THE SEARCH FOR BIOMARKER IN RCC

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

WHICH BIOMARKERS CAN BE USED FOR PREDICTION?

• baseline marker (pre-therapeutic)

• RCC subtypes

• TNM

• IMDC

• molecular marker (PBRM1, BAP1)

• Immunogenicity (PD-L1, CD8 cells)

• on-treatment marker

• CT changes (RECIST)

• serum marker

DEFINITIONS

Marker can be predictive, prognostic or both

Prognostic

• correlates with overall survival (OS) upon

standard intervention

Predictive

• correlates with therapeutic outcome (PFS)

Gore et al. ASCO 2007

ESTABLISHED CLINICAL PROGNOSTIC PARAMETERS

Clinical and laboratory parameters are standard prognostic factors

time to

medical

treatmen

t

Hyper-

calcaemi

a

Anemia

Perform

ance

status

LDH

Thromb

o-

cytophili

a

Neutro-

philia IMDCtime to

medical

treatmen

t

Hyper-

calcaemi

a

Anemia

Perform

ance

status

GOOD RISK RCC HAVE A DISTINCT BIOLOGY

Selection of VEGF-driven tumors

Heng et al. (2009). JCO, 27(34), 5794–5799.

Rini et al. ESMO 2018: LBA31

∆ good vs. interm./poor risk (%) P-value

HIF2a +57 0.03

VEGFA +67 0.07

VEGFR-1 +100 0.02

VEGFR-2 +128 0.009

VEGFR-3 +52 0.03

Beuselinck et al. ESMO 2018: 869PD

CHROMATIN REMODELING IS KEY IN RCC CARCINOGENESIS

Kapur, P. et al. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell

carcinoma: a retrospective analysis with independent validation. Lancet Oncol 14, 159–167 (2013).

CCRCC - A DIVERSE DISEASE

Hsieh, J., Le, V., Oyama, T., Ricketts, C., Ho, T., Cheng, E. (2018). Chromosome 3p Loss-Orchestrated VHL, HIF, and Epigenetic Deregulation in Clear Cell

Renal Cell Carcinoma. Journal of Clinical Oncology 36(36), JCO2018792549 - 3539. https://dx.doi.org/10.1200/jco.2018.79.2549

POTENTIAL IMPROVEMENT OF CURRENT CLINICAL SCOREBAP1, PBRM1 and TP53 may improve clinical risk systems - validation to be

performed

TP53mt

BAP1mt

PBRM1wt*

1. MD, M. H. V. et al. Genomically annotated risk model for advanced renal-cell carcinoma: a retrospective cohort study. Lancet Oncology 1–11 (2018). doi:10.1016/S1470-2045(18)30648-X

negative prognosticators

*or mutated in

combination with

concurrent TP53 or BAP1

mutation

KDM5C, TERT SETD2 were not significant

PBRM1mt

PBRM1, ALSO A PUTATIVE PREDICTIVE MARKER FOR PD-

1I?

Miao, D., Margolis, C., Gao, W., Voss, M., Li, W., Martini, D., Norton, C., Bossé, D., Wankowicz, S., Cullen, D., Horak, C., Wind-Rotolo, M., Tracy, A., Giannakis,

M., Hodi, F., Drake, C., Ball, M., Allaf, M., Snyder, A., Hellmann, M., Ho, T., Motzer, R., Signoretti, S., Kaelin, W., Choueiri, T., Allen, E. (2018). Genomic

correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma Science (New York, NY) 359(6377), 801 - 806.

https://dx.doi.org/10.1126/science.aan5951

NOT CONFIRMED IN SUBGROUPS FROM PROSPECTIVE TRIAL

McDermott, D. et al. (2018). Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma Nature Medicine 24(6), 749-757. https://dx.doi.org/10.1038/s41591

NEITHER IN A SEPARATE COHORT

Study did not show association in pts. treated with checkpoint inhibitors

Hakimi et al. 2019 ASCO GU : abstr. 666 Total cohort N=2,152. RCC cohort: 143

n=143 (RCC only)

PRECISION ONCOLOGY - ANY CHANCE IN MRCC?

Genetic differences may lead to molecular oncology

Gerlinger et al. (2012). NEJM, 366(10), 883–892.

http://doi.org/10.1056/NEJMoa1113205Bailey, M. et al. (2018). Comprehensive Characterization of Cancer Driver Genes and

Mutations Cell 173(2), 371 - 385.e18. https://dx.doi.org/10.1016/j.cell.2018.02.060

WHOLE EXOME SEQUENCING - WORK IN PROCESS

Always consider limitations of a given technique in the clinic

Shi, W. et al. Reliability of Whole-Exome Sequencing for Assessing Intratumor Genetic Heterogeneity. CellReports 25, 1446–1457 (2018).

• intratumor heterogeneity difficult to distinguish from

sequencing artifacts

• 69% of somatic mutations are false positive

• 34-80% of somatic mutation are background noise

• exclusion of mutations in low-mappable regions may

help

TYPE 1 PAPILLARY RCC - A MET-DRIVEN DISEASE?

Albiges, et al. J Clin Oncol 2018

MOLECULAR ONCOLOGY IN MRCC

Crizotinib is active in MET+ papillary type 1 mRCC

Schöffski, P., Wozniak, A., Escudier, B., Rutkowski, P., Anthoney, A., Bauer, S., Sufliarsky, J., Herpen, C., Lindner, L., Grünwald, V., Zakotnik, B., Lerut, E., Debiec-Rychter, M.,

Marreaud, S., Lia, M., Raveloarivahy, T., Collette, S., Albiges, L. (2017). Crizotinib achieves long-lasting disease control in advanced papillary renal-cell carcinoma type 1 patients with

MET mutations or amplification. EORTC 90101 CREATE trial EUROPEAN JOURNAL OF CANCER 87(), 147 - 163. https://dx.doi.org/10.1016/j.ejca.2017.10.014

TSC MUTATIONS

A putative predictor for mTOR inhibition?

Rosset, C., Netto, C., Ashton-Prolla, P. (2017). TSC1 and TSC2 gene

mutations and their implications for treatment in Tuberous Sclerosis

Complex: a review Genetics and Molecular Biology 40(AHEAD), 0-0.

https://dx.doi.org/10.1590/1678-4685-gmb-2015-0321

Voss, M., Chen, D., Reising, A. et al.. (2019). PTEN Expression, Not Mutation Status in TSC1, TSC2, or mTOR,

Correlates with the Outcome on Everolimus in Patients with Renal Cell Carcinoma Treated on the Randomized

RECORD-3 Trial. Clinical cancer research : an official journal of the American Association for Cancer Research

25(2), 506 - 514. https://dx.doi.org/10.1158/1078-0432.ccr-18-1833

PTEN EXPRESSION

Instead PTEN level predicts PFS for mTORi, but not for TKI

Voss, M., Chen, D., Reising, A. et al.. (2019). PTEN Expression, Not Mutation Status in TSC1, TSC2, or mTOR, Correlates with the Outcome on Everolimus in Patients with Renal Cell Carcinoma

Treated on the Randomized RECORD-3 Trial. Clinical cancer research : an official journal of the American Association for Cancer Research 25(2), 506 - 514. https://dx.doi.org/10.1158/1078-

0432.ccr-18-1833

SunitinibEverolimus

BASELINE QOL IS PROGNOSTIC

Poor QoL scores correlate with poor OS

FKSI-DRS-P FACIT-F

Grünwald et al. ESMO 2016: 817P

IS QOL IMPROVEMENT PROGNOSTIC IN MRCC?

Patients who improve in QoL achieve a better OS

Cella, D. et al. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol 17,

994–1003 (2016).

QoLlow QoLhigh

EARLY TUMOR SHRINKAGE IS PROGNOSTIC IN MRCC

Patients with ≧10% tumor shrinkage have favorable outcome

1. Grünwald, V., Lin, X., Kalanovic, D. & Simantov, R. Early Tumour Shrinkage: A Tool for the Detection of Early Clinical Activity in Metastatic Renal Cell Carcinoma. Eur Urol 70, 1006–1015

(2016).

2. Grünwald, V., Dietrich, M. & Pond, G. R. Early tumor shrinkage is independently associated with improved overall survival among patients with metastatic renal cell carcinoma: a validation

study using the COMPARZ cohort. World journal of urology 369, 722–7 (2018).

DIFFERENCES IN RESPONSE PATTERN BETWEEN CPI AND TKI EXIST

≧ 50% tumor shrinkage is prognostic with CPI treatment

950P Grünwald et al. ESMO 2019

HYPERPROGRESSION IS A CLINICAL REALITY (CPI THERAPY)

Patient selection may help to decrease this risk

1. Escudier, B. et al. Treatment Beyond Progression in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab in CheckMate 025. Eur Urol 72, 368–376 (2017).

INTERPLAY OF PD-L1 AND TILS

PD-L1 is only 1 component of a complex system

H&E PD-L1 TILs (CD3+)

Mansfield et al. (2016). Annals of Oncology, mdw289. http://doi.org/10.1093/annonc/mdw289

NSCLC (primary)

CNS mets.

N=146 paired lesions, 73 cases. Discrepencies: 14% (tumor), 26% (TILs)

PD-L1 IS A REASONABLE PREDICTOR IN 1ST LINE

Enrichment for CR can be achieved by PD-L1 status in mRCC

Pembrolizumab1 Atezolizuamb2 Ipilimumab + nivolumab3

PD-L1+ PD-L1- PD-L1+ PD-L1- PD-L1+ PD-L1-

ORR 50 26 28 NR 53 36

PR 44 26 13 NR 39 27

CR 7 0 15 NR 14 9

1McDermott et al. ASCO 2018: 4500. 2McDermott et al. Nat Med 2018 pp1-14. 3Escudier et al. ESMO 2017: LBA5

PD-L1 STATUS IS PREDICTIVE FOR IPI-NIVO

284 202 155 119 102 90 70 23 9 1 0278 200 138 105 83 67 43 25 11 1 0

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)NIVO + IPI 22.8 (9.4–NE)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 + IPI 11.0 (8.1–14.9)SUN 10.4 (7.5–13.8)

NIVOSUN

No. at Risk

100 77 61 54 50 48 41 21 8 2 0114 63 40 24 17 13 9 4 0 0 3

0.8

0.9

1.0

0.4

0.5

0.6

0.7

0 963 21181512 302724

0.1

0.0

0.2

0.3

0.8

0.9

1.0

0.4

0.5

0.6

0.7

0 963 21181512 302724

0.1

0.0

0.2

0.3

Prog

ress

ion-

Free

Sur

viva

l (Pr

obab

ility

)

MonthsMonths

Escudier et al ESMO 2017 LBA5

HOWEVER, IT LACKS PROGNOSTIC ABILITY

Motzer et al. SITC 2017: O38

BEST OF BOTH WORLDS - TIME TO RE-THINK

VEGFi-CPI combos dilute predictivity of risk categories

Motzer et al, ESMO 2018 LBA6_PR

JAVELIN101: AXI-AVELU

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

CAN WE DO BETTER?

Genetic signatures may dissect treatment strategies

Mod. Rini BI et al. ESMO 2018, Proffered paper session – Genitourinary tumours, non prostate, Abstract No. LBA31

Tumour cells

T-effector cells

Myeloid cells

Vasculature

AngiogenesisHigh

T-effectorHigh

T-effectorHigh

MyeloidHighT-effectorHigh

MyeloidLow

PD-L1 IHC

Angi

o-ge

nesi

sIm

mun

e, A

ntig

en

Pres

enta

tion

Mye

loid

In

flam

-m

atio

n

3 -3-2-1012 PD-L1 IHC

IC0 IC1 IC2 IC3

IMMOTION151: ANGIOGENIC SIGNATURE

Impact is not exclusive to sunitinib treatment

Mod. Rini BI et al. ESMO 2018, Proffered paper session – Genitourinary tumours, non prostate, Abstract No. LBA31

Sunitinib

PFS

Months

AngiogenesisLow (n=177)AngiogenesisHigh (n=230)

PFS

Atezolizumab + Bevacizumab

AngiogenesisLow (n=151)AngiogenesisHigh (n=265)

Months

HR (95% CI)

Sunitinib Atezo + Bev

Angiogenesis (High vs. Low) 0.59 (0.47, 0.75) 0.86 (0.67, 1.1)

5.95 10.12 8.94 12.45

IMMOTION151: T-EFFECTOR CELLS

Teff high RCC are more responsive to ATEZO-BEV

Mod. Rini BI et al. ESMO 2018, Proffered paper session – Genitourinary tumours, non prostate, Abstract No. LBA31

T-effectorLow

PFS

Months

Sunitinib (n=182)Atezo + Bev (n=164)

PFS

T-effectorHigh

Sunitinib (n=234)Atezo + Bev (n=243)

Months

HR (95% CI)

T-effectorLow T-effectorHigh

Atezo + Bev vs. Sunitinib 0.91 (0.73, 1.14) 0.76 (0.59, 0.99)

8.41 9.72 8.34 12.45

• T-effector gene signature did not differentiate PFS within the Sunitinib or Atezolizumab + Bevacizumab treatment arms

Rini B, et al. IMmotion151 Biomarkers. ESMO 2018 [abstract LBA31]. http://bit.ly/2yaVgyI

P = 0.35PD-L1 Expression

61%

39% 43%

57%

25%

Patie

nts

(%)

100%

75%

50%

0%

Favourable Intermediate/Poorn = 156 n = 667

Patie

nts

(%)

100%

75%

50%

25%

0%

Favourable Intermediate/Poorn = 156 n = 667

P = 0.1T-effector Gene Signature

64%

36% 43%

57%

Patie

nts

(%)

100%

75%

50%

25%

0%

Favourable Intermediate/Poorn = 156 n = 667

P = 8.26e-05Angiogenesis Gene Signature

26%

74%

57%

43%

AngioLow

AngioHighTeff

Low

TeffHigh

NegativePositive

Angiogenesis Gene Expression Is Higher in Favourable MSKCC Risk Group

CONCLUSIONS

• pre-therapeutic marker guide treatment choice in mRCC

• Current clinical risk categories are both, predictive and prognostic

• QoL, PBRM1, TP53 and BAP1 are candidate markers for further advancement

• On-treatment markers are more difficult to interpret

• Improvement in QoL or quality of response correlate with better prognosis

• PD-L1 enriches for complete responses during CPI treatment

• Combinations of TKI + CPI require novel marker for prediction