Treatment Sequencing Patterns in Patients with Metastatic Urothelial Cancer Treated in the Community Practice Setting in the United States: SPEAR-Bladder (Study informing treatment Pathway dEcision in bladder cAnceR)

Figures & data

Figure 1 Study attrition.

Notes: *These groups of patients were selected for the treatment sequencing subanalyses: patients who received 1L chemotherapy, followed by either 2L chemotherapy (n=38) or IO-based regimens (n=79) without a 3L of treatment.

Abbreviations: 1L, first-line treatment; 2L, second-line; 3L, third-line; chemo, chemotherapy; EHR, electronic health record; IO, immuno-oncology; iKM, iKnowMed; mUC, metastatic urothelial carcinoma; USON, US Oncology Network.

Figure 2 Regimen distribution by line of therapy.

Abbreviations: 1L, first-line treatment; 2L, second-line; 3L, third-line; carbo-gem, carboplatin-gemcitabine; cis-gem, cisplatin-gemcitabine; IO, immuno-oncology.

Table 1 Demographic and Clinical Characteristics Among Treatment Sequence Subgroups

	Overall (n = 117)	C-IO Subgroup (n = 79)	C-C Subgroup (n = 38)
Median age at 1L treatment initiation (years; range)	69 (38, 90+)	71 (40, 90+)	67 (38, 90+)
Male – n (%)	87 (74.4)	60 (75.9)	27 (71.1)
Race – n (%)
Caucasian	103 (88.0)	66 (83.5)	37 (97.4)
Other/no information	14 (12.0)	13 (16.5)	1 (2.6)
Smoking status – n (%)
Current	23 (19.7)	14 (17.7)	9 (23.7)
Former	60 (51.3)	40 (50.6)	20 (52.6)
Never	29 (24.8)	20 (25.3)	9 (23.7)
No information	5 (4.3)	5 (6.3)	0 (0.0)
ECOG performance score – n (%)
0	12 (10.3)	9 (11.4)	3 (7.9)
1	67 (57.3)	44 (55.7)	23 (60.5)
2	18 (15.4)	11 (13.9)	7 (18.4)
3+	2 (1.7)	1 (1.3)	1 (2.6)
No information	18 (15.4)	14 (17.7)	4 (10.5)
Stage – n (%)
0	4 (3.4)	3 (3.8)	1 (2.6)
I	1 (0.9)	1 (1.3)	0 (0.0)
II	16 (13.7)	7 (8.9)	9 (23.7)
III	6 (5.1)	4 (5.1)	2 (5.3)
IV	6 6 (56.4)	48 (60.8)	18 (47.4)
No information	24 (20.5)	16 (20.3)	8 (21.1)
Median ALT (U/L; range)	18.0 (7.0, 44.0)	17.0 (7.0, 44.0)	18.5 (7.0, 42.0)
Median AST (U/L; range)	18.0 (9.0, 36.0)	18.0 (9.0, 32.0)	18.0 (9.0, 36.0)
Median hemoglobin (g/dL; range)^a	11.6 (7.6, 13.7)	12.2 (7.7, 13.7)	10.8 (7.6, 13.7)
Median creatinine clearance (mL/m^2; range)	65.2 (22.9, 147.1)	67.5 (22.9, 138.9)	63.3 (24.5, 147.1)
Median serum creatinine (mg/dL; range)	1.2 (0.6, 2.0)	1.2 (0.7, 2.0)	1.2 (0.6, 1.9)
Aggressive disease status – n (%)
No	19 (16.2)	14 (17.7)	5 (13.2)
Yes	71 (60.7)	46 (58.2)	25 (65.8)
No information	27 (23.1)	19 (24.1)	8 (21.1)
Median disease free-interval (weeks; range)	9.1 (0.1, 282.7)	11.1 (0.1, 282.7)	8.0 (0.1, 270.7)
Median time from locally advanced/mUC diagnosis to 1L initiation (weeks; range)	2.3 (0.1, 266.9)	2.3 (0.1, 103.3)	2.4 (0.1, 266.9)
Median time to 2L (weeks; range)^b	24.9 (0.1, 102.1)	29.0 (4.1, 102.1)	20.0 (0.1, 63.1)
Metastatic sites recorded – n (%)
Patients with at least one recorded metastatic site	68 (58.1)	45 (57.0)	23 (60.5)
Lung	37 (31.6)	24 (30.4)	13 (34.2)
Bone	23 (19.7)	13 (16.5)	10 (26.3)
Liver	13 (11.1)	6 (7.6)	7 (18.4)
Retroperitoneum	12 (10.3)	9 (11.4)	3 (7.9)
Other	10 (8.5)	6 (7.6)	4 (10.5)
Mediastinum	8 (6.8)	5 (6.3)	3 (7.9)
Peritoneum	5 (4.3)	2 (2.5)	3 (7.9)
Brain	4 (3.4)	3 (3.8)	1 (2.6)
Skin	2 (1.7)	2 (2.5)	0 (0.0)

Notes: ^aBetween-group p-value = 0.0091. ^bBetween-group p-value = 0.0047.

Abbreviations: 1L, first-line treatment; 2L, second-line; ALT, alanine aminotransferase; AST, aspartate aminotransferase; C-C, first-line chemotherapy followed by second-line chemotherapy; C-IO, first-line chemotherapy followed by second-line immuno-oncology therapy; ECOG, Eastern Cooperative Oncology Group; IO, immuno-oncology; mUC, metastatic urothelial carcinoma.

Table 2 Demographic and Clinical Characteristics at the Start of 1L and 2L Therapy

	Overall	Systemic Chemotherapies	IO Regimens
At the start of 1L treatment
Patients with available data – n (%)	430 (100.0)	396 (92.1)	34 (7.9)
Median age at 1L treatment initiation (years; range)	72 (31, 90+)	72 (31, 90+)	72 (54, 90+)
Male – n (%)	337 (78.4)	312 (78.8)	25 (73.5)
Race – n (%)
Caucasian	375 (87.2)	345 (87.1)	30 (88.2)
Black or African American	17 (4.0)	15 (3.8)	2 (5.9)
No information	32 (7.4)	31 (7.8)	1 (2.9)
Other	6 (1.4)	5 (1.3)	1 (2.9)
Smoking status – n (%)
Current	67 (15.6)	64 (16.2)	3 (8.8)
Former	249 (57.9)	232 (58.6)	17 (50.0)
Never	103 (24.0)	91 (23.0)	12 (35.3)
No information	11 (2.6)	9 (2.3)	2 (5.9)
ECOG performance score at 1L initiation – n (%)
0	52 (12.1)	48 (12.1)	4 (11.8)
1	242 (56.3)	227 (57.3)	15 (44.1)
2	61 (14.2)	55 (13.9)	6 (17.6)
3+	6 (1.4)	5 (1.3)	1 (2.9)
No information	69 (16.0)	61 (15.4)	8 (23.5)
Stage at diagnosis – n (%)
0	10 (2.3)	9 (2.3)	1 (2.9)
I	16 (3.7)	15 (3.8)	1 (2.9)
II	91 (21.2)	86 (21.7)	5 (14.7)
III	24 (5.6)	22 (5.6)	2 (5.9)
IV	198 (46.0)	184 (46.5)	14 (41.2)
No information	91 (21.2)	80 (20.2)	11 (32.4)
Aggressive disease status^a - n (%)
No	86 (20.0)	75 (18.9)	11 (32.4)
Yes	260 (60.5)	246 (62.1)	14 (41.2)
No information	84 (19.5)	75 (18.9)	9 (26.5)
Median time from locally advanced/mUC diagnosis to 1L initiation (weeks; range)	2.1 (0.1, 330.7)	2.1 (0.1, 330.7)	4.4 (0.1, 68.0)
At the start of 2L treatment
Patients with available data – n (%)	218 (100.0)	92 (42.2)	126 (57.8)
Median age at 2L treatment initiation (years; range)	69 (39, 90+)	68 (39, 90+)	69 (41, 90+)
Male – n (%)	166 (76.1)	71 (77.2)	95 (75.4)
Race – n (%)
Caucasian	184 (84.4)	81 (88.0)	103 (81.7)
Black or African American	11 (5.0)	6 (6.5)	5 (4.0)
No information	20 (9.2)	5 (5.4)	15 (11.9)
Other	3 (1.4)	0 (0.0)	3 (2.4)
Smoking status – n (%)
Current	32 (14.7)	14 (15.2)	18 (14.3)
Former	113 (51.8)	51 (55.4)	62 (49.2)
Never	62 (28.4)	23 (25.0)	39 (31.0)
No information	11 (5.0)	4 (4.3)	7 (5.6)
ECOG performance score at 2L initiation – n (%)
0	13 (6.0)	3 (3.3)	10 (7.9)
1	118 (54.1)	49 (53.3)	69 (54.8)
2	45 (20.6)	18 (19.6)	27 (21.4)
3+	1 (0.5)	0 (0.00)	1 (0.8)
No information	41 (18.8)	22 (23.9)	19 (15.1)
Stage at diagnosis – n (%)
0	4 (1.8)	1 (1.1)	3 (2.4)
I	4 (1.8)	2 (2.2)	2 (1.6)
II	33 (15.1)	17 (18.5)	16 (12.7)
III	20 (9.2)	5 (5.4)	15 (11.9)
IV	97 (44.5)	35 (38.0)	62 (49.2)
No information	60 (27.5)	32 (34.8)	28 (22.2)
Aggressive disease status^a – n (%)
No	31 (14.2)	14 (15.2)	17 (13.5)
Yes	121 (55.5)	51 (55.4)	70 (55.6)
No information	66 (30.3)	27 (29.3)	39 (31.0)
Median time from locally advanced/mUC diagnosis to 1L initiation (weeks, range)^b	2.4 (0.1, 330.7)	2.4 (0.1, 330.7)	2.4 (0.1, 103.3)

Notes: ^aAggressive disease was identified based on disease-free interval (time between diagnosis and presentation of locally advanced or metastatic disease < 12 months), pre-index performance status (ECOG ≥ 3), and tumor grade (high-grade/grade 3/poorly differentiated). ^bIn the subset of patients who initiated 2L treatment.

Abbreviations: 1L, first-line treatment; 2L, second-line; 3L, third-line; ECOG, Eastern Cooperative Oncology Group; IO, immuno-oncology; mUC, metastatic urothelial carcinoma.

Table 3 Clinical Outcomes Across Lines of Therapy Among the Overall Study Population (n=502)

	Systemic Chemotherapy Restricted Mean (SE)	IO Regimen Restricted Mean (SE)	Systemic Chemotherapy Median (95% CI)	IO Regimen Median (95% CI)	Log-Rank p-Value	Unadjusted Hazard Ratio (95% CI)	Effect p-Value
Time to treatment failure (TTF; months)
1L	n = 396	n = 34	2.4 (2.3, 2.7)	3.0 (2.3, 5.8)	0.0263	0.621 (0.404, 0.955)	0.0300
	3.6 (0.2)	4.1 (0.5)
2L	n = 92	n = 126	2.1 (1.5, 2.8)	3.1 (2.1, 4.9)	0.0004	0.568 (0.412, 0.782)	0.0005
	3.0 (0.3)	3.6 (0.3)
3L	n = 16	n = 29	2.3 (0.3, 4.3)	5.8 (1.6, NR)	0.0371	0.440 (0.195, 0.995)	0.0487
	2.5 (0.6)	3.9 (0.5)
Treatment-free interval (TFI; months)
1L → 2L	n = 370	n = 22	4.1 (3.2, 5.2)	1.3 (0.6, 2.0)	< 0.0001	4.007 (2.348, 6.836)	< 0.0001
	7.0 (0.4)	7.0 (0.4)
Overall survival (OS; months)
1L	n = 396	n = 34	16.4 (13.4, 18.9)	13.0 (4.3, NR)	0.0607	1.841 (0.963, 3.521)	0.0649
	15.1 (0.5)	9.2 (1.1)
2L	n = 92	n = 126	11.8 (7.9, NR)	6.8 (4.9, 9.6)	0.0567	1.544 (0.984, 2.422)	0.0587
	11.7 (0.9)	7.1 (0.5)
3L	n = 16	n = 29	3.9 (1.3, NR)	6.7 (3.9, NR)	0.2347	0.556 (0.208, 1.484)	0.2413
	4.2 (0.7)	5.5 (0.5)

Abbreviations: 1L, first-line; 2L, second-line; 3L, third-line; CI, confidence interval; IO, immuno-oncology; NR, not reached; SE, standard error.

Table 4 Clinical Outcomes by Most Common Treatment Sequences

	C-IO	C-C	Unadjusted Hazard Ratio^a (95% CI)	Hazard Ratio p-Value
	(n = 79)	(n = 38)
Median (95% CI) TTF (months)	2.5 (2.3, 3.0)	2.3 (1.4, 3.7)	0.832 (0.562, 1.232)	0.3582
Restricted mean (SE) TTF (months)	3.7 (0.3)	3.3 (0.4)
Median (95% CI) TFI (months)	2.2 (1.6, 3.5)	1.4 (0.9, 1.6)	1.434 (0.965, 2.130)	0.0742
Restricted mean (SE) TFI (months)	3.6 (0.4)	2.6 (0.6)
Median (95% CI) OS (months)	19.2 (11.9, NR)	11.9 (8.5, 20.8)	0.627 (0.342, 1.150)	0.1318
Restricted mean (SE) OS (months)	14.7 (0.7)	13.4 (1.3)

Notes: ^aUnadjusted hazard ratios and hazard ratio p-values are based on univariate Cox regression analyses.

Abbreviations: C-C, first-line chemotherapy followed by second-line chemotherapy; CI, confidence interval; C-IO, first-line chemotherapy followed by second-line immuno-oncology therapy; NR, not reached; OS, overall survival; TFI, treatment-free interval; TTF, time to treatment failure; SE, standard error.

Figure 3 Kaplan–Meier curves for clinical outcomes by treatment sequence.

Notes: Time to treatment failure (A) and overall survival (B).

Abbreviations: C-C, first-line chemotherapy followed by second-line chemotherapy; C-IO, first-line chemotherapy followed by second-line immuno-oncology therapy.