selected Secondary Outcomes	Reference(s)
Alemtuzumab
B-CLL, previously untreated		3	N = 297	Alemtuzumab versus chlorambucil	PFS: 14.6 versus 11.7 months^*	RR: 83.2% versus 55.4% ^*	(Hillmen et al., 2007)
Initial accelerated approval		3	N = 297	Alemtuzumab versus chlorambucil	PFS: 14.6 versus 11.7 months^*	RR: 83.2% versus 55.4% ^*	(Hillmen et al., 2007)
		N/A	N = 149; 3 single-arm studies	Alemtuzumab		PR: 21%–31%	PI
		N/A	N = 149; 3 single-arm studies	Alemtuzumab		CR: 0%–2%	PI
Axitinib
Advanced RCC after failure of prior systemic therapy	AXIS	3	N = 723	Axitinib versus sorafenib	PFS: 6.7 versus 4.7 months^*	ORR: 19.4% versus 9.4%^*	(Rini et al., 2011)
Bevacizumab
Metastatic CRC, with 5-FU, first- or second-line therapy	Study 2107	3	Previously untreated, N = 813	Bevacizumab versus placebo, with IFL	OS: 20.3 versus 15.6 months^*	PFS: 10.6 versus 6.2 months^*	(Hurwitz et al., 2004)
Metastatic CRC, with 5-FU, first- or second-line therapy	Study 2107	3	Previously untreated, N = 813	Bevacizumab versus placebo, with IFL	OS: 20.3 versus 15.6 months^*	ORR: 44.8% versus 34.8%^*	(Hurwitz et al., 2004)
	E3200	3	Previously treated, N = 829	FOLFOX4, bevacizumab, versus both	OS: 12.9 (combination) versus 10.8 months (FOLFOX)^*	PFS: 7.3 versus 4.7 months^*	(Giantonio et al., 2007)
	E3200	3	Previously treated, N = 829	FOLFOX4, bevacizumab, versus both	OS: 12.9 (combination) versus 10.8 months (FOLFOX)^*	ORR: 22.7% versus 8.6% ^*	(Giantonio et al., 2007)
		2	Previously treated, N = 339	Bevacizumab with 5-FU/LV	ORR 1%	PFS: 3.5 months	(Chen et al., 2006)
		2	Previously treated, N = 339	Bevacizumab with 5-FU/LV	ORR 1%	OS: 9 months	(Chen et al., 2006)
Metastatic CRC, second-line after first progression on bevacizumab-based chemotherapy	ML18147	3	N = 820	Bevacizumab with chemotherapy (oxaliplatin- or irinotecan-based) versus chemotherapy alone	OS: 11.2 versus 9.8 months^*	PFS: 5.7 versus 4.1 months^*	(Bennouna et al., 2013)
Advanced NSCLC, nonsquamous, with carboplatin/paclitaxel, first-line	E4599	3	N = 878	Paclitaxel and carboplatin +/− bevacizumab	OS: 12.3 versus 10.3 months^*	PFS: 6.2 versus 4.5 months^*	(Sandler et al., 2006)
	E4599	3	N = 878	Paclitaxel and carboplatin +/− bevacizumab	OS: 12.3 versus 10.3 months^*	ORR: 33% versus 15%^*	(Sandler et al., 2006)
	AVAiL	3	N = 1043	Cisplatin/gemcitabine with bevacizumab 7.5 mg/kg versus bevacizumab 15 mg/kg versus placebo	PFS: 6.7 (7.5 mg/kg) versus 6.5 (15 mg/kg) versus 6.1 months (chemotherapy) ^*	OS: 13.1 (placebo) versus 13.6 months (7.5 mg/kg) versus 13.4 months (15 mg/kg)	(Reck et al., 2009, 2010)
Glioblastoma, progressive after prior therapy	NCI-06-C-0064E	2	N = 48	Bevacizumab	Radiographic response rate: 71%	OS: 31 weeks	(Kreisl et al., 2009)
Accelerated approval	NCI-06-C-0064E	2	N = 48	Bevacizumab	PFS: 16 weeks	OS: 31 weeks	(Kreisl et al., 2009)
	BRAIN	2	First or second relapse, N = 167	Bevacizumab +/− irinotecan	PFS at 6 months: 42.6% bevacizumab versus 50.3% combination^*	OS: 9.2 versus 8.7 months (significance testing not provided)	(Friedman et al., 2009)
Ovarian cancer, advanced newly diagnosed and stage IV		3	N = 1873	Carboplatin + paclitexal with placebo or bevacizumab initiation or bevacizumab throughout	PFS 10.3 versus 11.2 versus 14.1 months	OS 39.3 versus 38.7 versus 39.7	(Burger et al., 2011)
Metastatic RCC, with INFα	AVOREN Trial	3	Previously untreated, N = 649	IFN-α2a with bevacizumab versus IFN with placebo	OS: 23.3 versus 21.3 months	PFS: 10.2 versus 5.4 months^*	(Escudier et al., 2007a, 2010)
Bortezomib
Multiple myeloma, first-line	VISTA	3	Ineligible for stem cell transplant, N = 682	Melphalan/prednisone +/− bortezomib	TTP: 24 versus 16.6 months^*	CR: 30% versus 4%^*	(San Miguel et al., 2008)
Multiple myeloma, first-line	VISTA	3	Ineligible for stem cell transplant, N = 682	Melphalan/prednisone +/− bortezomib	TTP: 24 versus 16.6 months^*	OS, median: 56.4 versus 43.1 months ^*	(San Miguel et al., 2008)
Multiple myeloma, relapsed/refractory	APEX	3	Relapsed after 1-3 prior therapies, N = 669	Bortezomib versus high-dose dexamethasone	TTP: 6.22 versus 3.49 months^*	ORR: 38% versus 18%^*	(Richardson et al., 2005, 2007)
Multiple myeloma, relapsed/refractory	APEX	3	Relapsed after 1-3 prior therapies, N = 669	Bortezomib versus high-dose dexamethasone	TTP: 6.22 versus 3.49 months^*	OS: 29.8 versus 23 months^*	(Richardson et al., 2005, 2007)
	SUMMIT	2	N = 202	Bortezomib (+dexamethasone if poor response)	ORR: 35%	OS: 16 months	(Richardson et al., 2003)
	SUMMIT	2	N = 202	Bortezomib (+dexamethasone if poor response)	ORR: 35%	DR: 12 months	(Richardson et al., 2003)
	CREST	2	N = 54	Bortezomib (two dosages, with dexamethasone if poor response)	ORR: 50% (1.3 mg/m²), 33% (1 mg/m²)	TTP: 11 months (1.3 mg/m²), 7 months (1 mg/m²)	(Jagannath et al., 2004)
	CREST	2	N = 54		ORR: 50% (1.3 mg/m²), 33% (1 mg/m²)	OS: median not reached (1.3 mg/m²) and 26.7 months (1 mg/m²)	(Jagannath et al., 2004)
Multiple myeloma, SQ administration		3	Relapsed after 1–3 prior therapies, N = 222	Bortezomib SQ versus i.v.	ORR at 4 months: 42% in both groups	TTP: 10.4 versus 11.7 months	(Moreau et al., 2011)
Multiple myeloma, SQ administration		3	Relapsed after 1–3 prior therapies, N = 222	Bortezomib SQ versus i.v.	ORR at 4 months: 42% in both groups	OS, 1 year: 72.6% versus 76.7%	(Moreau et al., 2011)
Mantle cell lymphoma, previously treated	PINNACLE	2	N = 155	Bortezomib	TTP versus historical controls: insufficient controls	ORR: 33%	(Fisher et al., 2006)
						DR 9.2 months
						TTP: 6.2 months
Brentuximab vedotin
Hodgkin’s lymphoma, relapsed/refractory after auto SCT or at least two chemotherapy regimens		2	N = 102	Brentuximab vedotin	ORR: 75%	PFS: 5.6 months	(Younes et al., 2012)
Accelerated approval		2	N = 102	Brentuximab vedotin	CR 34%	OS: 22.4 months	(Younes et al., 2012)
sALCL, after failed systemic therapy		2	N = 58	Brentuximab vedotin	ORR: 86%	DR: 12.6 months	PI
Accelerated approval		2	N = 58	Brentuximab vedotin	ORR: 86%	DR: 12.6 months	PI
Carfilzomib
Multiple myeloma, relapsed/refractory		2	N = 266	Carfilzomib	ORR: 23.7%	DR: 7.8 months	(Siegel et al., 2012)
Accelerated approval						OS: 15.6 months
Accelerated approval						PFS: 3.7 months
Cetuximab
Metastatic CRC, K-RAS WT, EGFR+, with FOLFIRI, first-line	CRYSTAL	3	N = 1198	FOLFIRI with versus without cetuximab	PFS: 8.9 versus 8.0 months^*	OS (K-RAS WT): 23.5 versus 20 months^*	(Van Cutsem et al., 2009, 2011)
Metastatic CRC, K-RAS WT, EGFR+, with FOLFIRI, first-line	CRYSTAL	3	N = 1198	FOLFIRI with versus without cetuximab	PFS (K-RAS WT): 9.9 versus 8.4 months^*	ORR (K-RAS WT): 59.3 versus 43.2%^*	(Van Cutsem et al., 2009, 2011)
Metastatic CRC, K-RAS WT, EGFR+, with irinotecan, in patients refractory to irinotecan-based chemotherapy	BOND	2	N = 329	Cetuximab with versus without irinotecan	ORR: 22.9% (combination) versus 10.8% (cetuximab)^*	TTP: 4.1 versus 1.5 months^*	(Cunningham et al., 2004)
	BOND	2	N = 329	Cetuximab with versus without irinotecan	ORR: 22.9% (combination) versus 10.8% (cetuximab)^*	OS: 8.6 versus 6.9 months	(Cunningham et al., 2004)
Metastatic CRC, K-RAS WT, EGFR+, single agent, in patients who have failed oxaliplatin and irinotecan-based therapy or are intolerant to irinotecan			N = 572	Cetuximab versus BSC	OS:6.1 months versus 4.6 months^*	PFS: HR 0.68^*	(Jonker et al., 2007)
Locoregionally advanced SCCHN, with radiation therapy		3	N = 424	Radiotherapy with versus without cetuximab	Duration of disease control: 24.4 versus 14.9 months^*	OS: 49 versus 29.3 months^*	(Bonner et al., 2006)
Locoregionally advanced SCCHN, with radiation therapy		3	N = 424	Radiotherapy with versus without cetuximab	Duration of disease control: 24.4 versus 14.9 months^*	PFS: 17.1 versus 12.4 months^*	(Bonner et al., 2006)
Recurrent or metastatic SCCHN, with platinum-based therapy/5-FU	EXTREME	3	N = 442	Platinum-based chemotherapy with versus without cetuximab	OS: 10.1 versus 7.4 months^*	PFS: 5.6 versus 3.3 months^*	(Vermorken et al., 2008)
	EXTREME	3	N = 442	Platinum-based chemotherapy with versus without cetuximab	OS: 10.1 versus 7.4 months^*	ORR: 36% versus 20%^*	(Vermorken et al., 2008)
Recurrent locoregional/metastatic SCCHN, single agent, after failure of platinum-based chemotherapy		2	N = 103	Cetuximab, with platinum-based chemotherapy if poor response	ORR: 13%	TTP: 70 days	(Vermorken et al., 2007)
		2	N = 103		ORR: 13%	OS: 178 days	(Vermorken et al., 2007)
Crizotinib
NSCLC, locally advanced or metastatic, ALK positive	Study A	2	N = 136	Crizotinib	ORR: 50%	DR: 41.9 weeks	PI^a
Accelerated approval	Study A	2	N = 136	Crizotinib	ORR: 50%	DR: 41.9 weeks	PI^a
	Study B	1	N = 119	Crizotinib	ORR: 61%	DR: 48 weeks	^b
	Study B	1	N = 119	Crizotinib	ORR: 61%	PFS: 10 months	^b
Dasatinib
CML-CP, Ph+, newly diagnosed	DASISION	3	CML-CP, N = 519	Dasatinib (once daily) versus imatinib	CCyR at 12 months: 77 versus 66%^*	MMR: 52% versus 34%^*	(Kantarjian et al., 2010, 2012)
Accelerated approval	DASISION	3	CML-CP, N = 519	Dasatinib (once daily) versus imatinib	CCyR at 12 months: 77 versus 66%^*	MMR: 52% versus 34%^*	(Kantarjian et al., 2010, 2012)
CML-CP, resistant or intolerant to imatinib, once daily dosing		3	CML-CP, N = 670	Dasatinib dose optimization	MCyR:	OS, estimated at 24 months	(Shah et al., 2008, 2010)
Accelerated approval for daily dosing					140 mg daily: 63%	140 mg daily: 94$
					70 mg BID: 61%	70 mg BID: 88%
					100 mg daily: 63%	100 mg daily: 91%
					50 mg BID: 61%	50 mg BID: 90%
	START-C	2	CML-CP, N = 186	Dasatinib BID	MCyR: 52%	CHR: 90%	(Hochhaus et al., 2007)
	START-R	2	CML-CP, N = 150	Dasatinib BID (70 mg PO BID) versus imatinib	MCyR at 24 months: 53% versus 33%^*	CHR: 93% versus 82%^*	(Kantarjian et al., 2007a)
						TTF: not reached versus 3.5 months^*
						PFS: HR 0.14^*
CML advanced phase or Ph+ ALL, resistant or intolerant to imatinib		3	CML-AP, MB, LB, Ph+ ALL, N = 611	Dasatinib 140 mg daily versus 70 mg BID	MaHR: Daily versus BID	OS: 63 vs. 72% (no significant difference)	(Kantarjian et al., 2009; Lilly et al., 2010; Saglio et al., 2010a)
Accelerated approval					CML-AP: 66% versus 68%	CML-AP: 63% versus 72%, Est 24-month
					CML-MB: 28% versus 28%	CML-MB: 7.9 versus 7.7 months, median
					CML-LB: 42% versus 32%	CML-LB: 11.4 versus 9.0 months, median
					Ph+ ALL: 38% vs32%	Ph+ ALL: 6.5 versus 9.1 months, median
	START-A	2	CML-AP, N = 174	Dasatinib BID	MaHR: 64%	PFS, at 12 months: 66%	(Apperley et al., 2009)
	START-A	2	CML-AP, N = 174	Dasatinib BID	MaHR: 64%	OS, at 12 months: 82%	(Apperley et al., 2009)
	START-B and START-L	2	CML-MB, N = 74	Dasatinib BID	MaHR: 34% (CML-MB), 31% (CML-LB)	PFS: 6.7 months (CML-MB), 3.0 months (CML-LB)	(Cortes et al., 2007)
	START-B and START-L	2	CML-LB, N = 42	Dasatinib BID	OHR: 53% (CML-MB), 36% (CML-LB)	OS: 11.8 months (CML-MB), 5.3 months (CML-LB)	(Cortes et al., 2007)
	START-L	2	Ph+ ALL, N = 36	Dasatinib BID	MaHR: 42%	PFS: 3 months	(Ottmann et al., 2007)
	START-L	2	Ph+ ALL, N = 36	Dasatinib BID	OHR: 50%	OS at 24 months: 31%	(Ottmann et al., 2007)
Denileukin diftitox
Persistent or recurrent CD25+ CTCL		3	CTCL, stage IA to III, N = 144	Denileukin diftitox versus placebo	ORR: 49.1% (18 μg/kg)^* versus 37.8% (9 μg/kg)^* versus 15.9% (placebo)	PFS: 971 days (18 μg/kg) ^* versus 794 days (9 μg/kg) ^* versus 124 days (placebo)	(Prince et al., 2010)
Initial accelerated approval		3	CTCL, stage IA to III, N = 144	Denileukin diftitox versus placebo			(Prince et al., 2010)
		3	CTCL, stage Ib to IVa, N = 71	Denileukin diftitox	ORR: 30%	DR: 6.9 months	(Olsen et al., 2001)
Erlotinib
Locally advanced or metastatic NSCLC, maintenance after first-line therapy	SATURN	3	N = 889	Erlotinib versus placebo	PFS: 12.3 versus 11.1 weeks^*	OS: 12.0 vs11.0 months^*	(Cappuzzo et al., 2010; Shepherd et al., 2005).
Locally advanced or metastatic NSCLC, after prior failed chemotherapy		3	N = 731	Erlotinib	OS: 6.7 versus 4.7 months^*	ORR: 8.9% versus <1%^*
		3	N = 731	Erlotinib	OS: 6.7 versus 4.7 months^*	PFS: 2.2 versus 1.8 months^*
Locally advanced or metastatic pancreatic cancer, with gemcitabine, first-line		3	N = 569	Gemcitabine with versus without erlotinib	OS: 6.24 versus 5.91 months^*	One year survival: 23% versus 17%^*	(Moore et al., 2007)
		3	N = 569	Gemcitabine with versus without erlotinib	OS: 6.24 versus 5.91 months^*	PFS: 3.75 versus 3.55 months^*	(Moore et al., 2007)
Everolimus
Advanced HER2(−), HR(+) breast cancer, postmenopausal women, with exemestane, after failed letrozole or anastrozole	BOLERO-2	3	N = 724	Exemestane, with everolimus versus placebo	PFS: 10.6 versus 4.1 months^*	ORR: 9.5% versus 0.4%^*	(Baselga et al., 2012a)
Progressive PNET, locally advanced/metastatic disease	RADIANT-3	3	N = 410	Everolimus versus placebo	PFS:11.0 versus 4.6 months^*		(Yao et al., 2011)
Advanced RCC, after failure of sunitinib or sorafenib	RECORD-1	3	N = 410	Everolimus versus placebo	PFS: 4.0 versus 1.9 months^*	OS: no significant difference	(Motzer et al., 2008)
Renal angiomyolipoma with TSC, not requiring immediate surgery	EXIST-2	3	N = 118	Everolimus versus placebo	ORR: 42% versus 0%^*		(Bissler et al., 2013)
SEGA, TSC-associated, unresectable	EXIST-1	3	N = 117	Everolimus (suspension) versus placebo	50%+ reduction of target lesion volume: 35% versus 0%^*	Est PFS at 6 months: 100% versus 86% ^*	(Franz et al., 2013)
Accelerated approval for oral suspension and tablets	EXIST-1	3	N = 117	Everolimus (suspension) versus placebo	50%+ reduction of target lesion volume: 35% versus 0%^*	Est PFS at 6 months: 100% versus 86% ^*	(Franz et al., 2013)
		1-2	N = 28	Everolimus (tablets)	Median reduction in primary lesion volume at 6 months: 0.80 cm3^*	Median one fewer seizure over 6 months^*	(Krueger et al., 2010)
Ibritumomab tiuxetan
Follicular lymphoma, consolidation therapy after response to first-line therapy	FIT	3	Stage III/IV, N = 414	Ibritumomab regimen versus observation	PFS: 36.5 versus 13.3 months^*	CR/CRu: 87.5% versus 53.3% (significance testing not provided)	(Morschhauser et al., 2008)
Relapsed/refractory low-grade or follicular non–Hodgkin’s lymphoma		3	Rituximab naïve, N = 130	Ibritumomab regimen versus rituximab	ORR: 83% versus 55%^*	TTP: 12.1 versus 10.1 months	(Witzig et al., 2002a)
Accelerated approval		3	Rituximab naïve, N = 130	Ibritumomab regimen versus rituximab	ORR: 83% versus 55%^*	TTP: 12.1 versus 10.1 months	(Witzig et al., 2002a)
		NS	Refractory to rituximab, N = 54	Ibritumomab regimen	ORR: 74%	TTP: 6.8 months	(Witzig et al., 2002b)
		NS	Refractory to rituximab, N = 54	Ibritumomab regimen	CR: 15%	DR: 6.4 months	(Witzig et al., 2002b)
		2	N = 30	Ibritumomab regimen	ORR: 83%	TTP: 9.4 months	(Wiseman et al., 2002)
		2	N = 30	Ibritumomab regimen	CR 37%	DR: 11.6 months	(Wiseman et al., 2002)
Imatinib
Ph+ CML, chronic phase, newly diagnosed	IRIS	3	N = 1106	Imatinib versus INF-α + low-dose cytarabine	PFS at 84 months: 81.2% versus 60.6%^*	OS at 84 months: 86.4% versus 83.3%^*	(O’Brien et al., 2003)
Initial accelerated approval						CHR: 96.6% versus 56.6%^*
Initial accelerated approval						MCyR: 85.4% versus 16.8%^*
Ph+ CML (CP, AP, or BC), after failed IFN-α therapy		2	CML, late chronic phase, N = 532	Imatinib	MCyR: 60%	CHR: 96%	(Hochhaus et al., 2008; Kantarjian et al., 2002)
Initial accelerated approval						OS, 6 year estimated: 76%
Initial accelerated approval						CCyR 57%
		2	CML-AP, N = 235	Imatinib	CHR: 53%	MCyR: 24%	(Talpaz et al., 2002)
						PFS, 12 month: 59%
						OS, 12 month: 74%
		2	CML-blast crisis, N = 260	Imatinib	Sustained hematological response, lasting at least 4 weeks: 30.6%	DR, hematological: 10 months	(Sawyers et al., 2002)
						MCyR: 16.2%
						OS: 6.9 months
CML, pediatric (initial) accelerated approval		2	Pediatric CML-CP, N = 51	Imatinib	CHR 78% at 8 weeks	CCyR 65%	PI
		1	Pediatric CML-CP, recurrent, N = 14	Imatinib	CCyR 7/13		PI
		1	CML-CP, resistant to IFN-α, N = 3	Imatinib	CCyR: 2 of 3 patients		PI
KIT+ GIST, adjuvant treatment after resection	Scandinavian Sarcoma Group XVIII/AIO	3	N = 397	Imatinib for 12 versus 36 months	5-year RFS: 65.6% versus 47.9%^*	5-year OS: 92% versus 81.7%^*	(Joensuu et al., 2012)
Initial accelerated approval	Scandinavian Sarcoma Group XVIII/AIO	3	N = 397	Imatinib for 12 versus 36 months	5-year RFS: 65.6% versus 47.9%^*	5-year OS: 92% versus 81.7%^*	(Joensuu et al., 2012)
	ACOSOG Z9001 Trial		N = 713	Imatinib versus placebo	1-year RFS: 98% versus 83%^*	1-year OS: No significant difference	(Dematteo et al., 2009)
KIT+ GIST, unresectable/metastatic	SWOB S0033	3	N = 746	Imatinib daily versus BID	PFS: 18 months (daily) versus 20 months (BID)	OS: 55 months (daily) versus 51 months (BID)	(Blanke et al., 2008)
Initial accelerated approval	SWOB S0033	3	N = 746	Imatinib daily versus BID	PFS: 18 months (daily) versus 20 months (BID)	OS: 55 months (daily) versus 51 months (BID)	(Blanke et al., 2008)
	EORTC Study STSBG62005	3	N = 946	Imatinib daily versus BID	PFS at median 760 day follow-up: 56% (one daily) versus 50% (twice daily)^*	CR: 5%, no significant difference between groups	(Verweij et al., 2004)
Ph+ ALL, relapsed/refractory		2	N = 48	Imatinib	CHR: 19%	TTP 2.2 months	(Ottmann et al., 2002)
Ph+ ALL, relapsed/refractory		2	N = 48	Imatinib	CHR: 19%	OS: 4.9 months	(Ottmann et al., 2002)
MDS/MPD, with PDGFR rearrangement		NA	Phase 2/case reports, N = 31	Imatinib		CHR 45%	PI
MDS/MPD, with PDGFR rearrangement		NA	Phase 2/case reports, N = 31	Imatinib		MCyR: 39%	PI
ASM without c-Kit mutation/unknown c-Kit status		NA	Phase 2/case reports, N = 28	Imatinib		CHR: 29%	PI
ASM without c-Kit mutation/unknown c-Kit status		NA	Phase 2/case reports, N = 28	Imatinib		Partial hematological response: 32%	PI
HES/CEL, with FIP1L1-PDGFRalpha or unknown status		NA	Phase 2/case reports, N = 176	Imatinib		CHR: 61%	PI
HES/CEL, with FIP1L1-PDGFRalpha or unknown status		NA	Phase 2/case reports, N = 176	Imatinib		Partial hematological response: 13%	PI
DFSP, unresectable/recurrent/metastatic		NA	Phase 2/case reports, N = 18	Imatinib		CR: 39%	PI
DFSP, unresectable/recurrent/metastatic		NA	Phase 2/case reports, N = 18	Imatinib		PR: 44%	PI
Ipilimumab
Melanoma, unresectable/metastatic		3	N = 676	Ipilimumab with gp100 vaccine, versusipilumimab versus vaccine	OS: 10.0 months (combination) ^* versus 10.1 months (ipilimumab)^* versus 6.4 months (gp100)	ORR: 10.9% (ipilimumab)^* versus 5.7% (combination)^* versus 1.5% (gp 100 alone)	(Hodi et al., 2010)
Lapatinib
HER2+ breast cancer, locally advanced or metastatic, with capecitabine, after prior therapy			N = 399	Capecitabine with versus without lapatinib	TTP: 8.4 versus 4.4 months^*	ORR: 22% versus 14%^*	(Cameron et al., 2010; Geyer et al., 2006)
			N = 399	Capecitabine with versus without lapatinib	TTP: 8.4 versus 4.4 months^*	OS, adjusted for crossover: 75 versus 56.4 weeks^*	(Cameron et al., 2010; Geyer et al., 2006)
HER2+, HR+ breast cancer, metastatic, with letrozole, for postmenopausal women in whom hormonal therapy is indicated		3	N = 1286 (219 HER2+ patients)	Letrozole with versus without lapatinib	PFS (HER2+): 35.4 versus 13.0 weeks^*	ORR (HER2+): 27.9 versus 14.8%^*	(Schwartzberg et al., 2010), PI
Accelerated approval		3	N = 1286 (219 HER2+ patients)	Letrozole with versus without lapatinib	PFS (HER2+): 35.4 versus 13.0 weeks^*	ORR (HER2+): 27.9 versus 14.8%^*	(Schwartzberg et al., 2010), PI
Nilotinib
Ph+ CML-CP, newly diagnosed	ENESTnd	3	N = 846	Nilotinib 300 or 400 mg PO BID versus imatinib	12 month MMR: 44% (300 mg nilotinib)^* versus 43% (400 mg nilotinib)^* versus 22% (imatinib)	CCyR at 12 months: 80% (nilotinib 300 mg)^* versus 78% (nilotinib 400 mg) ^* versus 65% (imatinib)	(Larson et al., 2012; Saglio et al., 2010b)
Accelerated approval	ENESTnd	3	N = 846	Nilotinib 300 or 400 mg PO BID versus imatinib		OS at 3 years: no significant difference	(Larson et al., 2012; Saglio et al., 2010b)
Ph+ CML, CP or AP, imatinib resistant/intolerant		2	N = 321(CP cohort) and 137 (AP cohort)	Nilotinib	CP: MCyR: 59%	CML - CP:	(le Coutre et al., 2008, 2012; Kantarjian et al., 2007b, 2011)
Accelerated approval					AP: Hematological response: 55%	CCyR: 44%
						Est OS, at 24 months: 87%
						CML - AP:
						CCyR 21%
						Est OS at 24 months: 70%
Ofatumumab
CLL, relapsed/refractory		NS	N = 154	Ofatumumab	ORR: 42%	DR: 6.5 months	(Wierda et al., 2010), PI
Accelerated approval		NS	N = 154	Ofatumumab	ORR: 42%	DR: 6.5 months	(Wierda et al., 2010), PI
		1/2	N = 33	Ofatumumab dose escalation	ORR: 44%		(Coiffier et al., 2008)
Ponatinib
CML or Ph+ ALL, resistant or intolerant to tyrosine kinase inhibitor therapy	PACE	2	N = 444	Ponatinib	MCyR	Time to MCyR:	(Cortes et al., 2012)
Accelerated approval					CML-CP: 54%	CML-CP: 84 days
					MaHR:	Duration of MaHR:
					CML-AP:52%	CML-AP: 9.5 months
					CML-BP: 31%	CML-BP: 4.7 months
					Ph+ ALL: 41%	Ph+ ALL: 3.2 months
Panitumumab
Metastatic CRC, K-RAS WT, single agent, after progression on fluoropyrimidine, oxaliplatin, and irinotecan		3	N = 463	Panitumomab versus BSC	PFS: 8 weeks versus 7.3 weeks^*	ORR: 10% versus 0%^*	(Amado et al., 2008; Van Cutsem et al., 2007)
					Retrospective:	OS, K-RAS WT: 8.1 versus 7.6 months^*
					K-RAS WT: 12.3 versus 7.3 weeks^*
					K-RAS+: 7.4 versus 7.3 weeks
Pazopanib
Advanced RCC		3	First-line or cytokine refractory, N = 435	Pazopanib versus placebo	PFS: 9.2 versus 4.2 months^*	ORR: 30% versus 3%^*	(Sternberg et al., 2010)
Advanced soft tissue sarcoma, after prior chemotherapy	PALETTE	3	N = 369	Pazopanib versus placebo	PFS: 4.6 versus 1.6 months^*	OS: 12.5 months versus 10.7 months	(van der Graaf et al., 2012)
Pertuzumab
Metastatic breast cancer, HER2+, no prior HER2 therapy or chemotherapy for metastatic disease, with trastuzumab/docetaxel	CLEOPATRA	3	N = 808	Trastuzumab plus docetaxel, with versus without pertuzumab	PFS: 18.5 months versus 12.4 months^*	OS (median 19.3 month follow-up): 23.6% versus 17.2%^*	(Baselga et al., 2012b)
Rituximab
Low-grade/follicular NHL, after response to first-line induction	PRIMA	3	After response to rituximab + chemotherapy, N = 1018	Rituximab maintenance versus observation	PFS at mean 36 months follow-up: 74.9% versus 57.6%^*	OS: no significant difference	(Salles et al., 2011)
	ECOG 1496	3	N = 311	CVP followed by rituximab versus observation	PFS: 4.3 versus 1.3 years^*	3-year OS: 92% versus 86%^*	(Hochster et al., 2009)
Follicular lymphoma, previously untreated		3	N = 321	CVP chemotherapy with versus without rituximab	TTF: 27 versus 7 months^*	CR: 30% versus 8%^*	(Marcus et al., 2005)
Follicular lymphoma, previously untreated		3	N = 321	CVP chemotherapy with versus without rituximab	TTF: 27 versus 7 months^*	TTP: 32 versus 15 months^*	(Marcus et al., 2005)
Follicular/low-grade NHL, relapsed/refractory		NS	N = 166	Rituximab		ORR 48%	(McLaughlin et al., 1998)
Follicular/low-grade NHL, relapsed/refractory		NS	N = 166	Rituximab		Estimated TTP: 12.5 months	(McLaughlin et al., 1998)
		2	N = 37	Rituximab		ORR 57%	(Piro et al., 1999)
		2	N = 37	Rituximab		TTP: not reached at 19.4 months.	(Piro et al., 1999)
		2	N = 60	Rituximab		ORR 40%	(Davis et al., 2000)
		2	N = 60	Rituximab		Estimated TTP: 17.8 months	(Davis et al., 2000)
DLBCL, in combination with CHOP or anthracycline-based chemotherapy	MInT Study	3	Age 18–60 years, N = 824	CHOP-like chemotherapy+/− rituximab	3-year event-free survival: 79% versus 59%^*	OS, at 3 years: 93% versus 84%^*	(Pfreundschuh et al., 2006)
	ECOG 4494 trial	3	Age 60–80, N = 632	CHOP with versus without rituximab	3-year FFS: 53% versus 46%^*	PFS, adjusted: 3.1 versus 1.6 years^*	(Habermann et al., 2006), PI
	ECOG 4494 trial	3	Age 60–80, N = 632	CHOP with versus without rituximab	3-year FFS: 53% versus 46%^*	OS, 2 year, adjusted: 74% versus 63%^*	(Habermann et al., 2006), PI
	GELA/LNH-98.5	3	Age 60–80, N = 399	CHOP with versus without rituximab	EFS, at median 24 months: 57% versus 49%^*	OS: 8.4 versus 3.5 years^*	(Coiffier et al., 2002)
Previously untreated follicular NHL or DLBCL, as 90-minute infusion	RATE	NS	N = 363	Follicular lymphoma: R- CVP	Grade 3–4 infusion reactions: 2.8% starting at cycle 2		^c
	RATE	NS	N = 363	DLBCL: R-CHOP	Grade 3–4 infusion reactions: 2.8% starting at cycle 2		^c
CLL		3	CLL, previously untreated, N = 817	Fludarabine/cyclophosphamide with versus without rituximab	PFS at 3 years: 65% versus 45%^*	OS at 3 years: 87% versus 83%	(Hallek et al., 2010)
	REACH	3	CLL, previously treated, N = 552	Fludarabine/cyclophosphamide with versus without rituximab	PFS: 27 versus 21.9 months^*	OS: No significant difference, crossover design	(Robak et al., 2010)
	REACH	3	CLL, previously treated, N = 552	Fludarabine/cyclophosphamide with versus without rituximab	PFS: 27 versus 21.9 months^*	ORR: 69.9% versus 58%^*	(Robak et al., 2010)
Regorafenib
Metastatic CRC, previously treated with fluoropyrimidine/oxaliplatin/irinotecan-based chemotherapy, VEGF therapy and anti-EGFR therapy if K-RAS WT	CORRECT	3	N = 760	Regorafenib versus placebo	OS: 6.4 versus 5.0 months^*	PFS: 2.0 versus 1.7 months^*	(Grothey et al., 2013), PI
	CORRECT	3	N = 760	Regorafenib versus placebo	OS: 6.4 versus 5.0 months^*	ORR: 1% versus 0.4%	(Grothey et al., 2013), PI
Romidepsin
CTCL after at least one prior systemic therapy		2	N = 96	Romidepsin	ORR: 34%	DR: 15 months	(Whittaker et al., 2010)
CTCL after at least one prior systemic therapy		2	N = 96	Romidepsin	ORR: 34%	Improved pruritus: 43%, median duration 6 months	(Whittaker et al., 2010)
		2	N = 71	Romidepsin		ORR: 34%	(Piekarz et al., 2009)
						CRR 7%
						DR: 13.7 months
PTCL, after at least one prior therapy		2	N = 130	Romidepsin	CR+CRu: 14.6% (95% CI 9%–21.9%)	ORR: 25.4%	(Coiffier et al., 2012)
Accelerated approval						TTR: 1.9 months
						DR: 16.6 months
		2	N = 47	Romidepsin	ORR: 38% (95% CI 24%–53%) CR: 18%	DR: 8.9 months	(Piekarz et al., 2011)
Ruxolitinib
Intermediate or high-risk myelofibrosis	COMFORT-I	3	N = 309	Ruxolitinib versus placebo	Spleen volume decreased by >35% at 24 weeks: 41.9% versus 0.7% ^*	Symptom improvement: 45.9% versus 5.3%^*	(Verstovsek et al., 2012)
Intermediate or high-risk myelofibrosis	COMFORT-I	3	N = 309	Ruxolitinib versus placebo		OS at median 51 weeks: 91.6% versus 84.4%^*	(Verstovsek et al., 2012)
	COMFORT-II	3	N = 219	Ruxolitinib versus best available therapy	Spleen volume decreased by >35%, at 48 weeks: 28 versus 0%^*	No significant difference in TTP or OS at 48-week follow-up	(Harrison et al., 2012)
Sorafenib
Advanced RCC	TARGET	3	Refractory to standard therapy, N = 903	Sorafenib versus placebo	OS: 14.7 months versus not reached^*	PFS: 5.5 versus 2.8 months^*	(Escudier et al., 2007b)
		2	Refractory to standard therapy, N = 202	Sorafenib versus placebo	PFS at 24 weeks: 50% versus 18%^*	PFS: 24 versus 6 weeks^*	(Ratain et al., 2006)
Unresectable HCC	SHARP	3	No prior systemic treatment, N = 602	Sorafenib versus placebo	OS: 10.7 versus 7.9 months^*	Time to radiological progression: 5.5 versus 2.8 months^*	(Llovet et al., 2008)
Unresectable HCC	SHARP	3	No prior systemic treatment, N = 602	Sorafenib versus placebo	Time to symptomatic progression: 4.9 versus 4.1 months	Time to radiological progression: 5.5 versus 2.8 months^*	(Llovet et al., 2008)
Sunitinib
GIST, after imatinib resistance/intolerance		3	N = 312	Sunitinib versus placebo	TTP: 27.3 versus 6.4 weeks^*	PFS: 24.1 versus 6 weeks^*	(Demetri et al., 2006)
		NS	N = 55	Sunitinib dose escalation		PR: 9.1%	PI
Advanced RCC		3	No prior treatment, N = 750	Sunitinib versus IFN-α	PFS: 11 versus 5 months^*	ORR: 31% versus 6%^*	(Motzer et al., 2007)
Initial accelerated approval		3	No prior treatment, N = 750	Sunitinib versus IFN-α	PFS: 11 versus 5 months^*	ORR: 31% versus 6%^*	(Motzer et al., 2007)
		2	Refractory to cytokines, N = 106	Sunitinib	ORR: 34%	PFS: 8.3 months	(Motzer et al., 2006a)
		2	Refractory to cytokines, N = 63	Sunitinib	ORR: 40% PR	TTP: 8.7 months	(Motzer et al., 2006b)
		2	Refractory to cytokines, N = 63	Sunitinib	ORR: 40% PR	OS: 16.4 months	(Motzer et al., 2006b)
PNET, unresectable or metastatic		3	N = 171	Sunitinib versus placebo	PFS: 11.4 versus 5.5 months^*	ORR: 9.3% versus 0%^*	(Raymond et al., 2011)
PNET, unresectable or metastatic		3	N = 171	Sunitinib versus placebo	PFS: 11.4 versus 5.5 months^*	OS at 6 months: 92.6% versus 85.2%^*	(Raymond et al., 2011)
Temsirolimus
Advanced RCC		3	Metastatic RCC, N = 626	Temsirolimus versus IFN-α versus combination	OS: 10.9 months (temsirolimus)^* versus 7.3 months (IFN) versus 8.4 months (combination)	ORR: 8.6% (temsirolimus) versus 4.8% (IFN) versus 8.1% (combination)	(Hudes et al., 2007)
Tositumomab
Relapsed/refractory CD20+ NHL, progression after/on rituximab		2	N = 40	Tositumomab therapeutic regimen	ORR: 68%	PFS: 10.4 months	(Horning et al., 2005)
						CR: 33%
						DR: 16 months
Trastuzumab
Metastatic gastric or GE junction adenocarcinoma, HER2+	ToGA	3	Previously untreated for metastatic disease, N = 594	Capecitabine or fluorouracil, with cisplatin, with versus without trastuzumab	OS: 13.8 versus 11,1 months^*	PFS: 6.7 versus 5.5 months^*	(Bang et al., 2010)
Breast cancer, HER2+, adjuvant	NCCTG N9831; NSABP B-31	3	N = 3351	Doxorubicin/cyclophosphamide with paclitaxel, with versus without trastuzumab	Disease-free survival, median 4-month follow-up: 85.3% versus 67.1%^*	OS at 4 years: 91.4% versus 86.6%^*	(Romond et al., 2005)
	HERA	3	N = 3401	Trastuzumab versus observation	DFS at 4 years: 78.6% versus 72.2%^*	OS at 4 years: 89.3% versus 87.7%	(Gianni et al., 2011; Piccart-Gebhart et al., 2005)
	BCIRG 006	3	N = 3222	AC-T (doxorubicin + cyclophosphamide and docetaxel q3 weeks) versus AC-T with trastuzumab for 52 weeks versus docetaxel and carboplatin with trastuzumab for 52 weeks (TCH)	DFS at 5 years (estimated): 75% (AC-T), 84% (AC-T + trastuzumab) ^* versus 81% (TCH) ^*	OS at 5 years (estimated): 87% (AC-T) versus 92% (AC-T + trastuzumab) versus 91% (TCH) ^*	(Slamon et al., 2011)
HER2+ breast cancer, metastatic	H0648g	3	Previously untreated, N = 469	Paclitaxel or AC with versus without trastuzumab	TTP: 7.2 versus 4.5 months^*	ORR: 45% versus 29%^*	(Eiermann, 2001; Slamon et al., 2001),PI
HER2+ breast cancer, metastatic	H0648g	3	Previously untreated, N = 469	Paclitaxel or AC with versus without trastuzumab	TTP: 7.2 versus 4.5 months^*	OS: 25.1 versus 20.3 months^*	(Eiermann, 2001; Slamon et al., 2001),PI
	H0649g	2	Progressive despite 1–2 prior chemotherapy regimens, N = 222	Trastuzumab	ORR: 15%	DR: 9.1 months	(Cobleigh et al., 1999)
	H0649g	2		Trastuzumab	ORR: 15%	OS: 13 months	(Cobleigh et al., 1999)
Trastuzumab-DM1
Metastatic breast cancer, HER2 +, second-line after prior treatment with trastuzumab and a taxane	EMILIA	3	N = 991	Trastuzumab-DM1 versus lapatinib with capecitabine	PFS: 9.6 versus 6.4 months^*	ORR: 43.6% versus 30.8%^*	(Verma et al., 2012)
	EMILIA	3	N = 991	Trastuzumab-DM1 versus lapatinib with capecitabine	OS: 30.9 versus 25.1 months^*	ORR: 43.6% versus 30.8%^*	(Verma et al., 2012)
Vandetanib
Medullary thyroid cancer, symptomatic or progressive, and unresectable/metastatic	ZETA	3	N = 331	Vandetanib versus placebo	PFS: 30.5 versus 19.3 months^*	ORR: 45% versus 13%^*	(Wells et al., 2010, 2012)
Vemurafenib
Melanoma, with the BRAF V600E mutation, unresectable or metastatic	BRIM3	3	Previously untreated, N = 675	Vemurafenib versus dacarbazine	OS at 6 months: 84% versus 64%^*	ORR: 48% versus 5%^*	(Chapman et al., 2011; Flaherty et al., 2010)
	BRIM3	3	Previously untreated, N = 675	Vemurafenib versus dacarbazine	PFS: 5.3 versus 1.6 months^*	ORR: 48% versus 5%^*	(Chapman et al., 2011; Flaherty et al., 2010)
	BRIM2	2	Previously treated, N = 132	Vemurafenib	ORR at 12.9-month follow-up: 53%	DR: 6.7 months	(Sosman et al., 2012)
						PFS: 6.8 months
						OS: 15.9 months
Vismodegib
BCC, metastatic or recurrent locally advanced, not surgical or radiation therapy candidate	ERIVANCE	2	N = 96	Vismodegib	ORR: 30% (metastatic), 43% (locally advanced)	DR: 7.6 months	(Sekulic et al., 2012)
	ERIVANCE	2	N = 96	Vismodegib	ORR: 30% (metastatic), 43% (locally advanced)	PFS: 9.5 months	(Sekulic et al., 2012)
Vorinostat
CTCL, cutaneous manifestations, despite two prior systemic therapies		2B	N = 74	Vorinostat	ORR: 29.7%	DR: Est 185+ days	(Olsen et al., 2007)
		2	N = 33	Vorinostat	ORR: 24.2%	DR: 15.1 weeks	(Duvic et al., 2007)
Ziv-aflibercept
Metastatic CRC, with FOLFIRI, after progression on an oxaliplatin-containing regimen	VELOUR	3	N = 1226	FOLFIRI with Ziv-aflibercept versus placebo	OS: 13.5 versus 12.06 months^*	PFS: 6.90 versus 4.67 months^*	PI^d
	VELOUR	3	N = 1226	FOLFIRI with Ziv-aflibercept versus placebo	OS: 13.5 versus 12.06 months^*	ORR: 19.8% versus 11.1%^*	PI^d

AC, anthracycline plus cyclophosphamide; AC-T, anthracycline, cyclophosphamide, taxol; ALL, acute lymphoblastic leukemia; AP, accelerated phase; ASM, aggressive systemic mastocytosis; BCC, basal cell carcinoma; B-CLL, B cell CLL; BID, twice daily; BP, blast phase; BSC, best supportive care; CCyR, complete cytogenetic response; CEL, chronic eosinophilic leukemia; CHOP, cyclophosphamide, hydroxyldaunorubicin, oncovin, and prednisone; CHR, complete hematological response; CP, chronic phase; CR, complete response; CRu, unconfirmed complete response; CTCL, cutaneous T-cell lymphoma; CVP, cyclophosphamide, vincristine, and prednisone; DFS, disease-free survival; DFSP, dermatofibrosarcoma protuberans; DLBCL, diffuse large B cell lymphoma; DR, disease recurrence; EFS, event-free survival; FFS, failure-free survival; 5-FU, 5-fluorouracil; FOLFIRI, leucovorin, fluorouracil, irinotecan; FOLFOX, leucovorin, fluorouracil, oxaliplatin; GE, gastroesophageal; HCC, hepatocellular carcinoma; HES, hypereosinophilic syndrome; HR, hazard ratio; IFN-α, interferon-α; LB, lymphoid blast; LV, leucovorin; MaHR, major hematological response; MB, myeloid blast; MCyR, major cytogenetic response; MDS, myelodysplastic syndromes; MMR, major molecular response; MPD, myeloproliferative disease; N/A, not applicable; NHL, non–Hodgkin's lymphoma; NS, not significant; OHR, overall hematological response; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PI, package information, package insert; PO, by mouth; PR, partial response; PTCL, peripheral T cell lymphoma; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-CVP, rituximab, cyclophosphamide, vincristine, prednisone; RFS, recurrence-free survival; RR, response rate; sALCL, systemic anaplastic large-cell lymphoma; SCCHN, squamous cell carcinoma of the head and neck; SCT, stem cell transplant; SEGA, subependymal giant cell astrocytoma; SQ, subcutaneous; TCH, docetaxel, carboplatin, trastuzumab; TSC, tuberous sclerosis complex; TTF, time to treatment failure; TTP, time to progression; TTR, time to recurrence.
↵^a Crinò et al., 2011.
↵^b Camidge et al., 2011.
↵^c Dakhil et al., 2011.
↵^d Joulain et al., 2012.
↵* Statistically significant difference (P < 0.05).