Quale strategia terapeutica di seconda linea a progressione dopo TKI nel mRCC?

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Quale strategia terapeutica di seconda linea a progressione dopo

TKI nel mRCC?

Giandomenico Roviello

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(3)

Quale strategia terapeutica di II Linea ?

Everolimus

Sorafenib Axitinib

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Quale strategia terapeutica di II Linea ?

Everolimus

Sorafenib

Nivolumab Axitinib

Cabozantinib

Lenvatinib + Everolimus

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Quale strategia terapeutica di II Linea ?

Everolimus

Sorafenib

Nivolumab Axitinib

Cabozantinib

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Immune-checkpoint inhibitors:

Mechanism of action

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Nivolumab 3 mg/kg intravenously every 2 weeks

N = 410 Everolimus 10 mg orally

once daily N = 411

R and omiz e 1: 1

Endpoints: OS (primary); ORR, safety (key secondary) Patient eligibility

•aRCC with clear-cell component

•KPS ≥7

•1 or 2 prior anti-

angiogenic therapies

•Progression within 6 months prior to enrollment

KPS = Karnofsky performance status

CheckMate 025: study design

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Nivolumab

PFS OS data

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CHECKMATE 025: Improved OS Irrespective of MSKCC Risk Score, Number of Previous Anti-Angiogenic Therapies, Region, or Gender

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Subgroup Nivolumab

n/N Everolimus

n/N MSKCC risk group

Favorable 45/145 52/148

Intermediate 101/201 116/203

Poor 37/64 47/60

Prior anti-angiogenic regimens

1 128/294 158/297

2 55/116 57/114

Region

US/Canada 66/174 87/172

Western Europe 78/140 84/141

Rest of the world 39/96 44/98

Age, years

<65 111/257 118/240

≥65 to <75 53/119 77/131

≥75 19/34 20/40

Sex

Female 48/95 56/107

Male 135/315 159/304

Nivolumab

0.25 0.5 0.75 1 1.5 2.25

Everolimus Favors

Analyses based on interactive voice response system data.

MSKCC=Memorial Sloan Kettering Cancer Center.

Motzer RJ et al. N Engl J Med. 2015. doi:10.1056/NEJMoa1510665. Figure adapted from Motzer et al.

OS Hazard Ratios

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Treatment beyond progression

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How immunotherapy works

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Quale strategia terapeutica di II Linea ?

Everolimus

Sorafenib

Nivolumab Axitinib

Cabozantinib

(19)

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(21)

METEOR: Study design

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Cabozantinib

PFS data

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25 Overall Survival in Subgroups

Hazard Ratio Cabozantinib Everolimus

Overall 658 0.66 21.4 16.5

MSKCC risk group

Favorable 300 0.66 NE 19.3

Intermediate 274 0.67 19.9 14.9

Poor 84 0.65 10.5 6.5

Prior VEGFR TKI

1 464 0.65 21.4 16.5

≥2 194 0.73 20.8 17.2

Duration of 1st VEGFR TKI

≤ 6 months 190 0.69 21.3 13.8

> 6 months 466 0.69 22.0 18.4

Bone metastases

No 516 0.71 NE 17.5

Yes 142 0.54 20.1 12.1

Visceral+bone metastases

No 546 0.73 22.0 18.4

Yes 112 0.45 20.1 10.7

Tumor MET status

High 101 0.55 22.0 15.2

Low 312 0.72 20.8 18.4

Unknown 245 0.67 21.3 15.0

Overall Survival No. of pts

Median, months

Favors cabozantinib

Favors everolimus

0,125 0,25 0,5 1 2 4

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Everolimus

Sorafenib

Nivolumab Axitinib

Cabozantinib

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Lenvatinib: Mechanism of action

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Disegno lenvatinib

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Lenvatinib+everolimus

PFS OS data

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Second-line Treatment Options for mRCC:

Summary of Efficacy

1. Motzer RJ, et al. N Engl J Med. 2015;373:1803-1813. 2. Choueiri TK, et al. Lancet Oncol. 2016;17:917-927.

3. Rini BI, et al. Lancet. 2011;378:1931-1939. 4. Motzer RJ, et al. Lancet Oncol. 2013; 14:552-562.

5. Motzer RJ, et al. Lancet Oncol. 2015;16:1473-1482. 6. Hutson TE, et al. ASCO 2016. Abstract 4553.

Nivolumab

^[1]

Cabozantinib

^[2]

Axitinib

^[3,4]

Lenvatinib/

Everolimus

^[5,6]

Median PFS,

mos 4.6 7.4 6.7 14.6

ORR, % 25 17 19 43

Median OS,

mos 25.0 21.4 20.1 25.5

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ASCO 2016

mRCC: CONCLUSIONS

• Advanced RCC Second Line Treatment Options characterized by a continuously changing Scenario

• I-O Studies resulted in a Paradigm Shift for mRCC, introducing the concept of a possibility of cure (in a % of treated pts):

• Sequencing remain at the moment the Option of Choice for treating

mRCC, but new (and awaited) Data may change this condition.

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