Comparative effectiveness of second-line targeted therapies for metastatic renal cell carcinoma: synthesis of findings from two multi-practice chart reviews in the United States

Figures & data

Figure 1. Sample selection (2010–2012 chart review). mRCC: metastatic renal cell carcinoma; TKI: tyrosine kinase inhibitor.

Table 1. Patient baseline characteristics (2010–2012 chart review study)^a.

Characteristics	Overall	Second Targeted Therapy			p Value
		Everolimus (n = 138)	Temsirolimus (n = 64)	TKI (n = 79)
Age at mRCC diagnosis, years, mean (SD)	63.03 (10.36)	63.62 (10.36)	62.53 (9.69)	62.41 (10.94)	0.867
Gender, n (%)					0.149
Male	182 (64.8)	85 (61.6)	48 (75.0)	49 (62.0)
Female	99 (35.2)	53 (38.4)	16 (25.0)	30 (38.0)
RCC at time of diagnosis, n (%)					0.620
Metastasized	115 (40.9)	60 (43.5)	26 (40.6)	29 (36.7)
Not metastasized	166 (59.1)	78 (56.5)	38 (59.4)	50 (63.3)
mRCC duration at second targeted therapy initiation, n (%)					0.306
Less than 12 months	163 (59.1)	87 (63.5)	35 (56.5)	41 (53.2)
12 months or more	113 (40.9)	50 (36.5)	27 (43.5)	36 (46.8)
First targeted therapy, n (%)					0.046*
Sunitinib	206 (73.3)	100 (72.5)	53 (82.8)	53 (67.1)
Sorafenib	49 (17.4)	21 (15.2)	7 (10.9)	21 (26.6)
Pazopanib	26 (9.3)	17 (12.3)	4 (6.3)	5 (6.3)
Second targeted therapy, n (%)					–
Everolimus	138 (49.1)	138 (100.0)	–	–
Temsirolimus	64 (22.8)	–	64 (100.0)	–
Sorafenib	20 (7.1)	–	–	20 (25.3)
Sunitinib	16 (5.7)	–	–	16 (20.3)
Pazopanib	35 (12.5)	–	–	35 (44.3)
Axitinib	8 (2.8)	–	–	8 (10.1)
Responded during first targeted therapy, n (%)					0.667
Yes	184 (65.5)	93 (67.4)	39 (60.9)	52 (65.8)
No	97 (34.5)	45 (32.6)	25 (39.1)	27 (34.2)
Progressed during first targeted therapy, n (%)					0.990
Yes	236 (84.0)	116 (84.1)	54 (84.4)	66 (83.5)
No	45 (16.0)	22 (15.9)	10 (15.6)	13 (16.5)
Duration of first targeted therapy, months, mean (SD)	10.56 (7.92)	9.95 (6.37)	11.20 (10.79)	11.10 (7.57)	0.559
Treatments received before first targeted therapy, n (%)					0.550
No treatment	106 (37.7)	55 (39.9)	26 (40.6)	25 (31.6)
Complete or partial nephrectomy	130 (46.3)	66 (47.8)	25 (39.1)	39 (49.4)
Systemic	11 (3.9)	5 (3.6)	3 (4.7)	3 (3.8)
Radiation	7 (2.5)	1 (0.7)	3 (4.7)	3 (3.8)
Other	5 (1.8)	3 (2.2)	0 (0.0)	2 (2.5)
More than one type of treatment	22 (7.8)	8 (5.8)	7 (10.9)	7 (8.9)
Number of comorbidities at second targeted therapy initiation, mean (SD)	2.04 (1.53)	2.17 (1.59)	2.03 (1.31)	1.84 (1.60)	0.232
Existence of any comorbidities at second targeted therapy initiation, n (%)					0.335
Yes	232 (82.6)	117 (84.8)	54 (84.4)	61 (77.2)
No	49 (17.4)	21 (15.2)	10 (15.6)	18 (22.8)
Clear cell RCC at second targeted therapy initiation, n (%)					0.436
Yes	236 (84.0)	112 (81.2)	55 (85.9)	69 (87.3)
No	45 (16.0)	26 (18.8)	9 (14.1)	10 (12.7)
Number of metastatic sites at second targeted therapy initiation, mean (SD)	2.53 (1.03)	2.49 (1.03)	2.61 (0.90)	2.54 (1.12)	0.607
Sites of metastasis at second targeted therapy initiation, n (%)
Lung	232 (82.6)	117 (84.8)	54 (84.4)	61 (77.2)	0.335
Lymph nodes	152 (54.1)	79 (57.2)	32 (50.0)	41 (51.9)	0.566
Bone	148 (52.7)	62 (44.9)	41 (64.1)	45 (57.0)	0.027*
Liver	76 (27.0)	40 (29.0)	11 (17.2)	25 (31.6)	0.119
Adrenal	35 (12.5)	14 (10.1)	11 (17.2)	10 (12.7)	0.369
Soft tissue other than lymph nodes	49 (17.4)	22 (15.9)	14 (21.9)	13 (16.5)	0.565
Central nervous system (CNS)	13 (4.6)	7 (5.1)	3 (4.7)	3 (3.8)	0.911
Other^b	6 (2.1)	2 (1.4)	1 (1.6)	3 (3.8)	0.483
ECOG at initiation of second targeted therapy, n (%)					0.074
0	40 (14.6)	18 (13.3)	4 (6.6)	18 (23.1)
1 or more	234 (85.4)	117 (86.7)	57 (93.4)	60 (76.9)
KPS at initiation of second targeted therapy, mean (SD)	79.47 (12.83)	78.40 (12.04)	76.67 (12.84)	83.80 (13.54)	0.002**
MSKCC at initiation of second targeted therapy, n (%)					0.068
Favorable	67 (23.8)	36 (26.1)	9 (14.1)	22 (27.8)
Intermediate	138 (49.1)	74 (53.6)	30 (46.9)	34 (43.0)
Poor	30 (10.7)	12 (8.7)	11 (17.2)	7 (8.9)
Missing	46 (16.4)	16 (11.6)	14 (21.9)	16 (20.3)
Years of practice of treating physicians, mean (SD)	14.59 (6.70)	14.70 (6.76)	14.80 (6.34)	14.24 (6.94)	0.529
Comorbidities
Diabetes mellitus (type I or II)	95 (33.9)	50 (36.5)	21 (32.8)	24 (30.4)	0.643
Chronic renal disease	87 (31.1)	42 (30.4)	20 (31.7)	25 (31.6)	0.974
Cardiovascular diseases	57 (20.4)	35 (25.4)	9 (14.3)	13 (16.5)	0.116
Hypertension	179 (63.7)	90 (65.2)	44 (68.8)	45 (57.0)	0.302
Hypercholesterolemia/hypertriglyceridemia	117 (41.8)	59 (42.8)	29 (46.0)	29 (36.7)	0.507
Liver disorders	15 (5.3)	10 (7.2)	2 (3.1)	3 (3.8)	0.370
History of stroke	17 (6.0)	10 (7.2)	4 (6.3)	3 (3.8)	0.589
Neurological diseases	4 (1.4)	2 (1.4)	1 (1.6)	1 (1.3)	0.987

^aPatients who used an mTOR or bevacizumab as first targeted therapy, discontinued first targeted therapy for non-medical reasons, or used bevacizumab as second targeted therapy were excluded from the analysis.

^bOther metastatic sites included ‘Pancreas’ (2), ‘Brain’ (1), ‘Renal fossa’ (1), ‘Peritoneal surface’ (1), and ‘Pelvis’ (1).

*Groups are statistically significant at the 5% significance level.

**Groups are statistically significant at the 1% significance level.

ECOG: Eastern Cooperative Oncology Group; KPS: Karnofsky performance status; mRCC: metastatic renal cell carcinoma; MSKCC: Memorial Sloan–Kettering Cancer Center; N: number; SD: standard deviation; TKI: tyrosine kinase inhibitor.

Table 2. Survival and follow-up time summary for second-line treatments in both (2009–2011 and 2010–2012) chart review studies.

Data source/treatment	N	Observed deaths	Adjusted median OS^a	% patients deceased	Median follow-up (months)
2009–2011 chart review study
Everolimus	233	100	19.0	42.90	12.9
Temsirolimus	178	85	12.9	47.80	9.9
Sorafenib	123	48	13.8	39.00	12.1
2010–2012 chart review study
Everolimus	138	29	27.4	21.00	5.8
Temsirolimus	64	13	18.8	20.30	5.8
TKI	79	16	NR	20.30	7.2

^aOverall survival (OS) is measured from the start of the second-line therapy. The adjusted median OS is estimated using Cox proportional hazard models.

NR: not reached; TKI: tyrosine kinase inhibitor.

Table 3. Adjusted comparisons of time to treatment failure and overall survival (2010–2012 chart review study)^a,b.

	Hazard Ratio	95% Confidence Interval	p Value
Overall Survival^c
Everolimus versus  temsirolimus	0.627	(0.301–1.306)	0.212
Everolimus versus TKI^e	1.156	(0.553–2.418)	0.700
Temsirolimus versus TKI	1.845	(0.754–4.511)	0.180
Time to Treatment Failure^d
Everolimus versus  temsirolimus	0.724	(0.450–1.164)	0.182
Everolimus versus TKI^e	0.740	(0.477–1.146)	0.177
Temsirolimus versus TKI	1.022	(0.605–1.725)	0.936

^aOverall survival was defined as the time from the initiation of second targeted therapy to death from any cause. Patients without recorded death events during the study period were censored at the last follow-up date.

^bTime to treatment failure was defined as the time to progression of disease, discontinuation of second line therapy, or death from any cause. Patients without treatment failure events during the study period were censored at the last follow-up date.

^cResults were based on a combined regression model, which included patients on everolimus, temsirolimus, or TKI. A total of 264 patients were included in the final model. The test of proportional hazards for second targeted therapy had a p-value of 0.8521.

^dA total of 264 patients were included in the final model. The test of proportional hazards for second targeted therapy had a p-value of 0.1390.

^eSecond-line TKI treatment included sorafenib, sunitinib, pazopanib, and axitinib.

TKI: tyrosine kinase inhibitor.

Table 4. Multivariable Cox proportional hazards model for time to treatment failure (2010–2012 chart review).

Characteristic (Reference Group)	Hazard Ratio	95% Confidence Interval	p Value
2nd targeted therapy (everolimus)
Temsirolimus	1.381	(0.859–2.221)	0.182
TKI	1.352	(0.873–2.094)	0.177
Age at mRCC diagnosis, years	0.996	(0.977–1.014)	0.652
Gender (female)
Male	0.782	(0.522–1.173)	0.235
Metastasized RRC at time of diagnosis (no)
Yes	1.237	(0.824–1.856)	0.305
1st targeted therapy (sorafenib or pazopanib)
Sunitinib	1.121	(0.750–1.674)	0.578
Response history during 1st targeted therapy (no)
Yes	1.018	(0.682–1.520)	0.929
Progression history during 1st targeted therapy (no)
Yes	0.772	(0.465–1.282)	0.318
Duration of mRCC at 2nd targeted therapy initiation (less than 12 months)
12 months or more	0.927	(0.589–1.457)	0.741
Duration of first targeted therapy, months	0.977	(0.951–1.003)	0.085
Treatments received before 1st targeted therapy (no treatment)
Complete or partial nephrectomy	0.661	(0.428–1.020)	0.061
Other treatment	0.760	(0.450–1.283)	0.305
Site of metastasis at the time of 2nd targeted therapy initiation
Bone	0.797	(0.541–1.175)	0.252
Lung	1.616	(0.950–2.749)	0.077
Liver	1.442	(0.911–2.282)	0.118
Central nervous system	3.562	(1.701–7.457)	0.001**
Other sites	1.099	(0.751–1.610)	0.627
mRCC histologic subtype (non-clear cell)
Clear cell RCC	1.122	(0.671–1.875)	0.661
Existence of any comorbidities at the time of 2nd targeted therapy initiation (no)
Yes	0.818	(0.466–1.435)	0.484
ECOG status at the time of 2nd targeted therapy initiation (ECOG = 0)
1 or more	1.911	(1.043–3.502)	0.036*
Years of practice of treating physicians	1.021	(0.992–1.050)	0.155

Time to treatment failure was defined as the time to progression of disease, discontinuation of second line therapy, or death from any cause. Patients without treatment failure events during the study period were censored at the last follow-up date.

After excluding patients who used an mTOR or bevacizumab as first targeted therapy, discontinued first targeted therapy for non-medical reasons, or used bevacizumab as second targeted therapy, a total of 281 patients were eligible for the analysis of time to treatment failure. Seventeen patients were excluded due to missing values for some of the covariates, resulting in a total of 264 patients included in the final model. The test of proportional hazards for second targeted therapy had a p-value of 0.1390.

*Groups are statistically significant at the 5% significance level.

**Groups are statistically significant at the 1% significance level.

Figure 2. Meta-analysis of targeted agent effects on time to treatment failure. Fixed-effects inverse variance weighting was performed to obtain the pooled hazard ratio for each comparison of time to treatment failure. TKIs in the 2009–2011 chart review included sorafenib only, while TKIs in the 2010–2012 chart review included sorafenib, sunitinib, pazopanib, and axitinib. TKI: tyrosine kinase inhibitor.

Figure 3. Meta-analysis of targeted agent effects on overall survival. Fixed-effects inverse variance weighting was performed to obtain the pooled hazard ratio for overall survival for everolimus vs. temsirolimus, everolimus vs. TKIs as a class, and temsirolimus vs. TKIs as a class. TKIs in the previous (2009–2011) dataset included sorafenib only, while TKIs in the current (2010–2012) dataset included sorafenib, sunitinib, pazopanib, and axitinib. Overall survival was defined as the time from the initiation of second targeted therapy to death from any cause. Patients without recorded death events during the study period were censored at the last follow-up date. *The upper bound of the 95% confidence interval for the hazard ratio for everolimus vs. TKI extends past the area of the graph and has been truncated for display purposes.