Immunotherapy in metastatic RCC

Naveen Vasudev

Disclosures

Honoraria / Hospitality /Speaker fees from:

• Ipsen

• Pfizer

• Bristol Myers Squibb

• Novartis

• EUSA pharma

• Bayer

ESMO RCC Guidelines 2016

Escudier et al. Annals of Oncology, 2016;27:v58–v68

Single agent nivolumab is recommended post-TKI

ESMO Guidelines for RCC 2016

Escudier et al. Annals of Oncology, 2016;27:v58–v68

The current landscape in mRCC…..

EAU Guidelines RCC 2018; http://uroweb.org/guideline/renal-cell-carcinoma

Boxed category represents strong recommendation

Escudier et al. Annals of Oncology, 2016;27:v58–v68

MSKCC=Memorial Sloan Kettering Cancer Center; RECIST=Response Evaluation Criteria In Solid Tumours

Adapted from 1. Sharma P, et al. ESMO 2015; Presentation: Abstract #3LBA; 2. Motzer RJ, et al. NEJM. 2015;373:1803–13

Key eligibility criteria:

• Advanced or metastatic clear cell RCC• Patients aged ≥18 years

• One or two prior anti-angiogenic therapies

• Measurable disease (RECIST v1.1)

• Karnofsky performance status ≥70%

• Progression on or after most recent therapy and within 6 months of

enrolment

Primary endpoint:

• OSSecondary endpoints included:

• Objective response rate

• Progression-free survival

• Adverse events

• Quality of life

• OS by PD-L1 expression

Previously treated mRCC

Stratification factorsStratification factorsStratification factorsStratification factors

Region

MSKCC risk group

Number of prior

anti-angiogenic therapies for

advanced RCC

Nivolumab

3 mg/kg IV every 2 weeks

(n=410)

Everolimus 10 mg orally once

daily

(n=411)

Ra

nd

om

ise

1:1

• Patients were treated until progression or intolerable toxicity occurred

• Treatment beyond progression was permitted if drug was tolerated and clinical benefit was noted

CheckMate 025: study design

64% and 68% pts

in nivo and eve

arms received

subsequent

therapy

CM025: 3-year OS update

Improved response rates and DOR

*Any grade AEs occurring in >10% patients

**Values expressed as <1% in the nivolumab group have been represented on the diagram as 1%Ɨ Based on data across all nivolumab clinical trials, rare cases (≥10,000 to <1,000) of toxic epidermal necrolysis have been reported

Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.02

Nivolumab

1. Motzer RJ, et al. N Engl J Med. 2015;373:1803–13; 2. National Cancer Institute. National Cancer Institution Common Terminology

Criteria for Adverse Events Version 4.0. Available at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed April 2016

Substantially fewer G3–4 AEs compared with everolimus

Quality of Life scores favour nivolumab

Mean change from baseline in quality of life scores on FKSI-DRS: scores in the nivolumab group increased over time and differed significantly from the everolimus group at each assessment

through to Week 104 (p<0.05)

Questionnaire completion rate: ≥80% during the first year of follow up

Adapted from 1. Cella D, et al. Lancet Oncol. 2016:17:994–1003; 2. Sharma P, et al. ESMO 2015; Presentation: Abstract #3LBA

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

TreatmentPatients

Randomize 1:1

Arm A3 mg/kg nivolumab IV +

1 mg/kg ipilimumab IV Q3W

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

Arm B50 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)

CheckMate 214: Study design

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)

Ove

rall

Su

rviv

al

(Pro

ba

bil

ity)

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 RiskNIVO + IPI

SUN

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 3315129630

Co-primary endpoint

OS: IMDC intermediate/poor risk

N = 847

OutcomeNIVO + IPI

N = 425SUN

N = 422

Confirmed ORR,a % (95% CI) 42 (37–47) 27 (22–31)

P < 0.0001

Confirmed BOR,a %Complete responsePartial responseStable disease

Progressive diseaseUnable to determine/not reported

9b

3231

208

1b

2545

1712

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

NIVO + IPI

No. at Risk

177177177177 146146146146 120120120120 55555555 3333

112112112112 75757575 52525252 17171717 0000

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 24Months

Du

rati

on

of

Re

spo

nse

(P

rob

ab

ility

)D

ura

tio

n o

f R

esp

on

se (

Pro

ba

bili

ty)

Du

rati

on

of

Re

spo

nse

(P

rob

ab

ility

)D

ura

tio

n o

f R

esp

on

se (

Pro

ba

bili

ty)

ORR and DOR: IMDC intermediate/poor riskCo-primary endpoint: ORR

Median duration of response,

months (95% CI)

Patients with ongoing

response, %

NIVO + IPI NR (21.8–NE) 72

SUN 18.2 (14.8–NE) 63

Motzer et al. NEJM 2018; 378:1277-90

CM214: OS by PD-L1 expression

IMDC Intermediate

and Poor risk patients

a11% of patients in both arms had tumor PD-L1 expression ≥1%bIRRC-assessed by RECIST v1.1cIRRC-assessed

N = 249a

OutcomeNIVO + IPI

N = 125

SUN

N = 124

Confirmed ORR,b % (95% CI) 29 (21–38) 52 (43–61)

P = 0.0002

PFS,c 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

ORR and PFS: IMDC favorable risk Exploratory endpoint

NIVO + IPIN = 547

SUNN = 535

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

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 = 7b n = 4c

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

Treatment-related adverse events: All treated patients

NIVO + IPIN = 547

Category, % Any grade Grade 3–4Rash 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

Immune-mediated adverse events: All treated patients

What don’t we know about the combo?

• Does everyone need it? cf TITAN and OMNIVORE trials

Tailored ImmunoTherapy Approach With

Nivolumab in Subjects With Metastatic or

Advanced Renal Cell Carcinoma (TITAN-RCC)

IO + Anti-VEGF – Is there a rationale for these combinations?

Vanneman & Dranoff

Nature Reviews Cancer 2012;12, 237-251

• VEGF signalling decreases dendritic cell (DC) co-stimulatory molecule expression and T cell priming

• VEGF signalling encourages the formation of myeloid-derived suppressor cells (MDSCs)

• VEGF antagonists reverse these effects and promote the formation of potent anti-tumour T cells

IMmotion 151 study

Motzer et al. ASCO GU 2018

• First phase III study to report activity of PD-L1/PD-1 plus anti-VEGF

IMmotion 151: PFS in PD-L1+

Motzer et al. ASCO GU 2018

IMmotion 151: PFS in PD-L1 Subgroups (ITT)

Motzer et al. ASCO GU 2018

Motzer et al. ASCO GU 2018

IMmotion 151: PFS and ORR by IRC

Median OS, mo (95% CI)

Atezo + Bev Not reached

Sunitinib 23.3 (21.3, NR)

HR, 0.68 (95% CI: 0.46, 1.00)

Secondary

Endpoint

• OS data are immature; 30%of patients had an OS event

at data cutoff

Overall Survival in PD-L1+

NR, not reached. Minimum follow-up, 12 mo. Median follow-up, 15 mo. Event/patient ratio: 25% for atezo + bev, 35% for sunitinib.

Motzer et al. ASCO GU 2018

SunitinibAtezo + Bev

Grade 3-4 AEsAll-grade AEs

Grade 3-4 AEsAll-grade AEs

40% 20% 0 20%10%60% 60%40%50% 30% 50%10%30%

Secondary

EndpointTreatment-related AEs≥ 20% frequency in either arm and > 5% difference between arms

PPE, palmar-plantar erythrodysesthesia.

Dysgeusia

Asthenia

Mucosal inflammation

Diarrhea

Nausea

PPE

Decreased appetite

Stomatitis

Vomiting

Hypertension

Fatigue

Proteinuria

Motzer et al. ASCO GU 2018

Adapted from Albiges ESMO 2017

CPI plus TKI combination therapy in mRCC

Nivolumab +

Sunitinib

Nivolumab +

Pazopanib

Pembrolizumab +

Axitinib

Avelumab +

Axitinib

Pembrolizumab

+ Lenvatinib

N 33 20 52 55 30

ORR 52 45 71.2 58 63

CR NE NE 5.8 5.5 0

PR NE NE 65.4 53 63

Dose-limiting

liver toxicity

Pembrolizumab plus axitinib

Atkins et al. Lancet Oncol 2018;19:405-15

Trial Experimental arm Comparator Primary

Endpoint

Status

Checkmate214 Nivolumab + Ipilimumab

Sunitinib PFS/OS (intermed/poor risk pts)

Positive. OS advantage

IMmotion151 Atezolizumab/ Bevacizumab

Sunitinib PFS in PD-L1+

Positive by Inv assess

CLEAR Lenvatinib +PembrolizumaborEverolimus

Sunitinib PFS Recruiting

KEYNOTE-426 Pembrolizumab+ axitinib

Sunitinib PFS/OS Recruiting

JAVELIN Renal 101

Avelumab + axitinib

Sunitinib PFS/OS in PD-L1 +

Recruiting

CheckMate 9ER Cabozantinib + Nivolumab

Sunitinib PFS Recruiting

First-line Phase III trials of IO in mRCC

Take home messages….

• Use single agent nivolumab following failure of one or two lines of VEGF TKI

• Use ipilimumab plus nivolumab in treatment-naïve patients with clear-cell metastatic RCC of

IMDC intermediate and poor risk (if available)

• Do not use PD-L1 tumour expression as a predictive biomarker

• The timing and nature of AE with immunotherapy are different to TKI

• Administer nivolumab plus ipilimumab in centres with experience of immune combination

therapy and appropriate supportive care within the context of a multidisciplinary team