Table 7.

Treatment-related outcomes and dose adjustment of everolimus in previous studies

Study, (year)	n	Regimen (n)	Treatment duration, median	Reasons of discontinuation		Dose adjustment of Eve		Dose intensity of Eve, median (mg/day)	Eve-related mortality
				AEs	Disease progression	Reduction (R)	Interruption (I)
Phase I-III studies
RADIANT-1, phase II; Yao et al (2008)[20]	60	Eve + Oct	-	5%	-	13%	-	-	-
RADIANT-2, phase III; Pavel et al (2011)[21]	216	Eve + Oct	9.2 mo	19%	44%	65% (R+I)		8.3	0%
RADIANT-3, phase III; Yao et al (2011)[22]	207	Eve	8.8 mo	17%	44%	59% (R+I)			<1% a
Sub-analysis Yao et al (2016)[65]	225	Eve (open label)	44 wk	24%	55%	-	-	-	0%
RADIANT-4, phase III; Yao et al (2016)[23]	205	Eve	40.4 wk	12%	37%	67% (R+I)		-	1% b
Phase II; Yao et al (2010)[72]	115 45	Eve Eve + Oct	- -	- -	- -	- -	- -	9.9 9.4	- -
Phase II; Bajetta et al (2014)[73]	50	Eve + Oct	74 wk	16%	-	26%	0%	9.4	0%
COOPERATE-2, phase II;  Kulke et al (2017)[75]	79 81	Eve + Pas Eve	49.4 wk 48.3 wk	23% 21%	40% 43%	53% 36%	65% 56%	7.8 9.8	3% c 1% c
LUNA, Phase II; Ferolla et al (2015)[76]	42 41	Eve Eve + Pas	-	35% 32%	17% 24%	67% (R+I) 54% (R+I)		9.4 8.4	2% d 5% d
Phase I; Chan et al (2012)[77]	22	Eve + Pas	6 cycles (4-wk)	5%	36%	14%	-	-	0%
Phase II; Salazar et al (2017)[86]	31	Eve	39.4 wk	16%	-	-	-	-	0%
Phase I/II; Chan et al (2013)[83]	43	Eve + temozolomide	8.5 cycles (4-wk)	21%	49%	-	-	-	0%
Phase I; Chan et al (2013)[84]	21	Eve + sorafenib	4 cycles (4-wk)	14%	57%	14%	-	-	0%
Phase I; Dasari et al (2015)[78]	19	Eve + Oct + cixutumumab	10 cycles (3-wk)	21%	42%	-	-	-	0%
NETTLE, Phase I; Claringbold et al (2015)[85]	16	Eve + PRRT	24 wk (Eve) + 4 cycles of PRRT (8-wk)	-	0%	100% (R+I) in 10mg cohort		8.3, 8.0, 4.8 in 5mg, 7.5mg, 10mg cohort	0%
Prospective /retrospective studies
Yao et al (2015)[96]	39	BV or Eve → Bv + Eve	-	-	-	25% (R+I)		-	0%
Pavel et al (2016) [166]	123 117	Eve (PANNET) Eve (non PANNET)	12.1 wk 24 wk	17% 25%	- -	39% (R+I) 53% (R+I)		- -	0% 0%
Panzuto et al [91]	169	Eve	6 mo	9%	50%	17%	63%	-	0%
Berardi et al (2017)[92]	116	Eve	-	-	-	22%	66%	-	0%
Capdevila et al (2015) [100]	73	Eve + lanreotide	4.7mo	14%	32%	-	-	-	-
Liu et al (2016) [93]	53	Eve	-	6%	51%	-	-	-	2% e
Lee et al (2017) [94]	47	Eve	50 wk	34%	43%	-	-	-	0%
Lee et al (2017) [95]	40	Eve	8 mo	5%	-	-	-	-	0%
Angelousi et al (2017)[98]	20 11	Eve (1st line) Eve (2nd line)	13.6 mo 7 mo	10% 9%	90% 63%	- -	- -	- -	0% 0%
Kamp et al (2013) [97]	24	Eve	10.2 mo	17%	29%	17%	29%	-	0%
Yoo et al (2017) [99]	17	Eve	-	24%	-	29%	-	-	0%

AEs, adverse events; Bv,bevacizumab; Eve, everolimus; Plt, platelet; panNET, pancreatic NET; Oct,octreotide; Pas, pasireotide; PRRT, peptide receptor radionuclide therapy .

^aIncluded acute respiratory distress syndrome (n=1).

^bIncluded respiratory failure (n=1), septic shock (n=1), and cardiac failure (n=1).

^cIncluded ketoacidosis (n=1) and sepsis (n=1) in combination arm; pulmonary embolism (n=1) in Eve arm.

^dIncluded acute kidney injury associated with diarrhea(n=1) in Eve arm; diarrhea and urinary sepsis (n=1), acute renal failure and respiratory failure (n=1) in combination arm.

^eIncluded interstitial pneumonitis (n=1).