Atezolizumab Adjuvant

RCC Trial:A Surgical Perspective

Robert G. Uzzo, M.D.

Willing G. Pepper Chairman of Surgery Fox Chase Cancer Center

Temple University School of MedicineChair, Department of Urology

Urological Institute at Einstein Healthcare NetworkPhiladelphia, PA USA

Adjuvant Therapy

The Holy Grail of Surgery

Incompletely

effective

(high quality)

surgery

Completely

effective

systemic RxvElusive

Incompletely

effective

systemic Rx

X

Ineffective

Adjuvant RCC Trials: The Dark Ages“Incompletely effective surgery with completely ineffective systemic Therapy”

Treatment Outcome

Radiation vs observation (N=72) NO BENEFIT

MPA vs observation (N=136) NO BENEFIT

Tumor cells + BCG vs observation (N=120) NO BENEFIT

Recombinant IFN-α2b vs observation (N=247) NO BENEFIT

IFN-α vs observation (N=283) NO BENEFIT

High-dose IL-2 vs observation (N=69) NO BENEFIT

Tumor cell vaccine vs observation (N=558) 5-year PFS: 77.4% vs 67.8% (P=0.02)

IL-2 + IFN-α2a + FU vs observation (N=203) NO BENEFIT

Thalidomide vs observation (goal N=220 – closed) NO BENEFIT

Oncophage (HSPPC-96) vs observation (N >800) NO BENEFIT

IL-2 + IFN-α2a + FU vs observation (N=550) NO BENEFIT

ARISER = Girentuximab vs placebo (n=864) NO BENEFIT**

Kunkle, Haas, Uzzo Current Urol Rept 8(1):19

v

almost

Adjuvant RCC Trials: The Middle Ages

Trial Sponsor N Clear Cell

Only?

Duration of Rx

(yrs)

Eligibility Model 1° endpoint

ASSURE

sorafenib/ sunitinib

ECOG 1943 No 1 Intermediate and

high risk UISS

DFS

HR = 1.02

No change in DFS/OS

S-TRAC

Sunitinib

PFE 615 Yes 1

High risk UISS

DFS

HR = 0.76

Improved DFS but not OS

(central review)

SORCE

Sorafenib

MRC 1656 No 1 vs 3 Intermediate and high

Leibovich risk (3-11)

DFS

PROTECT

Pazopanib

Novartis

/GSK

1540 Yes 1 Intermediate or high risk

AJCC TNM v.2010

DFS

ATLAS

Axitinib

PFE 700 Yes 3 Intermediate and

high-risk,

AJCC TNM v.2010

DFS

EVEREST

Everolimus

SWOG 1537 No 1

(9 cycles)

Intermediate and high pTNM

risk

RFS

“Incompletely effective surgery with more effective systemic Therapy”

Adjuvant RCC Trials: The “New” Age

Trial Sponsor n Clear cell

only?

Duration of

Rx

Eligibility Model Randomization 1° endpoint

EA8143

PROSPER

(Nivolumab)

ECOG 766 No…but

Cap

nonccRCC

at 15%

10mo

(1 neo then

9 mo

adjuvant)

= 240mg

> cT2aNoMo

Or

TanyN+Mo

Metastasectomy

excluded

Neoadjuvant then

resect + adjuvant

Vs

Resect and

Observe

> 13%

improvement

in RFS

W039210

IMmotion

(Atezolizumab)

Genentech

with

SUO-CTC

664 No…

Clear cell

component

Or

Any subtype

with

sarcomatoid

component

12 mo

(16 cycles)

> pT2 Gr4

N+ any T,

(resected

synchronous

adrenal/lung

metastases

OR

metastasectomy of

lung, soft tissue,

LN >12 months

after nephrectomy)

Adjuvant

Vs

Placebo

DFS

“Incompletely effective surgery with potentially more effective systemic Therapy”

Important Clinical

Differences

Important Clinical Differences

PROSPER IMmotion

Preoperative

biopsy

mandatory None

Time to surgery > 8 weeks

(2 + 4 + 2)

immediate

Control arm Observation Placebo

Metastasectomy Ineligible Eligible if >12 mo

Synchronous

metastasectomy?

Ineligible Eligible in lung/adrenal(s)

Biopsy at recurrence mandatory mandatory

Sequencing Investigator discretion Available without cost at

time of recurrence

Eligibility:

Differences and Implications

Risk Models for Localized RCC

Model n Histology Median f/u predicts Presentation Factors

UISS

1989-1999

477 All 37 mo OS, DSS, RFS KM estimates 1997 TNM

Grade

ECOG PS

MSKCC

1989-2002

701 ccRCC 32 mo RFS Nomogram pT (2002), pSize, Grade

necrosis, presentation

D-SSIGN

1970-1999

1560 ccRCC 11.2 yr CSS Points based

algorithm

pT (2002), pN, pM, size, grade,

necrosis

Leibovich

1970-2000

1671 ccRcc 5.4 yr MFS Points based

algorithm

pT (2002), pN, Size, grade, necrosis

Karakiewicz

1984-2006

2474 cc/pap/

chromo

4.2 yr RCC

mortality

Nomogram pT (2002), pM, pSize, presentation,

age, gender

PROSPER vs IMmotion

Model

(5 yr rates)

PROSPERLowest Risk eligible

cT2NoMoGany

IMMotionLowest Risk eligible

cT2NoG4

PROSPERHighest Risk eligible

TanyN+Mo*

IMMotionHighest Risk eligible

TanyN+M1# (metachronous >12

mo)

UISS 72% OS

80% DSS

95% RFS

72% OS

80% DSS

95% RFS

19% OS

19% DSS

19% RFS

likely worse

MSKCC 83% RFS 33% RFS 9% RFS likely worse

D-SSIGN 88% CSS 54% CSS 19% CSS likely worse

Leibovich 84% MFS

(Liebovich low risk)

40% MFS

(Liebovich high risk)

31% MFS

(Liebovich high risk)

likely worse

Karakiewicz 91% DSS 79% DSS 36% DSS likely worse

*assumes 10cm primary tumor, PS=0 and asymptomatic

# Resected metachronous M1 not calculable with current models

Urologic Participation:

Differences and Implications

J Urol 193:2015

Of 22,409 patients who underwent CRN

- Very few received preop therapy

Motzer RJ et al. N Engl J Med 2015;373:1803-1813.

Treatment-Related Adverse Events Reported in 10% or More

of Treated Patients in Either Group – CheckMate 025

http://www.opdivohcpinfo.com/advanced-RCC/opdivo-selected-safety-profile

PD1 All Cause Adverse Events in RCC

http://www.opdivohcpinfo.com/advanced-RCC/opdivo-selected-safety-profile

PD1 Lab abnormalities in RCC

http://www.opdivohcpinfo.com/advanced-RCC/opdivo-selected-safety-profile

Onset of Immune-mediated AEs in RCC

http://www.opdivohcpinfo.com/advanced-RCC/opdivo-selected-safety-profile

Time to onset and resolution of select TRAEs in phase II study

Organ category TRAE, na Median time to onset,

weeks (range)Resolved, n (%)

Median time to resolution,

weeks (95% CI)

Skin

Any grade 41 6.6 (0.1–71.4) 39 (95.1) 11.0 (3.9–22.6)

Grade 3–4 2 12.3 (2.9–21.7) 2 (100.0) 12.6 (2.9–22.4)

Gastrointestinal

Any grade 19 18.1 (0.4–225.7) 16 (84.2) 9.0 (2.0–11.9)

Grade 3–4 2 65.4 (49.9–80.9) 2 (100.0) 9.7 (9.1–10.3)

Endocrine

Any grade 17 18.0 (5.0–142.0) 8 (47.1) NR (1.3–211.9+)

Grade 3–4 2 11.8 (5.6–18.0) 2 (100.0) 1.5 (1.3–1.7)

Hepatic

Any grade 9 14.1 (3.0–67.1) 7 (77.8) 12.0 (0.7–NE)

Grade 3–4 3 18.1 (3.0–36.1) 3 (100.0) 12.0 (0.7–28.1)

Pulmonary

Any grade 11 31.3 (4.0–90.0) 11 (100.0) 7.3 (3.1–12.3)

Grade 3–4 0 0 0 0

Renal

Any grade 2 18.1 (9.1–27.1) 1 (50.0) NR (2.7–155.7+)

Grade 3–4 0 0 0 0

NR, not reached.

aAll treated patients with at least one select TRAE.

Most autoimmune toxicities are reversible with immunosuppression (steroids) – Implications for surgery

• Endocrinopathies• Hyper Hypothyroid• Central adrenal insufficiency

• Pneumonitis

• Diarrhea / Colitis

• Rash

• Myositis

• Neurotoxicity• Guillain-Barré syndrome• Cranial Nerve Palsy

Summary

IMmotion PROSPER

Pre op bx? No Yes

Randomization Post op Pre op

Delay in surgery No Yes

AEs possible within periop window

(including potentially irreversible iAEs)

No Yes

Potential overtreatment of lower risk RCC Less More

Pre op lab abnormalities No Yes

Placebo Yes No

Risk of pre-op Pseudo progression No Yes