Update on combined immunotherapy for the treatment of advanced renal cell carcinoma

Figures & data

Table 1. International Metastatic Renal Cell Carcinoma Database Consortium criteria.

IMDC criteria
Karnofsky performance status score <80
Time from original diagnosis to initiation of targeted therapy <1 year
Hemoglobin less than the lower limit of normal
Serum calcium greater than the upper limit of normal
Neutrophil count greater than the upper limit of normal
Platelet count greater than the upper limit of normal
Risk stratification
Favorable risk: 0 of the above criteria
Intermediate risk: 1 or 2 of the criteria
Poor risk: ≥3 of the above criteria

Table 2. Landmark phase III trials investigating the various IO combination therapies in the first-line setting for advanced RCC.

Trial	CheckMate 214		JAVELIN Renal 101		KEYNOTE-426		CheckMate 9ER		CLEAR
NCT	02231749		02684006		02853331		03141177		02811861
Combination therapy	IO + IO		IO+TKI		IO +TKI		IO+TKI		IO+TKI
FDA approval	April 2018		May 2019		April 2019		January 2021		August 2021
Approved indication	Intermediate/Poor risk (Preferred Regimen)		Favorable/Intermediate/Poor risk (Other Recommended Regimen)		Favorable/Intermediate/Poor risk (Preferred Regimen)		Favorable/Intermediate/Poor risk (Preferred Regimen)		Favorable/Intermediate/Poor risk (Pembrolizumab+Lenvatinib: Preferred Regimen) (Everolimus +Lenvatinib: 2^nd line therapy)
Primary endpoints	ORR, OS, PFS		OS, PFS		OS, PFS		PFS		PFS
Median follow-up (months)	67.7		19.3		42.8		32.9		26.6
Trial drug	Ipilimumab +Nivolumab→ Nivolumab	Sunitinib	Avelumab + Axitinib	Sunitinib	Pembrolizumab +Axitinib	Sunitinib	Nivolumab + Cabozantinib	Sunitinib	Pembrolizumab +Lenvatinib	Everolimus +Lenvatinib	Sunitinib
Number of patients	550	546	442	444	432	429	323	328	355	357	357
IMDC group (%)
Favorable	23	23	21.3	21.6	31.9	30.5	22.9	22	31	31.9	34.7
Intermediate	61	61	61.3	62.2	55.1	57.3	58.2	57.3	59.2	54.6	53.8
Poor	17	16	16.3	16	13.0	12.1	18.9	20.7	9.3	11.8	10.4
Prior nephrectomy (%)	82	80	79.6	80	82.6	83.4	68.7	71	73.8	72.8	77
Primary outcomes
Median OS	55.7	38.4	Not reached	Not reached	45.7	40.1	37.7	34.3	Not reached	Not reached	Not reached
OS hazard ratio (HR; 95% CI)	0.72 (0.62–0.85), p<.0001		0.8 (0.616–1.027), P=.039		0.73 (0.60–0.88), p<.001		0.70 (0.55–0.90)		0.66 (0.49–0.88), p=.005	1.15 (0.88–1.5), p=.30
Median PFS	12.3	12.3	13.3	8	15.7	11.1	16.6	8.3	23.9	14.7	9.2
PFS HR (95% CI)	0.86 (0.73–1.01), p=.063		0.69 (0.57–0.83), p<.0001		0.68 (0.58–0.80), p<.0001		0.56 (0.46–0.68), p<.0001		0.39 (0.32–0.49), p<.001	0.65 (0.53–0.80), p<.001
ORR	39.3%	32.4%	52.5%	27.3%	60.4%	39.6%	56%	28%	71%	53.5%	36.1%
CR	11.6%	3.1%	3.8%	2.0%	10%	3.5%	12.0%	5%	16.1%	9.8%	4.2%
PR	27.6%	29.3%	48.6%	25.2%	50.5%	36.1%	43%	23%	54.9%	43.7%	31.9%
PD	17.6%	14.1%	12.4%	19.4%	Not available	Not available	6%	14%	5.4%	7.3%	14.0%
Median duration of response (mo)	Not reached	24.8	18.5	Not estimable	23.6	15.3	23.1	15.1	25.8	16.6	14.6
Dose reduction	Not available	Not available	42.2%	42.6%	Not available	Not available	61%	54%	68.8%	73.2%	50.3%
Any grade treatment-related adverse event (AE), n (%)	515 (94)	522 (98)	414 (95.4)	423 (96.4)	413 (96.3)	415 (97.6)	311 (97)	298 (93)	341 (96.9)	347 (97.7)	313 (92.1)
Grade ≥ 3 AEs, n (%)	263 (48)	344 (64)	246 (56.7)	243 (55.4)	270 (62.9)	247 (58.1)	208 (65)	172 (54)	252 (71.6)	259 (73.0)	200 (58.8)
Most common grade ≥ 3 AEs	1. Increased lipase (12%) 2. Diarrhea (4%) 3. Fatigue (4%)	1. Hypertension (17%) 2. Fatigue (10%) 3. PPE (9%)	1.Hypertension (24.4%) 2. PPE (5.8%) 3. Diarrhea (5.1%)	1. Hypertension (15.3%) 2. Thrombo-cytopenia (5.5%) 3. Anemia (5%)	1. Hypertension (21.2%) 2. ALT increase (12.1%) 3. Diarrhea (7.2%)	1. Hypertension (18.4%) 2. Thrombocytopenia (7.3%) 3. Neutropenia (6.8%)	1. Hypertension (13%) 2. PPE (8%) 3. Diarrhea (7%)	1. Hypertension (12%) 2. PPE (8%) 3. Diarrhea (5%)	1. Hypertension (25.3%) 2. Lipase increase (9.7%) 3. Diarrhea (8.2%)	1. Hypertension (20.8%) 2. Hypertriglyceridemia (10.1%) 3. Diarrhea(9.6%)	1. Hypertension (17.9%) 2. Lipase increased (7.1%) 3. Platelet count decreased (5.3%)
AEs leading to discontinuation of any treatment, n (%)	127 (23)	70 (13)	33 (7.6)	59 (13.4)	111 (25.9)	43 (10.1)	87 (27)	33 (10)	Not reported (37.2%)	Not reported (27.0%)	Not reported (14.4%)
AE or treatment-associated deaths, n (%)	8 (1.5)	5 (1)	3 (0.7)	1(0.2)	4 (0.9)	7 (1.6)	1 (0.3)	2(0.6)	4 (1.1)	3 (0.8)	1(0.3)

Figure 1. Mechanism of action of the newer drugs currently being investigated in advanced RCC.³².

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