Carcinoma renale

Highlights in Immunoncologia

“Carcinoma renale”

Dott.ssa Laura Noto UOC Oncologia Medica

ASST Vimercate (MB)

RCC Treatment Paradigm

Low risk Intermediate

risk High risk

Diagnosed stage IV

First-line cytokine tx, antiangiogenic tx,

mTORi

Resection

Non-metastatic:

~70%

Metastatic:

~30%

Cytoreductive

nephrectomy/

metastasectomy

aWorldwide incidence as of 2012. ^bInitial stage IV treatment for select patients.

mTORi, mammalian target of rapamycin inhibitor; RCC, renal cell carcinoma; tx, treatment.

1. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. Available at: http://globocan.

iarc.fr/Pages/fact_sheets_population.aspx. Accessed June 7, 2017. 2. Abe H, Kamai T. Int J Urol 2013;20:944–55. 3. Escudier B et al. Ann Oncol 2016;27(suppl 5):v58–68. 4. National Cancer Institute. SEER Cancer Stat Facts: Kidney and Renal Pelvis Cancer. http://seer.cancer.gov/statfacts/html/kidrp.html#survival. Accessed March 22, 2016.

For patients with distant metastases

5-year survival 11.7%

Diagnosis

337,860

Resection ± clinical

trial

30%

Recurrence

Subsequent treatment

• A retrospective study utilizing 2000–2010 SEER data evaluated changes in survival between pretargeted and targeted therapy periods in advanced RCC

• Patients in the targeted therapy era showed improved survival compared to those diagnosed in the pretargeted therapy era (HR: 0.86, P<0.01)

Overall Survival in the Pretargeted vs Targeted Therapy Eras

HR, hazard ratio; RCC, renal cell carcinoma; SEER, Surveillance, Epidemiology, and End Results.

Li P et al. Cancer Med 2016;5:169–181.

Pretargeted Era (2000–2005): N=7,231 Targeted Era (2006–2010): N=6,439

Years 0

0.25 0.50 0.75 1.00

1 2 3 4 5 6

Overall Survival, Advanced RCC

O v eral l Su rv iv a l (Probab il ity )

Systemic Treatment Options for Advanced/

Metastatic Clear Cell RCC

Anti-angiogenic therapies:

mTOR inhibitors Temsirolimus

(Pfizer)

Everolimus

(Novartis)

Anti-angiogenic therapies:

AntiVEGF antibodies/VEGFR inhibitors Bevacizumab

(Roche)

Sorafenib

(Bayer Pharma AG)

Sunitinib

(Pfizer)

Pazopanib

(Glaxo Operations UK LTD)

Axitinib

(Pfizer)

Cabozantinib

(Exelixis)

Lenvatinib

(Eisai)

Immunotherapies: Cytokines

IFN-a (Roche)

IL-2 (Prometheus)

Immunotherapies:

PD-1 inhibitor Nivolumab

(Bristol-Myers Squibb)

aRoche no longer markets IFN-α in the US. ^bBevacizumab is approved for RCC in combination with IFN-α.^1cApproved in combination with everolimus.⁶

IFN-α, interferon alfa; mTOR, mammalian target of rapamycin; RCC, renal cell carcinoma; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

1. Hutson TE. Oncologist 2011;16 (Suppl 2):14–22. 2. BMS Press Release. April 6, 2016. Available at: http://news.bms.com/press-release/european-commission- approves-bristol-myers-squibbs-opdivo-nivolumab-previously-treated. Accessed April 7, 2016. 3. GSK Press Release. June 15, 2010. Available at:

https://www.firstwordpharma.com/node/666713?tsid=17. Accessed September 26, 2016. 4. Pfizer Press Release. September 4, 2012. Available at:

http://press.pfizer.com/press-release/pfizer-receives-eu-marketing-authorization-inlyta-axitinib. Accessed September 4, 2012. 5. Exelixis Press Release September 14, 2016. Available at http://www.exelixis.com/investors-media/press-releases. Accessed September 26, 2016. 6. Eisai Press Release. September 15, 2016.

Available at http://www.eisai.com/news/news201663.html. Accessed September 26, 2016.

• Spontaneous advanced RCC

remissions attributed to the immune system have been observed ¹

• RCC exhibits immune cell infiltrates, and several immune escape

mechanisms have been reported in RCC ^2,3

• Historically, the mainstay of treatment for patients with mRCC was

immunotherapy with interleukin-2 or interferon-α1

• I-O is an evolving treatment modality encompassing agents designed to directly harness the patient’s own immune system to fight cancer ^7,8

Rationale for Immunotherapy in RCC

Tregs CD45 + Memory T Cells CD8 + T Cells CD4 + T Cells

Studies have documented alterations in various immune cell types in RCC, including3–6:

 levels:

Poor Prognosis

 levels:

Fair/Poor Prognosis

 levels:

Fair/Poor Prognosis/No

Association

 levels:

Fair/Poor Prognosis

I-O, immuno-oncology; RCC, renal cell carcinoma; mRCC, metastatic renal cell carcinoma; Treg, regulatory T cell.

1. Escudier B. Ann Oncol 2012;23(Suppl 8):viii35–40 2. Noessner E et al. OncoImmunology 2012;1:1451–3. 3. Bockorny B et al. Expert Opin Biol Ther

2013;13:911–25. 4. Hotta K, et al. Br J Cancer 2011;105:1191–96. 5. Nakano O et al. Cancer Res 2001;61:5132–6. 6. Igarashi T et al. Urol Int 2002;69:51–6.

7. Ascierto PA et al. J Trans Med 2014;12:141. 8. Eggermont A et al. OncoImmunol 2014;3:e27560.

Rationale for Anti–PD-1 in RCC

a306 samples were analyzed by IHC; threshold was ≥5% tumor cells with membranous staining.

ccRCC, clear cell RCC: IHC, immunohistochemistry; PD-1, programmed death 1; PD-L1, programmed death ligand 1; RCC, renal cell carcinoma; TIL, tumor- infiltrating lymphocyte.

1. Thompson RH et al. Cancer Res 2006;66:3381–5. 2. Thompson RH et al. Proc Natl Acad Sci USA 2004;101:17174–9. 3. Thompson RH et al. Clin Cancer Res 2007;13:1757–61. 4. Kang MJ et al. Transl Oncol 2013;6:282–9.

Tumor cells

• 24% of ccRCC samples express PD-L1 ^1a

• PD-L1 expression significantly

correlated with cancer-specific death ¹

TILs

• >50% of RCC TILs express PD-L1+ ²

• High PD-1

expression on TILs associated with distant

metastatic relapse and poor survival ^3,4

RCC Tumor

Microenvironment

Recognition of tumor by T cell through MHC/antigen/TCR interaction mediates IFN-γ

release and PD-L1/2 up-regulation on tumor

Priming and activation of T cells through MHC/antigen/TCR and CD28/B7 interactions

with antigen-presenting cells

Nivolumab: Mechanism of Action

MHC

PD-L1

PD-1

PD-1

T-cell receptor T-cell

receptor

PD-L1

PD-L2

CD28

T cell

NFκB Other

PI3K

Tumor cell

IFNγR

Shp-2

Shp-2 Antigen

Antigen

MHC

B7 PD-1

PD-1

Nivolumab blocks the PD-1 receptor

PD-L2 IFNγ

Adapted from Pardoll DM et al. Nat Rev Cancer 2012.¹

Abbreviations, references, and footnotes are listed in the speaker notes.

Dendritic

cell

CheckMate 025 Study Design

aPatients were allowed to continue treatment beyond progression if investigator-assessed clinical benefit was achieved and treatment had an acceptable side- effect profile.

AE, adverse event; CNS, central nervous system; IV, intravenous; KPS, Karnofsky performance status; mTOR, mammalian target of rapamycin; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; PO, oral; qd, once daily; q2w, every 2 weeks;

R, randomized; RCC, renal cell carcinoma.

1. Motzer RJ et al. N Engl J Med 2015;373:1803–13. 2. Clinicaltrials.gov. NCT01668784. Accessed April 26, 2017.

Phase 3, randomized, open-label study of nivolumab vs everolimus in patients with advanced or metastatic clear cell RCC who have received prior anti-angiogenic therapy.

Nivolumab

3 mg/kg IV q2w Until progression,

unacceptable

toxicity, withdrawal of consent, or end of study

Key Inclusion Criteria

• Advanced/metastatic clear cell RCC

• ≤3 total prior regimens

• 1 or 2 prior anti-angiogenic therapies

• Progression <6 months before enrollment

• KPS ≥70

• No CNS metastases

• No prior therapy with mTOR inhibitor

• No condition requiring glucocorticoids

R 1:1

Everolimus 10 mg PO qd

Primary Endpoint: OS

Secondary Endpoints: ORR, PFS, OS by PD-L1 expression, incidence of AEs

Start Date: September 2012

Estimated Trial Completion Date: September 2018

Primary Completion Date: May 2015

Status: Ongoing but not recruiting

Trial Director: Bristol-Myers Squibb

N=821

CheckMate 025: monotherapy

Overall Survival

Minimum follow-up: 14 months; reported as of June 2015.

CI, confidence interval; HR, hazard ratio; NE, not estimable; OS, overall survival.

Motzer et al. N Engl J Med 2015;373:1803–13.

CheckMate 025: monotherapy

Median OS, Months (95% CI) Nivolumab 25.0 (21.8–NE) Everolimus 19.6 (17.6–23.1)

0 3 6 9 12 15

Months

18 21 24 27 30 33

No. of patients at risk

Nivolumab 410 389 359 337 305 275 213 139 73 29 3 0 411 366 324 287 265 241 187 115 61 20 2 0 Everolimus

0 0.3

0.1 0.2 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Ov erall Surv iv al (Proba bi lit y )

HR (98.5% CI), 0.73 (0.57–0.93)

P=0.002

OS by Subgroup ^a

Minimum follow-up: 14 months; reported as of June 2015.

aAnalyses are based on interactive voice response system data.

CI, confidence interval; MSKCC, Memorial Sloan Kettering Cancer Center; OS, overall survival.

Adapted from Motzer et al. N Engl J Med 2015;373:1803–13.

CheckMate 025: monotherapy

Subgroup Nivolumab

n/N

Everolimus n/N

Unstratified Hazard Ratio for Death (95% CI)

Overall 183/410 215/411

MSKCC prognostic score

Favorable 45/145 52/148

Intermediate 101/201 116/203

Poor 37/64 47/60

Previous anti-angiogenic regimens

1 128/294 158/297

2 55/116 57/114

Region

United States/Canada 66/174 87/172

Western Europe 78/140 84/141

Rest of the world 39/96 44/98

Age category, n (%)

<65 years 111/257 118/240

≥65–<75 years 53/119 77/131

≥75 years 19/34 20/40

Sex

Female 48/95 56/107

Male 135/315 159/304

0.25 0.5 0.75 1 1.5 2.25 Favors

Nivolumab

Favors

Everolimus

OS: 2-Year Follow-up

Minimum follow-up: 26 months; reported as of May 11, 2016.

CI, confidence interval; HR, hazard ratio; MSKCC, Memorial Sloan Kettering Cancer Center; OS, overall survival.

Plimack ER et al. Poster presentation at KCS 2016.

Median OS benefit was observed for nivolumab vs everolimus in patients with MSKCC intermediate risk (21.9 months vs 18.4 months) and poor risk (15.3 months vs 7.9 months)

Median OS, Months (95% CI)

Nivolumab 26.0 (22.2–29.6) Everolimus 19.7 (17.6–22.3) HR: 0.73 (95% CI, 0.61–0.88) P=0.0006

CheckMate 025: monotherapy

0 3 6 9 12 15

Months

18 21 24 27 33 42

0 0.3

0.1 0.2 0.4 0.5 0.6 0.7 0.8 0.9 1.0

O v eral l Su rv iv a l (Probab il ity )

36

30 39

No. of patients at risk Nivolumab

Everolimus

410 390 359 337 305 276 251 225 204 171 129 80 38 5 0 411 367 325 289 268 247 214 183 162 130 103 61 32 5 0

76%

67% _52%

42%

• 100 (26%) patients were treated beyond progression, of whom 25 patients obtained a subsequent benefit (6 had a partial response and 19 had stable disease)

Median OS not reached

Figure 1. Kaplan-Meier estimates of OS for patients treated beyond PD and patients not treated beyond PD

• One-year overall survival was 73.5% in patients treated beyond PD

and 43.5% for patients not treated beyond PD (Figure 1)

Efficacy

1 7

• Of 389 enrolled patients, 125 (32%) were

at least 70 years of age and 70 (18%) were

at least 75 years of age

Efficacy

• Median duration of response has not been reached in the overall population or either age subgroup

• The 6- and 12-month overall survival (OS) rates were, respectively:

― All patients, 80.2% and 64.1%

― ≥70 years of age, 87.2% and 77.8%

― ≥75 years of age, 83.6% and 77.7%

Immune Checkpoint Inhibitors:

Potential as Part of a Combination Regimen

Adapted from Pardoll DM et al. Nat Rev Cancer 2012.¹

Abbreviations, references, and footnotes are listed in the speaker notes.

T cell

Dendritic cell

MHC TCR

Antigen

B7 CD28 B7 CTLA-4

Anti–CTLA-4

Periphery

T cell

Antigen

PD-L1 PD-1

PD-1 PD-L2

CTLA-4 Pathway

(Blockade with ipilimumab)

Anti–PD-1 Anti–PD-1/PD-L1

PD-1 Pathway

(Blockade with nivolumab) Tumor Microenvironment

TCR MHC

Data suggest certain combinations may overcome the limitations of monotherapy ^1,2

Activation

(cytokines, lysis, proliferation,

migration to tumor)

CheckMate 016 Study Design

Phase 1 open-label trial of nivolumab plus sunitinib, pazopanib, or ipilimumab in patients with advanced/metastatic RCC.

Start Date: January 2012

Estimated Trial Completion Date: June 2018

Estimated Primary Completion Date: February 2016 Trial Director: Bristol-Myers Squibb

N=175

Arm N3I1: Nivolumab

3 mg/kg IV q3w for 4 doses and then q2w Ipilimumab 1 mg/kg IV q3w for 4 doses

Arm N1I3: Nivolumab

1 mg/kg IV q3w for 4 doses and then 3 mg/kg q2w Ipilimumab 3 mg/kg IV q3w for 4 doses

Arm P + N

: Nivolumab 2 mg/kg IV q3w Pazopanib 800 mg/day PO

Arm S + N

: Nivolumab 2 or 5 mg/kg IV q3w Sunitinib 50 mg/day PO days 1–28 of 42-day cycle

Arm N3I3

: Nivolumab

3 mg/kg IV q3w for 4 doses and then q2w Ipilimumab 3 mg/kg IV q3w for 4 doses Primary Outcome Measure: AEs, SAEs, lab abnormalities Secondary Outcome Measures: ORR, DOR, PFS

Exploratory Outcome Measure: OS, response by subgroup

aOne prior adjuvant or neoadjuvant therapy for localized or locally advanced RCC allowed if recurrence occurred ≥6 months after last dose; prior

IFN-α or IL-2 is also allowed.^3bOf 20 patients treated in this arm, 4 DLTs were observed, leading to closure of the arm.^2cMTD was not reached, leading to expansion of S + N5 cohort.^2dThis arm was stopped due to toxicity.³

AE, adverse event; CNS, central nervous system; DLT, dose-limiting toxicity; DOR, duration of response; IFN-α, interferon-alfa; IL-2, interleukin-2; IPI, ipilimumab;

IV, intravenous; MTD, maximum tolerated dose; N5, nivolumab 5 mg/kg; N, nivolumab; ORR, objective response rate; OS, overall survival;

P, pazopanib; PD-L1, programmed death ligand 1; PFS, progression-free survival; PO, oral; PS, performance status; q2w, every 2 weeks;

q3w, every 3 weeks; RCC, renal cell carcinoma; S, sunitinib; SAE, serious AE.

References are listed in the speaker notes.

CheckMate 016: nivo + ipi

Key Inclusion Criteria

• Advanced or metastatic RCC with a clear cell component

• Karnofsky PS ≥80%

• No active CNS metastases

• For arms P and S:

– Prior treatment with sunitinib/pazopanib in select dose escalation patients

– No poorly controlled hypertension

– No active bleeding or bleeding susceptibility

• For arms N3I1 and N1I3:

– Previously treated or treatment-naïve patients

• For arm N3I3:

– Treatment-naïve patients

Objective Response Rate

Median follow-up: 22.3 months (N3I1 and N1I3).

CI, confidence interval; N1I3, nivolumab 1 mg/kg + ipilimumab 3 mg/kg; N3I1, nivolumab 3 mg/kg + ipilimumab 1 mg/kg; ORR, objective response rate.

Adapted from Hammers HJ et al. J Clin Oncol 2017. http://dx.doi.org/10.1200/JCO.2016.72.1985.

N3I1 (n=47)

N1I3 (n=47) Confirmed ORR, %

95% CI

40.4 26.4–55.7

40.4 26.4–55.7 Best overall response, %

Complete response Partial response Stable disease

Disease progression Unable to determine

10.6 29.8 40.4 17.0 2.1

0 40.4 36.2 17.0 6.4 CheckMate 016: nivo + ipi

• Manageable safety and high antitumor activity in previously treated and treatment-naïve patients – ORR: 40%

– Ongoing responses: 42%

– Median PFS: 7.7 months, Median OS: 32.6 months in N1I3, not reached in N3I1

– G3/4 toxicities in 38.3% (N3I1) and 61.7% (N1I3)

CheckMate 214: Study design

IMDC, International Metastatic RCC Database Consortium; KPS, Karnofsky performance status; Q2W, every 2 weeks; Q3W, every 3 weeks

Treatment until progression or unacceptable

toxicity

• Treatment-naïve advanced or

metastatic clear-cell RCC

• Measurable disease

• KPS ≥70%

• Tumor tissue

available for PD-L1 testing

Treatment Patients

Randomize 1:1

Arm A

3 mg/kg nivolumab IV + 1 mg/kg ipilimumab IV Q3W

for four doses, then 3 mg/kg nivolumab IV Q2W

Arm B

50 mg sunitinib orally once daily for 4 weeks

(6-week cycles)

Stratified by

•IMDC prognostic score (0 vs 1–2 vs 3–6)

•Region (US vs

Canada/Europe vs

Rest of World)

• In IMDC intermediate- and poor-risk patients

– ORR (per independent radiology review committee, IRRC) – PFS (per IRRC)

– OS

• Statistical analyses

– Overall alpha is 0.05, split among the three co-primary endpoints – 0.001 for ORR, 0.009 for PFS, and 0.04 for OS

– PFS analysis had ~80% power and OS analysis had 90% power to detect a statistically significant difference between treatment arms

– The number of patients randomized was estimated to be ~1,070, 820 of whom would have IMDC intermediate/poor risk

Co-primary endpoints

• Secondary endpoints (in intention-to-treat [ITT] patients) – ORR

– PFS – OS

– Adverse event incidence rate (in all treated patients)

• PFS and OS secondary efficacy endpoints were subject to hierarchical testing, first testing in intermediate/poor-risk patients followed by testing in ITT patients, if significant

• Exploratory endpoints

– ORR, PFS, and OS in favorable-risk patients – Outcomes by tumor PD-L1 expression level

– HR QoL based on NCCN Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19)

Secondary and exploratory endpoints

Baseline characteristics

IMDC intermediate/poor risk Intention to treat

Characteristic NIVO + IPI

N = 425

SUN N = 422

NIVO + IPI N = 550

SUN N = 546

Median age, years 62 61 62 62

Male, % 74 71 75 72

IMDC prognostic score (IVRS), % Favorable (0)

Intermediate (1–2) Poor (3–6)

0 79 21

0 79 21

23 61 17

23 61 16 Region (IVRS), %

USA

Canada/Europe Rest of the world

26 35 39

26 35 39

28 37 35

28 36 36 Quantifiable tumor PD-L1 expression, %

<1%

≥1%

n = 384 74 26

n = 392 71 29

n = 499 77 23

n = 503 75 25

• Baseline characteristics in favorable-risk patients were similar, except tumor PD-L1

expression was lower than the intermediate/poor-risk patients and ITT population

Baseline disease characteristics

IMDC intermediate/poor risk Intention to treat

Characteristic NIVO + IPI

N = 425

SUN N = 422

NIVO + IPI N = 550

SUN N = 546 No. of sites with ≥1 target/non-target

lesion 1

≥2

21 79

20 80

22 78

22 78 Most common site of metastasis, %

Lung

Lymph node Liver

Bone

69 45 21 20

70 51 21 21

69 45 18 18

68

49

20

19

Patient disposition: All treated patients

NIVO + IPI N = 547

SUN N = 535

Treatment discontinuation, % 77 82

Reasons for treatment discontinuation, % Disease progression

Study drug toxicity

Adverse event unrelated to study drug Other

42 24 6 4

55 12 6 9

Median duration of therapy (95% CI), months 7.9 (6.5–8.4) 7.8 (6.4–8.5) Median doses received (range), no.

Nivolumab Ipilimumab

14 (1–63) 4 (1–4)

NA NA

Median daily dose (range), mg/day NA 31 (14–50)

• In the NIVO + IPI arm, 79% of patients received all four doses of IPI

• Median follow-up was 25.2 months

ORR and DOR: IMDC intermediate/poor risk

N = 847

Outcome NIVO + IPI

N = 425

SUN N = 422 Confirmed ORR,

% (95% CI) 42 (37–47) 27 (22–31)

P < 0.0001 Confirmed BOR,

%

Complete response Partial response Stable disease

Progressive disease

Unable to determine/not reported

9

32 31 20 8

1

25 45 17 12

aIRRC-assessed ORR and BOR by RECIST v1.1; ^bP < 0.0001

SUN NIVO + IPI No. at Risk

177 146 120 55 3

112 75 52 17 0

0 .0 0 .1 0 .2 0 .3 0 .4 0 .5 0 .6 0 .7 0 .8 0 .9 1 .0

0 6 12 18 24

Months

Duration of Response (Probability)

Co-primary endpoint: ORR

Median duration of response, months (95% CI)

Patients with ongoing response, %

SUN 18.2 (14.8–NE) 63

0 3 6 9 12 15 18 21 24 27 30

PFS per IRRC: IMDC intermediate/poor risk

Hazard ratio (99.1% CI), 0.82 (0.64–1.05) P = 0.0331

Median PFS, months (95% CI) NIVO + IPI 11.6 (8.7–15.5)

SUN 8.4 (7.0–10.8)

Progression-Free Survival (Probability)

425 304 233 187 163 149 118 46 17 3 0

422 282 191 139 107 86 57 33 11 1 0

No. at Risk

Months 1.0

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Co-primary endpoint

OS: IMDC intermediate/poor risk

Hazard ratio (99.8% CI), 0.63 (0.44–0.89) P < 0.0001

Median OS, months (95% CI) NIVO + IPI NR (28.2–NE)

SUN 26.0 (22.1–NE)

Overall Survival (Probability)

425 399 372 348 332 318 300 241 119 44 2 0

422 387 352 315 288 253 225 179 89 34 3 0

No. at Risk

Months 1.0

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

18 21 24 27 30 33

15 9 12

6 3

0

Co-primary endpoint

No crossover permitted

ORR, PFS, and OS: Intention to treat

a23% of patients in the NIVO + IPI arm and 25% of patients in the SUN arm had tumor PD-L1 expression ≥1%

bIRRC-assessed by RECIST v1.1

cIRRC-assessed

N = 1,096

Outcome NIVO + IPI

N = 550

SUN N = 546 Confirmed ORR,

% (95%

CI) 39 (35–43) 32 (28–36)

P = 0.0191 PFS,

median (95% CI),

months

12.4 (9.9–16.5) 12.3 (9.8–15.2) HR (99.1% CI) 0.98 (0.79–1.23)

P = 0.8498

550 523 492 464 443 426 404 339 197 71 4 0 546 506 471 432 402 363 334 283 173 66 6 0

Overall Survival (Probability)

0 . 8 0 . 9 1 . 0

0 . 4 0 . 5 0 . 6 0 . 7

0 6 1 2 1 8 2 4

0 . 1 0 . 0 0 . 2 0 . 3

3 3 3 0

3 9 1 5 2 1 2 7

Months

NIVO + IPI

HR (99.8% CI) 0.68 (0.49–0.95) P = 0.0003

Median OS, months (95% CI)

SUN 32.9 (NE–NE)

Secondary endpoint

ORR and PFS: IMDC favorable risk

a11% of patients in both arms had tumor PD-L1 expression ≥1%

bIRRC-assessed by RECIST v1.1

cIRRC-assessed

N = 249

Outcome

NIVO + IPI N = 125

SUN N = 124

Confirmed ORR,

% (95% CI) 29 (21–38) 52 (43–61)

P = 0.0002

PFS,

median (95% CI), months 15.3 (9.7–20.3) 25.1 (20.9–NE) HR (99.1% CI) 2.18 (1.29–3.68)

P < 0.0001

Exploratory endpoint

Antitumor activity by tumor PD-L1 expression level

IMDC intermediate/poor risk Intention to treat

PD-L1 <1% PD-L1 ≥1% PD-L1 <1% PD-L1 ≥1%

Outcome NIVO + IPI

N = 284

SUN N = 278

NIVO + IPI N = 100

SUN N = 114

NIVO + IPI N = 386

SUN N = 376

NIVO + IPI N = 113

SUN N = 127 ORR,

% (95% CI) 37

(32–43)

28 (23–34)

58 (48–68)

22 (15–31)

36 (31–41)

35 (31–40)

53 (44–63)

22 (15–30)

P = 0.0252 P < 0.0001 P = 0.8799 P < 0.0001

BOR,

%

Complete response Partial response Stable disease

Progressive disease NA

7 30 36 20 7

1 27 47 13 12

16 42 19 14 9

1 21 40 25 13

9 27 39 18 7

2 33 43 11 11

14 39 25 14 8

1 21 43 23 13

aIRRC-assessed

Exploratory endpoint

284 202 155 119 102 90 70 23 9 1 0 278 200 138 105 83 67 43 25 11 1 0

PFS by PD-L1 expression: IMDC intermediate/poor risk

PD-L1 <1% (n = 562) PD-L1 ≥1% (n = 214)

HR (95% CI) 0.48 (0.28–0.82) P = 0.0003

Median PFS, months (95% CI)

SUN 5.9 (4.4–7.1)

HR (95% CI) 1.00 (0.74–1.36) P = 0.9670

Median PFS, months (95% CI)

NIVO SUN No. at

Risk

100 77 61 54 50 48 41 21 8 2 0

114 63 40 24 17 13 9 4 0 0 3

0 . 8 0 . 9 1 . 0

0 . 4 0 . 5 0 . 6 0 . 7

0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0

0 . 1 0 . 0 0 . 2 0 . 3 0 . 8

0 . 9 1 . 0

0 . 4 0 . 5 0 . 6 0 . 7

0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0

0 . 1 0 . 0 0 . 2 0 . 3

Progression-Free Survival (Probability)

Months Months

Exploratory endpoint

Treatment-related adverse events: All treated patients

NIVO + IPI N = 547

SUN N = 535

Event, % Any grade Grade 3–5 Any grade Grade 3–5

Treatment-related adverse events in ≥25% of patients 93 46 97 63

Fatigue 37 4 49 9

Pruritus 28 <1 9 0

Diarrhea 27 4 52 5

Nausea 20 2 38 1

Hypothyroidism 16 <1 25 <1

Decreased appetite 14 1 25 1

Dysgeusia 6 0 33 <1

Stomatitis 4 0 28 3

Hypertension 2 <1 40 16

Mucosal inflammation 2 0 28 3

Palmar-plantar erythrodysesthesia syndrome 1 0 43 9

Treatment-related AEs leading to discontinuation, % 22 15 12 7

Treatment-related deaths n = 7

n = 4

aTwo patients had grade 5 cardiac arrest. ^bPneumonitis, immune mediated bronchitis, lower GI hemorrhage, hemophagocytic syndrome, sudden death, liver toxicity, lung infection. ^cCardiac arrest (n = 2), heart failure, multiple organ failure

Secondary endpoint

Immune-mediated adverse events: All treated patients

NIVO + IPI N = 547

Category, % Any grade Grade 3–4

Rash 17 3

Diarrhea/colitis 10 5

Hepatitis 7 6

Nephritis and renal dysfunction 5 2

Pneumonitis 4 2

Hypersensitivity/infusion reaction 1 0

Hypothyroidism 19 <1

Hyperthyroidism 12 <1

Adrenal insufficiency 8 3

Hypophysitis 5 3

Thyroiditis 3 <1

Diabetes mellitus 3 1

Immune-mediated AE analyses included events, regardless of causality, occurring <100 days of the last dose. These analyses were limited to patients who received immune modulating medication for treatment of the event, except endocrine events that were included in the analysis regardless of treatment since these events are often managed without immunosuppression

• 60% of patients treated with NIVO + IPI required systemic corticosteroids for an adverse event

• Secondary immunosuppression with infliximab (3%) and mycophenolic acid (1%) was reported

IMmotion150 (Phase II) Trial Design

Crossover treatment permitted

First-line treatment

• Coprimary endpoints: PFS (RECIST v1.1 by IRF) in ITT and PD-L1+ patients

• IMmotion150 designed to be hypothesis generating and inform the trial design of the Ph. III study IMmotion151

• Amendments included: Based on Phase 1a data, the definition of PD-L1 positivity was revised from ≥ 5% to ≥ 1% of IC expressing PD-L1

– In addition to ITT patients, PD-L1+ patients were included in the co-primary EP of IRF-assessed PFS, after interim analyses

Treatment naive, locally advanced or

metastatic RCC N = 305

R

1:1:1

Atezolizumab +

bevacizumab

Atezolizumab + bevacizumab PD

Atezolizumab 1200 mg IV q3w

Sunitinib 50 mg (4 wk on, 2 wk off) Atezolizumab 1200 mg IV + bevacizumab 15 mg/kg q3w Stratification:

•Prior

nephrectomy

•PD-L1 IHC expression

•(≥ 5% IC level)

•MSKCC risk category

IRF, independent review facility. 1. McDermott JCO 2016.

Crossover from atezolizumab monotherapy not allowed in Europe.

Presented by: Dr. Thomas Powles

A Phase II Study of Atezolizumab With or Without Bevacizumab vs Sunitinib in Untreated

Metastatic Renal Cell Carcinoma Patients

David McDermott,¹Michael Atkins,²Robert Motzer,³Brian Rini,⁴Bernard Escudier,⁵Lawrence Fong,⁶ Richard W. Joseph,⁷Sumanta Pal,⁸Mario Sznol,⁹John Hainsworth,¹⁰Walter M. Stadler,¹¹

Thomas Hutson,¹²Alain Ravaud,¹³Sergio Bracarda,¹⁴Cristina Suarez,¹⁵Toni Choueiri,¹⁶ YounJeong Choi,¹⁷Mahrukh A. Huseni,¹⁷ Gregg D. Fine,¹⁷Thomas Powles¹⁸

1Beth Israel Deaconess Medical Center, Boston, MA; ²Georgetown Lombardi Comprehensive Cancer Center, Washington, DC;

3Memorial Sloan Kettering Cancer Center, New York, NY; ⁴Cleveland Clinic, Cleveland, OH; ⁵Gustave Roussy, Villejuif, France;

6University of California, San Francisco School of Medicine, San Francisco, CA; ⁷Mayo Clinic Hospital – Florida, Jacksonville, FL;

8City of Hope Comprehensive Cancer Center, Duarte, CA;⁹Yale School Of Medicine, New Haven, CT; ¹⁰Sarah Cannon Research Institute, Nashville, TN; ¹¹University of Chicago Medicine, Chicago, IL; ¹²Texas Oncology - Baylor Charles A. Sammons Cancer Center, Dallas, TX; ¹³CHU Hopitaux de Bordeaux - Hôpital Saint-André, Bordeaux, France; ¹⁴Ospedale San Donato, Arezzo, Italy;

15Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain;

16Dana-Farber Cancer Institute, Boston, MA; ¹⁷Genentech, Inc., South San Francisco, CA, USA; ¹⁸Barts Cancer Institute, Queen Mary University of London, London, UK

IMmotion150: IRF-Assessed PFS

ITT

a P values are for descriptive purposes only and not adjusted for multiple comparisons.

Atezolizumab + bevacizumab Atezolizumab

Sunitinib

Atezo + bev: 11.7 mo (8.4, 17.3)

Atezo:

6.1 mo

(5.4, 13.6) Sunitinib:

8.4 mo (7.0, 14.0)

Stratified HR (95% CI)

P Value^a

Atezo + bev vs sunitinib

1.00 (0.69, 1.45)

0.982

Atezo vs sunitinib

1.19 (0.82, 1.71)

0.358

Presented by: Dr. Thomas Powles

IMmotion150: IRF-Assessed PFS

≥ 1% of IC Expressing PD-L1

a P values are for descriptive purposes only and not adjusted for multiple comparisons.

Atezo + bev: 14.7 mo

Atezo:

5.5 mo

(3.0, 13.9)

Sunitinib:

7.8 mo

Presented by: Dr. Thomas Powles

Stratified HR (95% CI)

P Value^a

Atezo + bev vs sunitinib

0.64 (0.38, 1.08)

0.095

Atezo vs sunitinib

1.03 (0.63, 1.67)

0.917

Atezolizumab + bevacizumab Atezolizumab

Sunitinib

IMmotion151:

Randomized phase 3 study of Atezolizumab + Bevacizumab versus Sunitinib in patients with untreated mRCC

www. clinicaltrials.gov (NCT02420821))

MPDL3280A + BEVA

SUNITINIB

Treat until disease progression

• Primary endpoint: PFS

• Secondary endpoints: OS, ORR, TTD, safety DoR

N =550

 PFS data are immature; only 14 (26.9%) events for the overall analysis

 In the overall population, median PFS was 15.1 mos (range: 11.4-NE); of 11 patients enrolled in the dose-finding phase, median PFS is not yet reached

Change in Tumor Burden by Best Response

Be st Ch ang e in T umor Size From Ba seli ne ( % )

10 80 0 60 40 20 0 -20 -40 -60 -80 -100

94% of patients with tumor shrinkage

Atkins MB, et al. ESMO 2016. Abstract 773PD.

Phase I Axitinib + Pembrolizumab for Untreated Advanced RCC: Preliminary Safety and Efficacy

Response, n (%) Axitinib + Pembro*

(n = 52

)

ORR 37 (71.2)

Best overall response

 CR

 PR

 SD

 PD

 Indeterminat e

3 (5.8) 34 (65.4) 10 (19.2)

2 (3.8) 3 (5.8)

*Axitinib 5 mg BID; pembro 2 mg/kg IV Q3W.

†

All patients with measurable disease at BL.

CR PR

Stable disease

Progressive disease

Indeterminate

JAVELIN 101 (BB9991003):

Randomized 1 ^st Line Phase III Study of Avelumab plus Axitinib versus Sunitinib in mRCC

N Engl J Med 2013;369:722-31. Randomized Registration Study

Enrollment Criteria

• Histological confirmed advanced clear cell RCC

• No prior systemic therapy

• Measurable disease by (RECIST) v 1.1

• No symptomatic brain metastasis

• No History of autoimmune disease or immunosuppressant excluded

• No prior Immune Check Point inhibitor therapies

• Mandatory archival tumor tissue FFPE block

• Mandatory pre-tx peripheral blood

Primary Endpoint: PFS by BIRC

Secondary Endpoints:

OS, ORR, DCR, TTR, DR, Safety (AEs, laboratory abnormalities), PK, ADA, biomarkers, PROs

Stratification ● ECOG PS (0 vs. 1) and region (US vs Canada/Western Europe vs ROW)

Outcomes:

● Aim: Evaluate

Avelumab + Axitinib in 1st-Line aRCC

● Target PFS : HR = 0.7, improvement 11 mo. to 15.7 mo.

● Target OS: HR = 0.75 improvement 26.4 mo. to 35.2

● mo. Accrual rate = 45 pts/mo.

● Accrual duration=

14 mo.

N = 583, 336 events

Arm A Avelumab +

Axitinib

Arm B Sunitinib

R and omi sati on 1: 1

We need data in these 2 settings!

axitinib

sorafenib

Median PFS 9–11 months

Median PFS 4–14 months

Median PFS 4–5 months

Porta C, et al. Expert Opin Pharmacother 2016;17:643-55.

FIRST-LINE SECOND-LINE THIRD-LINE

axitinib

sorafenib

Median PFS 9–11 months

Median PFS 4–14 months

Median PFS 4–5 months

Porta C, et al. Expert Opin Pharmacother 2016;17:643-55.

FIRST-LINE SECOND-LINE THIRD-LINE

Nivolumab +

ipilimumab

• There are no well-controlled prospective studies designed to evaluate the antitumor activity of antiangiogenic therapies after PD-1/PD-L1 inhibitors

• Although patients may have received TKIs after nivolumab in CheckMate 025 (as shown in the table below), their outcomes have not been reported ¹

Antiangiogenic Therapy After PD-1/PD-L1 Inhibitors

• Retrospective data (Nadal et al, Albiges et al) and a post hoc analysis of the phase 3 METEOR trial suggest antitumor activity of an antiangiogenic therapy after PD- 1/PD-L1 inhibition ^2–4

PD-1, programmed death 1; PD-L1, programmed death ligand 1; TKI, tyrosine kinase inhibitor.

1. Motzer RJ et al. N Engl J Med 2015;373:1803–13. 2. Albiges L et al. Eur J Cancer 2015;51:2580–6.

3. Nadal R et al. Ann Oncol 2016;27:1304–11. 4. Powles T et al. Poster presentation at ASCO 2016.P179.

Adapted from Motzer et al. N Engl J Med 2015.

CheckMate 025: nivo monotherapy (q2w)

Characteristic, n (%) Nivolumab

N=410

Everolimus N=411 Any subsequent anticancer therapy 227 (55) 260 (63)

Axitinib 99 (24) 149 (36)

Pazopanib 37 (9) 64 (16)

Sorafenib — 38 (9)

• retrospective analysis of 27 patients with mRCC treated with 1L ICI (17 N+I), followed by 2L TKI (Axi, Pazo, Cabo).

• 11 patients (41%) had PR (8 of whom had 40% tumor reduction), and 16 (59%) had SD as best response to TKI.

• Median PFS was 10.0 months

• Age, sex, IMDC risk score, nephrectomy status, and TKI agent did not predict PR or SD

• retrospective analysis of 78 mRCC patients progressing after a immune checkpoint inhibitor (ICI) treated with TKIs as subsequent therapy.

• 22 pts (28%) never received further treatment. 56 pts (72%) received further therapies: 18 (32%) Cabo, 25 (44%) Axitinib and13 (24%) other.

• ORR was 33%, median TTF was 7.99 mo and median OS was 12.33 mo.

• ORR for cabozantinib was 42%

ASCO 2016

CONCLUSIONS

• Advanced RCC characterized by a continuously changing Treatment Scenario.

• Sequencing remain at the moment the Option of Choice for

treating mRCC, but these new data are changing the treatment algoritm.

• Interactions between Immunological Drugs and/or other Agents will become the background of new Combinations, especially in first Line Setting.

• I-O Studies resulted in a Paradigm Shift for mRCC,

introducing the concept of a possibility of cure (in a % of treated pts):

• Finally, we moved from PFS to OS: not simply a change of

terms !

Grazie per l’attenzione