oncologypro - immunotherapy in metastatic rcc...naveen vasudev disclosures honoraria / hospitality...
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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