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RENAL CELL CARCINOMA PANEL

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Management of IO-Refractory RCC

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IO-Refractory Renal Cell Carcinoma Panel

Sumanta Pal, MD, FASCO

City of Hope

Toni Choueiri, MD

Dana-Farber Cancer Institute

Tian Zhang, MD

UT Southwestern

Brian Rini, MD

Vanderbilt-Ingram Cancer Center

​

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Why was CONTACT-03 negative?

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Atezo + Cabo �(n=259)

Cabo�(n=254)

ORR

41%

41%

CR

0%

2%

PR

41%

40%

SD

51%

48%

PD

4%

5%

Median DOR (mos)

12.7

14.8

Time (months)

PFS per central review (%)

Adapted from Choueiri, et al. CONTACT-03 (LBA4500).

Adverse event

Atezo + Cabo� (n=262)

Cabo�(n=256)

Grade 3 or 4 treatment-related AE

55%

47%

Death due to treatment-related AE

1%

0%

Serious treatment-related AE

24%

12%

a Treatment-related AEs leading to death were immune-mediated enterocolitis and renal failure (both related to atezo) and intestinal perforation (related to cabo).

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Predict the results of TiNivo-2…

  • Advanced RCC s/p 1 or 2 prior lines of therapy, one of which was an immune checkpoint inhibitor (ICI)
    • Previous nivolumab is allowed

​

  • Stratified by IMDC risk category and ICI as most recent prior therapy or not

RANDOMIZE 1:1

Tivozanib 1.34 mg

D1-21 of a 28-day cycle

​

Tivozanib 0.89 mg

D1-21 of a 28-day cycle

+

Nivolumab 480 mg q28D

​

N = 326

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​

​

Len/Pembro in IO-refractory*

(n=104)

Cabo/Atezo in CONTACT-03

(n=259)

ORR

55.8%

40.5%

CR rate

3.8%

0%

Median PFS

~11 months**

10.6 months

Median DoR

10.6 months

12.7 months

Grade 3-5 TRAEs

63%

56%

Treatment-related deaths

2%

1%

Lee et al. Lancet Oncology 2023

Is lenvatinib/pembrolizumab a more active combination in this setting?

*Of the 104 patients, 96 (92.3%) had anti-PD-1/PD-L1 as the most recent therapy

**11.1 months in prior Ipi/Nivo (n=39), 10.8 months in ICI +/- other (n=47), 9.7 months in IO/TKI (n=18)

​

All end points per IRC RECIST v1.1

​

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What is the current role of IO-based therapy after �prior IO-based therapy?

Is there a role for ipilimumab/�nivolumab salvage?

​

TITAN RCC1

FRACTION2

Salvage Ipi/Nivo3

N

49

46

45

Prior TKI?

No

Yes

Yes

Timing

Nivo🡪Ipi

(SD/PD at week 8 or 16)

Nivo + Ipi in IO-refractory

Nivo + Ipi in IO-refractory

Ipi doses

2-4

4

4

ORR

14%

17%

20%

PD

67%

30%

62%

CR

2%

0%

0%

1. Grimm, et al. ESMO 2022; 2. Choueiri, et al. JITC. 2022; 3. Gul, et al. JCO. 2020.

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What is the current role of IO-based therapy

after prior IO-based therapy?

  • Is there a role for ipilimumab/nivolumab salvage?

​

  • What treatment do you give after adjuvant pembrolizumab?

​

  • How much time needs to pass to consider IO rechallenge?

​

  • Are you comfortable with a PD(X)-based clinical trial in IO-refractory RCC?

​

​

​

​

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Belzutifan versus everolimus

Kaplan-Meier Estimate of PFS at IA2

IA2

Belzutifan

Everolimus

289 (77.3%)

276 (74.2%)

5.6 (3.8-6.5)

5.6 (4.8-5.8)

0.74 (0.63-0.88)

​

Events

Median, mo (95% CI)

HR (95% CI)

Albiges, et al. ESMO 2023.

Kaplan-Meier Estimate of OS at IA2

IA2

Belzutifan

Everolimus

213 (57.0%)

228 (61.3%)

21.4 (18.2-24.3)

18.1 (15.8-21.8)

0.88 (0.73-1.07); P=.099

​

Events

Median, mo (95% CI)

HR (95% CI)

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Belzutifan + Cabo in IO-refractory RCC (n=52)

ORR, 31% (4% CR); PFS, 13.8 months

Belzutifan + Lenva in IO-refractory RCC (n=24)

ORR, 50% (0% CR); PFS, 11.2 months

Change From Baseline, %

−100

−90

−80

−70

−60

−50

−40

−30

−20

−10

0

10

20

30

40

50

60

70

80

90

100

Choueiri, et al. ESMO 2023; Albiges, et al. ASCO 2023.

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Predict the results of belzutifan + TKI in IO-refractory RCC…

  • Advanced ccRCC with PD after first- or second-line anti-PD(L)-1 or as adjuvant if PD on/within 6 months
    • IO must be the most recent therapy
  • ≤2 prior systemic therapies

​

  • Stratified by IMDC, number of prior lines, and geographic region

RANDOMIZE 1:1

Cabozantinib 60 mg QD

​

Belzutifan 120 mg QD

+

Lenvatinib 20 mg QD

​

n=708

Primary end points: PFS, OS

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The ultimate place for belzutifan in mRCC will be…

  1. Monotherapy in a refractory setting

​

  • In combination with lenvatinib in second-line, IO-refractory RCC

​

  • As part of a frontline triplet regimen

​

  • In combination with pembrolizumab in the adjuvant setting

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Tivozanib versus belzutifan for refractory RCC

​

Tivozanib (n=175)

Belzutifan (n=374)

Population

​

0% second line

62% third line

38% fourth line

12% second line

42% third line

45% fourth line

IMDC

19%/62%/18%

21%/67%/12%

ORR

18%

23%

PFS

5.6 months

5.6 months

PFS HR

0.73 vs sorafenib

0.74 vs everolimus

Landmark PFS

24% at 18 months

23% at 18 months

Grade 3-5 TRAEs

46%

39%

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Chen, Rini, and Beckermann; 2022.

What are the most exciting novel targets in RCC?

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LIVESTREAM SESSION

Frontline Metastatic Renal Cancer: Time for Reflection

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Frontline Renal Cell Carcinoma Panel

David McDermott, MD

Beth Israel Deaconess �Medical Center

Michael Atkins, MD

Lombardi Comprehensive Cancer Center at Georgetown University

Brian Rini, MD

Vanderbilt-Ingram Cancer Center

​

Toni Choueiri, MD

Dana-Farber Cancer Institute

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First-line IO combination trials in mRCC: Did RENOTORCH influence your opinion?

​

1. Motzer, et al. Cancer. 2022; 2. Rini, et al. ASCO 2023; 3. Sheng, et al. ESMO 2023; 4. Motzer, et al. ASCO 2023.

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​

CheckMate 214 (Ipi/Nivo)1

(n=550 vs n=546)

KEYNOTE-426 (Axi/Pembro)2

(n=432 vs n=429)

RENOTORCH (Toripalimab/Axi)3

(n=210 vs n=211)

CLEAR (Len/Pembro)4

(N=355 vs n=357)

OS HR

mOS, months

0.72

55.7 vs 38.4

0.84

47.2 vs 40.8

0.61

NE vs 26.8

0.79

53.7 v. 54.3

Landmark OS

60% at 3 years (est.)

48% at 5 years

63% at 3 years

42% at 5 years

72% at 2 years

​

66% at 3 years

PFS HR

mPFS, months

0.86

12.3 vs 12.3

0.69

15.7 vs 11.1

0.65

18.0 vs 9.8

0.47

23.9 vs 9.2

Landmark PFS

32% (3 years; est.)

30% (5 years)

29% (3 years)

18% (5 years)

45% (2 years)

37% (3 years)

ORR, %

39 vs 32

61 vs 40

57 vs 31

71 vs 37

CR, %

12 vs 3

12 vs 4

5 vs 4

18 vs 4

Med f/u, months

68

67

15

48

Primary PD, %

18

12

NR

5

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First-line IO combination trials in mRCC (ITT): Did ASCO 2023 data influence your opinion?

1. Motzer, et al. Cancer. 2022; 2. Rini, et al. ASCO 2023; 3. Bottaro, et al. CITM. 2023; 4. Motzer, et al. ASCO 2023.

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​

CheckMate 214 (Ipi/Nivo)1

(n=550 vs n=546)

KEYNOTE-426 (Axi/Pembro)2

(n=432 vs n=429)

CheckMate 9ER (Cabo/Nivo)3

(n=323 vs n=328)

CLEAR (Len/Pembro)4

(n=355 vs n=357)

OS HR

mOS, months

0.72

55.7 vs 38.4

0.84

47.2 vs 40.8

0.70

49.5 vs 35.5

0.79

53.7 vs 54.3

Landmark OS

60% at 3 years (est.)

48% at 5 years

63% at 3 years

42% at 5 years

59% at 3 years

​

66% at 3 years

PFS HR

mPFS, months

0.86

12.3 vs 12.3

0.69

15.7 vs 11.1

0.59

16.6 vs 8.4

0.47

23.9 vs 9.2

Landmark PFS

32% (3 years; est.)

30% (5 years)

29% (3 years)

18% (5 years)

23% (3 years)

37% (3 years)

ORR, %

39 vs 32

61 vs 40

56 vs 28

71 vs 37

CR, %

12 vs 3

12 vs 4

13 vs 5

18 vs 4

Med f/u, months

68

67

44

48

Primary PD, %

18

12

7

5

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IO/IO

100 x 40% ORR x 56% durable responders at 5 years = 22.4 patients

100 patients

IO/TKI

100 x 71% ORR x 41% durable responders at 3 years = 29.1 patients

100 x 71% ORR x 30% durable responders at 5 years = 21.3 patients

Which type of regimen leads to the most durable responders?

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Motzer lancet 2023

Overall survival

Adjuvant nivolumab plus ipilimumab versus placebo for localized RCC after nephrectomy (CheckMate 914): a double-blind, randomized, phase 4 trial

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Predict the results of 8Y8…

Nivolumab 3 mg/kg + ipilimumab 1 mg/kg �q3w x4

Nivolumab 360 mg + �ipilimumab placebo �q3w x4

​

Key inclusion criteria

  • Histologic confirmation of advanced or metastatic RCC with a clear-cell component
  • Measurable disease per �RECIST v1.1
  • No prior systemic therapy for RCC
  • Intermediate- or poor-risk disease �per IMDC

n=418

Primary outcome measures: PFS, ORR

Select secondary outcome measures: OS, ORR, DCR, DOR, TTR, AEs

R�1:1

Nivolumab 480 mg q4w

Nivolumab 480 mg q4w

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Select frontline IO-based trials in mRCC: IMDC favorable risk

​

1. Motzer, et al. Cancer. 2022; 2. Rini, et al. ASCO 2023; 3. Bottaro, et al. ASCO GU 2024; 4. Motzer, et al. ASCO 2023/Grunwald, et al. �ASCO 2021/Choueiri, et al. KCRS 2021; 5. Atkins, et al. JCO. 2022; 6. McDermott, et al. JCO. 2021.

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​

CheckMate 214

(Ipi/Nivo)1

(n=125)

KEYNOTE-426 (Axi/Pembro)2

(n=138)

HCRN5

(Nivo)

(n=35)

KEYNOTE-4276

(Pembro)

(n=42)

OS HR

0.94

1.10

NA

NA

Landmark OS

63%

at 5 years

50%

at 5 years

NR

88%

at 2 years

PFS HR

1.60

0.76

NA

NA

mPFS, mos

12.4

20.7

32.5

9.7

Landmark PFS

26%

at 5 years

19%

at 5 years

58%

at 2 years

19%

at 2 years

ORR

30% vs 52%

69% vs 50%

57%

31%

CR

13% vs 6%

13% vs 6%

11%

2%

Primary PD

12%

4%

3%

19%

Med f/u, months

67.7

67

26.9

35.9

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IO doublets in sarcomatoid RCC

​

1. Rini, et al. JITC. 2022; 2. Rini, et al. ASCO 2019; 3. Motzer, et al. ASCO GU 2021; 4. Rini, et al. Eur Urol. 2021; 5. Choueiri, et al. ESMO Open. 2021.

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​

CheckMate 214 (Ipi/Nivo)1

(n=74 vs 65)

KEYNOTE-426 (Axi/Pembro)2

(n=51 vs 54)

CheckMate 9ER

(Cabo/Nivo)3

(n=34 vs 41)

Immotion 151

(Bev/Atezo)4

(n=68 vs 74)

JAVELIN 101

(Axi/Avelumab)5

(n=47 vs 61)

OS HR

(95% CI)

mOS, months

0.46

0.58

0.36

0.64

0.78

PFS HR

mPFS, months

0.50

0.54

0.42

0.52

0.57

ORR, %

61 vs 23

59 vs 32

56 vs 22

49 vs 14

47 vs 21

CR, %

23 vs 6

12 vs 0

9 vs 2

10 vs 3

4 vs 0

Med f/u, months

67

13

16 month min

17

6 month min

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Stratification factors

  • Geographic region (North America versus Western Europe versus ROW)
  • IMDC criteria (favorable vs intermediate vs poor)
  • Sarcomatoid features (yes vs no)

(n=1653 subjects)

Key eligibility criteria

  • Advanced ccRCC
  • Measurable disease by RECIST v1.1
  • No prior systemic therapy, including immunotherapy
  • Karnofsky performance status ≥70

Belzutifan + pembrolizumab + lenvatinib

Pembrolizumab + lenvatinib 

Primary end point:

PFS (BICR) and OS

​

Secondary end points:

ORR, DOR, safety, and tolerability

R�A�N�D�O

M

I�Z�E

 MK1308A (Pembro/Qmab) + lenvatinib

Predict the results of this frontline triplet trial…

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Does TKI need to be forever in IO/TKI regimens? TIDE-A

Patients free of PD after 8 weeks from axi interruption

Prof. Roberto Iacovelli, ESMO 2023

Median duration of 1st avelumab maintenance: 16.0 weeks (95%CI, 10.9 – 21.1)

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