METASTATIC RCC: IMMUNOTHERAPY

Viktor Grünwald, MD

Interdisciplinary GU Oncology

University Hospital Essen

DISCLOSURE OF INTEREST

Employment: University Hospital Essen

Honoraria for speaker engagements and advisory roles: Art tempi, AstraZeneca, Astellas, BMS, Cerulean, COCS, ClinSol, EUSAPharm, EISAI, Ipsen, MedUpdate, Merck Serono, MSD Merck, MedKomAkademie, Novartis, NewConceptOncology, Lilly, Johnson & Johnson, PharmaMar, PeerVoice, Pfizer, Roche, StreamedUp!, ThinkWired!

Funding: BMS, Novartis, EISAI, Pfizer, MSD, AstraZeneca, Roche, Ipsen

Ownership of any stocks and shares: AstraZeneca, BMS, MSD

THE WIND OF CHANGE

New benchmark for activity in 1st line mRCC treatment

1. Choueiri et al. (2018). Eur J Cancer, 94: 115-125.2. Motzer et al. (2018). NEJMoa1712126. http://doi.org/10.1056/NEJMoa1712126

3. Mod. Motzer R et al. ASCO-GU 2018, Abstract No. 578.

CA209-2142

ORR: 42 vs. 27%

JAVELIN 1015

ORR: 55 vs 26%

KN4264

ORR: 59 vs 36%

4. Rini, B. I. et al. N Engl J Med NEJMoa1816714–12 (2019).

5. Motzer, R. J. et al.. N Engl J Med NEJMoa1816047 (2019). doi:10.1056/NEJMoa1816047

IMmotion1513

ORR: 37 vs 33%

CABOSUN1

ORR: 20 vs 9%

CPI-BASED PHASE III CLINICAL TRIALS IN MRCC

Treatment-naive advanced or metastatic RCC with clear cell and/or

sarcomatoid histology; KPS ≥ 70; (N = 915)

Atezolizumab 1200 mg IV +Bevacizumab 15 mg/kg IV Q3W

Sunitinib 50 mg PO QD for 4 wks on, 2 wks off

IMmotion151Rini et al. Lancet

Treatment-naive advanced RCC with a clear cell component; ECOG

PS 0 or 1; (N = 886)

Avelumab 10 mg/kg IV Q2W +Axitinib 5 mg PO BID in 6-wk cycles

Sunitinib 50 mg PO QD for 4 wks on, 2 wks off

Treatment-naive advanced clear-cell RCC; KPS ≥ 70%; (N = 861)

Pembrolizumab 200 mg IV Q3W +Axitinib 5 mg PO BID

1o EP: PFS in PD-L1+ pts; OS in ITT pts

1o EP: PFS and OS in

PD-L1+ pts

1o EP: PFS and OS in ITT

Sunitinib 50 mg PO QD for 4 wks on, 2 wks off

JAVELIN Renal 101Motzer et al. NEJM

KEYNOTE-426Rini et al. NEJM

ATEZOLIZUMAB IS ACTIVE IN 1ST LINE MRCC

Activity is within the range of sunitinib at a fraction of toxicity

McDermott, D. F. et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med 1–14 (2018).

doi:10.1038/s41591-018-0053-3

PEMBROLIZUMAB ECHOES THIS CLINICAL ACTIVITY

Intermediate and poor risk have a higher chance for response

Pembrolizumab

Response all risks

(N=110)

good

(n=41)

intermediate/poor

(n=69)

CR (n,%) 3 (3) 1 (2) 2 (3)

PR (n,%) 39 (36) 12 (29) 27 (39)

ORR (n, %) 42 (38) 13 (32) 29 (42)

SD (n,%) 35 (32) 21 (51) 14 (20)

PD (n,%) 31 (28) 7 (17) 24 (35)

NE (n, %) 2 (2) 0 (0) 2 (3)McDermott et al. ASCO 2018: 4500

IMDC Category DOR,median (range), mo

Response≥6 Months, %

Favorable NR (1.4+ to 12.5+) 76.5

Intermediate/poor NR (2.3+ to 11.2+) 71.6

0 3 6 9 120

20

40

60

80

100

Time, months

Rem

aini

ng in

Res

pons

e, %

FavorableIntermediate/poor

1329

48

20

717

1123

No. at risk

TITAN: NIVOLUMAB HAS SINGLE AGENT ACTIVITY

Higher single agent activity of nivolumab in 1st line

Grimm et al. ESMO 2019: LBA57

1L

Nalone#

(n=108)

N N+I 2L

Nalone#

(n=99)

N N+I Total

Nalone#

(n=207)

N N+I

ORR (BOR), n (%) 31 (28.7) 40 (37.0) 18 (18.2) 28 (28.3) 49 (22.7) 68 (32.9)

Complete response, n (%) 2 (1.9) 2 (1.9) 0 4 (4.0) 2 (1.0) 6 (2.9)

Partial response, n (%) 29 (26.9) 38 (35.2) 18 (18.2) 24 (24.2) 47 (22.7) 62 (30.0)

Stable disease, n (%) 26 (24.1) 26 (24.1) 23 (23.2) 25 (25.3) 49 (23.7) 51 (24.6)

Progressive disease, n (%) 13 (12.0) 38 (35.2) 16 (16.2) 43 (43.4) 29 (14.0) 81 (39.6)

Early Progressive disease

/ ‘Boost’ Week 8, n (%)

22 (20.4) 26 (26.3) 48 (23.2)

Not evaluable *, n (%) 16 (14.8) 4 (3.7) 16 (16.2) 3 (3.0) 32 (15.5) 7 (3.4)

IPILIMUMAB + NIVOLUMAB IMPROVES OS

Intermediate and high risk patientsGrade 3-4 TRAE:

46,6% 63,9%

1. Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of

efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol (2019). doi:10.1016/S1470-2045(19)30413-9

ORR: 42%

CM214: BETTER QUALITY OF RESPONSE WITH CPI

Patients with ORR achieve longer duration of response with CPI treatment

Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled,

phase 3 trial. Lancet Oncol (2019). doi:10.1016/S1470-2045(19)30413-9

Motzer et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med NEJMoa1816047 (2019). doi:10.1056/NEJMoa1816047

JAVELIN101: AXITINIB + AVELUMAB

PFS

all risks

ORR: 51%

CR: 3%

EPAR Avelumab SEP 2019

OS

KN426: AXITINIB + PEMBROLIZUMAB

Rini, B. I. et al. N Engl J Med NEJMoa1816714–12 (2019).

ORR: 59%

CR: 6%

ATEZOLIZUMAB + BEVACIZUMAB WITHOUT OS

BENEFIT

IMmotion151

all risks, PD-L1+

ORR: 36%

CR: 15%

FU: 15 mo.

Motzer et al. (2018) ASCO GU: 578 Rini, B. et al. The Lancet 393(10189), 2404 - 2415. https://dx.doi.org/10.1016/s0140-6736(19)30723-8

CLINICAL 1ST LINE ACTIVITY OF CPI-BASED THERAPY

IM150

(n=103)

TITAN

(n=108)

KN427

(N=110)

KN426

(N=861)

JAVELIN101

(N=886)

IM151

(N=915)

CM214

(N=1.096)

Atezolizumab

*

Nivolumab* Pembrolizumab

*

Pembrolizumab

+ axitinib

Avelumab +

axitinib

Atezolizumab +

Bevacizumab*

Ipilimumab +

nivolumab

ORR, % 25 28.7 36.4 59.3 51.4 37.0 41.3

CR, % 11 1.9 2.7 5.8 3.4 5.0 10.5

PR, % 14 26.9 33.6 53.5 48.0 31.0 30.7

SD, % - 24.1 31.8 24.5 29.6 39.0 30.0

PD, % - 32.4 30.0 10.9 11.5 18.0 22.0

NE, % - 14.8 1.8 3.5 5.7 7.0 6.7

McDermott, D. F. et al. Nat Med 1–14 (2018). doi:10.1038/s41591-018-0053-3. McDermott et al. ASCO 2019; Poster 4570. Rini, B. I. et al. N Engl J Med NEJMoa1816714–12 (2019). Motzer et al. ASCO GU 2018: abstract

578. Motzer et al. N Engl J Med NEJMoa1816047 (2019). doi:10.1056/NEJMoa1816047. Rini et al. ESMO 2019: 875P. Grimm et al. ESMO 2019: LBA57

COMBINATIONS IMPROVE ORR AND CR

CPI-combinations enhance clinical activity of systemic treatment

0%

18%

35%

53%

70%

ORR CR

ATEZO Pembro ATEZO+BEV IPI-NIVO JAVELIN100 JAVELIN101 AXI-Pembro

McDermott et al. J Clin Oncol 2017; 35: 431.Motzer et al. SITC: O38. Motzer et al. ASCO GU 2018: 578. Motzer et al. ESMO 2018: LBA6. Choueiri et al. Lancet Oncol 2018 Apr;19(4):451-460. doi: 10.1016/S1470-2045(18)30107-4. Atkins et al. ASCO GU 2018: 579.

CPI-COMBINATIONS ACHIEVE A HIGHER DEGREE OF

TOXICITY

IPI-NIVO raises the risk for severe toxicity

TRAE Nivolumab 2nd

line1

Pembrolizumab 1st

line2

IPI 1 + NIVO 3

1st line3

All grades 80 % 80 % 94 %

Grade 3-4 21 % 30 % 47 %

fatal AEs 1.5%

discontinuation 8 % 11 % 22 %

Prednisone

≧40mg

- 13 % 29 %

1Sharma et al. KCS 2017. 2McDermott et al. ASCO 2018: 4500. 3Motzer et al. Lancer Oncol 2019 http://dx.doi.org/10.1016/S1470-2045(19)30413-9

8 (1.5%) treatment-related deaths (1 each): pneumonitis, pneumonia and aplastic anaemia, immune-mediated bronchitis, lower gastrointestinal haemorrhage, haemo-

phagocytic syndrome, sudden death, liver toxic effects, and lung infection

AND SO DO AXITINIB + CPI COMBINATIONS

*sudden cardiac death (1,2%), apoplexy (0,2%), myocarditis (0,2%), pancreatitis (0,2%)**cardiac arrest (n=3), LAE (n=2), cardiac failure (n=1), myasthenia gravis (n=1), gangrane (n=1), multiple myeloma (n=1), pleural effusion (n=1), pneumonitis (n=1), respiratoric failure (n=1)

AEs Grade ≧3

(%)

Fatal AEs (%) Discontinuation ≧1 agent for AE (%)

Prednisone ≧ 40

mg (%)

Avelumab + Axitinib 56,7 1,8* 22 11

Pembrolizumab +

Axitinib62,9 3,3** 31 27

Rini, B. I. et al. N Engl J Med NEJMoa1816714–12 (2019).

SARCOMATOID RCC - A CPI-RESPONSIVE SUBTYPEORR: 59 vs. 32%PFS: HR 0.54 (95% CI 0.29–1.00)

OS: HR 0.58 (95% CI 0.21–1.59); median NR

McDermott et al. ASCO 2019: 4513

Rini BI, et al. ASCO 2019: 4500

Choueiri, et al. ESMO 2019: 910PD

Rini et al. ASCO 2019: 4512

NIVOLUMAB HAS ACTIVITY AFTER TKI-FAILURE

Motzer, R. J. et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. NEJM 373, 1803–1813 (2015). Sharma et al. KCS 2017

3 year follow-up

ORR: 25%

CPI-ESCALATION - A VALID OPTION?

TITAN Study in mRCC

Primars endpoint: ORR

NivolumabNivolumab ORR

Ipilimumab +

Nivolumab

SD or PD

- mRCC

- 1st or 2nd line

- IMDC ≧1 point

- KPS ≧ 70

≦16 wks.

Grimm et al. ESMO 2019: LBA57

IPILIMUMAB RESCUE HAS SOME ACTIVITY

Initial effect* BOR during 1st boost phase

(1-4 treatments)

1L

(n=47)

2L

(n=57)

Total

(n=104)

Stable disease n (%) CR - - -

PR 3 (16.7) - 3 (8.1)

SD 15 (83.3) 16 (84.2) 31 (83.8)

PD - 2 (10.5) 2 (5.4)

Progressive disease n (%) CR 2 (4.8) 2 (2.7)

PR 3 (9.7) 4 (9.5) 7 (9.6)

SD 8 (25.8) 16 (38.1) 24 (32.9)

PD 18 (58.1) 17 (40.5) 35 (47.9)

12,3%

Grimm et al. ESMO 2019: LBA57

CONCLUSIONS

• CPI advanced clinical development in 1st line

• Quality of response differs between TKI und CPI

• Sarcomatoid RCC are a CPI-responsive subgroup

• CRs are associated with CPI treatment

• Combinations boost clinical efficacy, but too early to assess efficacy on CR rate

• Combinations come at the expense of clinical toxicity

• Overall, novel CPI-combinations are safe and feasible options in 1st line therapy