Molecular analysis and favorable clinical outcomes in real-world patients with metastatic renal cell carcinoma

Figures & data

Table 1. Summary of demographic, clinicopathologic, and 1 L treatment characteristics overall and by RCC histology subtype.

Characteristics	RCC Histology
	ccRCC n (%)	nccRCC n (%)	p-value^a
All subjects, N	227 (84.4)	42 (15.6)
Age at start of 1 L treatment
Mean (SD)	63.4 (9.54)	63.8 (9.82)	.80
Median (range)	64.0 (37, 89)	63.0 (38, 80)
Gender
Male	154 (67.8)	26 (61.9)	.45
Female	73 (32.2)	16 (38.1)
Fuhrman Grade from Histology Slides
1	5 (2.2)	1 (2.4)	.28
2	65 (28.6)	8 (19.0)
3	104 (45.8)	18 (42.9)
4	53 (23.3)	15 (35.7)
Sarcomatoid Differentiation
Yes	52 (22.9)	9 (21.4)	.41
No	171 (75.3)	31 (73.8)
Unknown	4 (1.8)	2 (4.8)
Necrosis
Yes – macroscopic	81 (35.7)	21 (50.0)	.20
Yes – microscopic	101 (44.5)	12 (28.6)
No	36 (15.9)	8 (19.0)
Unknown	9 (4.0)	1 (2.4)
Stage IV disease status
Recurrent Metastasis	134 (59.0)	30 (71.4)	.13
Initial Diagnosis	93 (41.0)	12 (28.6)
Karnofsky Performance Score at 1 L treatment baseline
90/100	129 (56.8)	20 (47.6)	.05
70/80	93 (41.0)	18 (42.9)
Other	5 (2.2)	4 (9.5)
IMDC Prognostic Score at 1 L treatment baseline
Subjects with data, n	212	42
Favorable	38 (17.9)	4 (9.5)	.38
Intermediate	102 (48.1)	21 (50.0)
Poor	72 (34.0)	17 (40.5)
MSKCC Prognostic Score at 1 L treatment baseline
Subjects with data, n	208	42
Favorable/good	51 (24.5)	9 (21.4)	.05
Intermediate	125 (60.1)	20 (47.6)
Poor	32 (15.4)	13 (31.0)
Number of metastatic sites at 1 L treatment baseline
<2	58 (25.6)	11 (26.2)	.93
≥2	169 (74.4)	31 (73.8)
Site of metastatic disease at 1 L treatment baseline
Lung	160 (70.5)	18 (42.9)	.001
Lymph Node	107 (47.1)	29 (69.0)	.009
Bone	68 (30.0)	12 (28.6)	.86
Liver	39 (17.2)	11 (26.2)	.17
Type of 1 L Therapy
Sunitinib	107 (47.1)	11 (26.2)	<.0001
Sorafenib	16 (7.0)	7 (16.7)
Axitinib	11 (4.8)	0 (0.0)
Pazopanib	90 (39.6)	11 (26.2)
Temsirolimus	2 (0.9)	13 (31.0)
Everolimus	1 (0.4)	0 (0.0)

%=n/N.

^a p-value to test whether there is difference between the subgroups in the overall cohort. Comparison of characteristics in subgroups will be performed using Chi-square test (or Fisher’s exact test if cells have very small counts [n < 5]) for categorical/binary variables, and Student’s t-test for continuous data.

Table 2. Association of clinical outcomes with PD-L1 by immunohistochemistry and angiogenesis gene signature for patients with clear-cell histology (N = 227) and non-clear cell histology (N = 42) adjusted for age, IMDC, and other significant baseline covariates.

		rwBOR			rwPFS	OS
	N^a	% (95%CI)	Adjusted OR^b (95%CI)	N	Adjusted HR^b (95%CI)	Adjusted HR^b (95%CI)
ccRCC
PD-L1 IHC	208			227
CPS ≥ 1	126	23.0% (0.16, 0.31)	0.81 (0.34, 1.92)	142	1.20 (0.81, 1.77)	1.44 (1.01, 2.07)
CPS < 1	82	29.3% (0.20, 0.40)	ref	85	ref	ref
PD-L1 IHC/ sarcomatoid^c	204			223
CPS ≥ 1, sarcomatoid+	34	14.7% (0.05, 0.31)	0.52 (0.14, 1.94)	43	1.37 (0.83, 2.25)	2.08 (1.31, 3.31)
CPS ≥ 1, sarcomatoid-	91	26.4% (0.18, 0.37)	0.90 (0.36, 2.25)	98	1.21 (0.79, 1.84)	1.35 (0.92, 1.99)
CPS < 1, sarcomatoid+	9	22.2% (0.03, 0.60)	0.62 (0.11, 3.57)	9	1.24 (0.55, 2.77)	1.04 (0.43, 2.49)
CPS < 1, sarcomatoid-	70	30.0% (0.20, 0.42)	ref	73	ref	ref
Angiogenesis	208			227
≥ Median	104	32.7% (0.24, 0.43)	2.85 (1.37, 5.93)	114	0.61 (0.45, 0.82)	0.74 (0.54, 1.00)
< Median	104	18.3% (0.11, 0.27)	ref	113	ref	ref
nccRCC
PD-L1 IHC	36			42
CPS ≥ 1	25	4.0% (0.00, 0.20)	NR	29	0.52 (0.21, 1.30)	0.55 (0.21, 1.43)
CPS < 1	11	–		13	ref	ref
PD-L1 IHC/ sarcomatoid^c	34			40
CPS ≥ 1, sarcomatoid+	7	–		8	0.84 (0.22, 3.18)	0.80 (0.21, 3.12)
CPS ≥ 1, sarcomatoid-	17	5.9% (0.00, 0.29)	NR	20	0.57 (0.22, 1.51)	0.50 (0.17, 1.46)
CPS < 1, sarcomatoid+	1	–		1	1.03 (0.07, 15.69)	0.44 (0.03, 7.28)
CPS < 1, sarcomatoid-	9	–		11	ref	ref
Angiogenesis	36			42
≥ Median	18	–	NR	21	1.31 (0.62, 2.76)	2.43 (1.04, 5.68)
< Median	18	5.6% (0.00, 0.27)		21	ref	ref

rw: real-world; rwBOR: best overall response= % complete or partial response based on clinical assessment of clinical and radiology data; rwPFS: progression-free survival based on clinician assessment; OS: overall survival; OR: odds ratio; HR: hazard ratio; CI: confidence interval; CPS: combined positive score; ref: reference for odds and hazard ratio estimates; sarcomatoid+: with sarcomatoid differentiation; sarcomatoid−: without sarcomatoid differentiation; NR: data not reported given few responses and unstable estimates.

^a Clear cell RCC: Of the 227 patients, 208 had complete biomarker data and response data; non-clear cell RCC: Of the 42 nccRCC patients, 36 had complete biomarker data and response data.

^b Variable selection for multivariable models used a stepwise approach including all covariates (demographic, clinical, and biomarkers) with a p-value of <.05 in univariate analysis and removal of variables if p-values were >.1, with age and IMDC forced into the models for PD-L1 and age, IMDC, and TcellinfGEP forced into the model for angiogenesis gene signature.

^c Clear cell RCC: four cases of unknown status for PD-L1/sarcomatoid unknown and not reported in table; non-clear cell RCC: two cases of unknown status for PD-L1/sarcomatoid unknown and not reported in table.

Figure 1. Moderate-strong (rho ≥ 0.4) biomarker correlations. mMDSC: monocytic myeloid derived suppressor cells; gMDSC: granulocytic myeloid derived suppressor cell; PD-L: programmed ligand death; IHC: immunohistochemistry; CPS: combined positive score; mRNA: messenger RNA; HIF: hypoxia inducible factor; TGF-β: transforming growth factor-β; EMT: epithelial-mesenchymal transition; GEP: gene expression profile.

Figure 2. Progression-free survival and overall survival for patients with clear cell RCC and non-clear cell RCC histology, by PD-L1 CPS expression.

Figure 3. Progression-free survival and overall survival for patients with clear cell RCC and non-clear cell RCC histology, by angiogenesis expression.

Table 3. Association of PD-L2 and gene expression profiles for patients with clear-cell histology (N = 227) and non-clear cell histology (n = 42) adjusted for age, IMDC, Tcell_infGEP and other significant baseline covariates.

		rwBOR			rwPFS		OS
		Adjusted OR	Adjusted		Adjusted HR	Adjusted	Adjusted HR	Adjusted
		(95%CI)^a	p-value^b		(95%CI)^a	p-value^b	(95%CI)^a	p-value^b
Clear cell RCC
PD-L2 IHC	208	0.929 (0.811, 1.064)	.9349	227	0.929 (0.972, 1.064)	.9191	0.994 (0.947, 1.044)	.9900
PD-L2 mRNA	208	0.320 (0.029, 3.577)	.9349	227	0.320 (0.416, 3.109)	.9191	0.961 (0.335, 2.754)	.9900
TcellinfGEP	208	3.713 (0.901, 15.303)	.6941	227	3.713 (0.461, 1.458)	.9191	0.897 (0.471, 1.708)	.9900
mMDSC	208	0.611 (0.027, 13.700)	.9349	227	0.611 (0.528, 7.233)	.9191	1.258 (0.328, 4.831)	.9900
gMDSC	208	0.734 (0.166, 3.251)	.9349	227	0.734 (0.565, 2.032)	.9191	1.156 (0.621, 2.155)	.9900
Stromal/EMT/ TGFbeta	208	1.913 (0.373, 9.819)	.9349	227	1.913 (0.428, 1.716)	.9191	0.716 (0.355, 1.444)	.9900
Glycolysis	208	1.101 (0.113, 10.688)	.9349	227	1.101 (0.262, 1.491)	.9191	0.994 (0.393, 2.512)	.9900
MYC	208	0.458 (0.004, 57.556)	.9349	227	0.458 (0.355, 16.599)	.9191	2.497 (0.368, 16.922)	.9900
Hypoxia	208	0.908 (0.090, 9.206)	.9349	227	0.908 (0.240, 1.419)	.9191	0.905 (0.356, 2.304)	.9900
HIF-1a co-expression	208	4.168 (0.038, 454.577)	.9349	227	4.168 (0.136, 9.169)	.9191	0.838 (0.113, 6.221)	.9900
HIF-2a co-expression	208	6.948 (1.569, 30.773)	.1175	227	6.948 (0.521, 2.829)	.9191	1.272 (0.532, 3.042)	.9900
Non-clear cell RCC
PD-L2 IHC	36	NR	NR	42	0.019 (0.986, 1.074)	.7859	1.052 (1.004, 1.102)	.2615
PD-L2 mRNA	36	NR	NR	42	0.757 (0.282, 239.003)	.7859	2.530 (0.093, 68.690)	.8371
TcellinfGEP	36	NR	NR	42	1.599 (0.413, 4.468)	.7859	0.876 (0.247, 3.103)	.8371
mMDSC	36	NR	NR	42	0.573 (0.046, 5.006)	.7859	0.417 (0.036, 4.852)	.8371
gMDSC	36	NR	NR	42	66.940 (0.198, 3.400)	.7859	0.532 (0.100, 2.843)	.8371
Stromal/EMT/ TGFbeta	36	NR	NR	42	1.634 (0.040, 2.340)	.7859	0.364 (0.020, 6.583)	.8371
Glycolysis	36	NR	NR	42	0.514 (0.826, 10.482)	.7859	7.027 (1.507, 32.759)	.1306
MYC	36	NR	NR	42	<0.001 (0.493, >999.999)	.7859	22.010 (0.306, >999.999)	.8371
Hypoxia	36	NR	NR	42	0.640 (0.781, 11.404)	.7859	8.826 (1.692, 46.049)	.1075
HIF-1a co-expression	36	NR	NR	42	0.373 (0.013, 23.664)	.7859	0.023 (<0.001, 4.268)	.8371
HIF-2a co-expression	36	NR	NR	42	<0.001 (0.031, 2.646)	.7859	0.071 (0.008, 0.660)	.1806

rw: real-world; rwBOR: best overall response based on clinician assessment; rwPFS: progression-free survival based on clinician assessment of progression; OS: overall survival; mMDSC: monocytic myeloid derived suppressor cells; gMDSC: granulocytic myeloid derived suppressor cell; EMT: epithelial-mesenchymal transition; TGF-β: transforming growth factor-β; PD-L: programmed death ligand; HIF: hypoxia inducible factor; IHC: immunohistochemistry; mRNA: messenger RNA; NR: data not reported given few responses and unstable estimates.

^a Variable selection for multivariable models used a stepwise approach including all covariates (demographic, clinical and biomarkers [included in table plus PD-L1 and angiogenesis]) with a p-value of <.05 in univariate analysis and removal of variables if p-values were >.1, with age and IMDC forced into the models for Tcell_infGEP and age, IMDC, and Tcell_infGEP forced into all other biomarker models included in the summary table. All biomarkers evaluated as continuous measures.

^b Multivariable testing for all biomarkers were treated as a separate family of tests and adjusted by the Hochberg step-up procedure at one-sided alpha of .10.