This presentation is the intellectual property of the author. Contact them for permission to reprint and/or distribute. Checkpoint inhibitors and the changing landscape of Renal Cell Carcinoma therapeutics Saby George, MD, FACP Associate Professor of Medicine and Oncology Genitourinary Program Roswell Park Cancer Institute 02‐04‐2017 • I have consulted/worked in an advisory role for – Astellas – Bayer – Bristol‐Myers Squibb – Exelixis – Novartis – Onclive – Pfizer – Sanofi – Virtualscopics – Xcenda • I (my institution) have received research funding from – Agensys – Acceleron – Bayer – Bristol‐Myers Squibb – Merck – Novartis – Pfizer Disclosures Objectives • Treatment options for metastatic RCC • Focused discussion of Nivolumab in RCC • Some challenges in managing RCC patients with the introduction of such novel agents (with response evaluation including the dissociation between PFS and OS/ toxicities) 1 Heterogeniety in gene signature Immunosuppressi on Morphological Characteristics Chemo and radiotherapy resistant Different histologies VEGF / HIF CCRCC: Lipid / glycogen accumulation Stauffler’s syndrome Continuous tumor formation into IVC, RA and RV Familial syndromes 2
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Checkpoint inhibitors and the changing landscape of Renal Cell Carcinoma therapeutics
Saby George, MD, FACP
Associate Professor of Medicine and OncologyGenitourinary Program
Roswell Park Cancer Institute02‐04‐2017
• I have consulted/worked in an advisory role for– Astellas– Bayer– Bristol‐Myers Squibb– Exelixis– Novartis– Onclive– Pfizer– Sanofi– Virtualscopics– Xcenda
• I (my institution) have received research funding from– Agensys– Acceleron– Bayer– Bristol‐Myers Squibb– Merck– Novartis– Pfizer
Disclosures
Objectives
• Treatment options for metastatic RCC
• Focused discussion of Nivolumab in RCC
• Some challenges in managing RCC patients with the introduction of such novel agents (with response evaluation including the dissociation between PFS and OS/ toxicities)
1
Heterogeniety in gene signature
Immunosuppression
Morphological Characteristics
Chemo and radiotherapy resistant
Different histologies
VEGF / HIF
CCRCC: Lipid / glycogen
accumulation
Stauffler’ssyndrome
Continuous tumor formation into IVC, RA and
RV
Familial syndromes
2
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Current data in metastatic RCCSETTING TRIAL PFS (months) OS (months)
FRONT LINE Sunitinib vs Interferon 11 VS 5.1
P=<.000001
26.4 vs 21.4
P=.051
FRONT LINE Temsirolimus vs IFN vs
Combination
3.8 vs 1.9 10.9 vs. 7.3, hr=.73,
P=.008
FRONT LINE AVOREN/ CALGB90206 Bev+
IFN vs IFN or placebo
10.2 vs 5.4, HR=.63,
P=.0001
8.5 vs 5.2, HR=.71
23.3 vs 21.3
P=.1291
18.3 VS 17.4, P=.069
FRONT LINE CABOSUN: Cabozantinib vs
Sunitinib
8.2 vs 5.6 months
P=.012
HR=.66
30.3 VS 21.8
Not significant
FRONT LINE and SECOND‐
LINE
PAZOPANIB vs Placebo 9.2 vs 4.2, HR=.46,
P<.0000001
Not significant
SECOND‐LINE TARGET Sorafenib vs Placebo 5.5 VS 2.8, HR=.44,
P<.000001
17.8 VS 14.3
P=.0287
SECOND‐LINE RECORD‐1 Everolimus vs
Placebo
4 VS 1.9, HR=.3,
P<.0001
Not significant
SECOND‐LINE AXIS trial axitinib vs
sorafenib
6.7 vs 4.7, HR=0.665,
p<.0001
Not significant
SECOND LINE Nivolumab vs everolimus 4.4 vs 4.6 months, HR=0.88,
P=.11
25 vs 19.6, HR=.73, P=0.002
SECOND LINE Cabozantinib vs Everolimus 7.4 vs 3.8, HR=.58, P=<0.001 21.4 vs 16.5, HR=.66,
P=.0003
SECOND LINE LenvatInib plus everolimus vs
LEV vs Everolimus
14.6 (VS 7.4) VS 5.5, HR=.40,
p=.0005
25.5 vs 18.7 vs 17.5
3
Checkpoint inhibitor, Nivolumab; A drug with a novel mechanism of action
• Mechanism of action
• Data from Checkmate 025 trial
• Treatment beyond progression data 025
• Challenges with the response evaluation
• Unique Toxicities and implications
• Possible novel endpoints or radiographic assessments
4
• In patients on immune therapy, antitumor effects is due to immune response that indirectly attacks and clears the tumors.
Nivolumab mechanism of action
MHC
PD-L1
PD-1 PD-1
PD-1 PD-1
T-cellreceptorT-cell
receptor
PD-L1PD-L2
PD-L2
MHC
CD28 B7
T cell
NFκBOther
PI3KDendritic
cellTumor cell
IFNγ
IFNγR
Shp-2Shp-2
Nivolumab: PD-1 Receptor Blocking Antibody
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Checkpoint inhibitor, Nivolumab; A drug with a novel mechanism of action
• Mechanism of action
• Data from Checkmate 025 trial
• Treatment beyond progression data 025
• Challenges with the response evaluation
• Unique Toxicities and implications
• Possible novel endpoints or radiographic assessments
6
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23
Conclusions (1)
• Checkmate 025 met its primary endpoint, demonstrating superior OS with Nivolumab compared to Everolimus.
• This was the first trial to demonstrated OS advantage in second‐line of RCC.
• Survival benefit with Nivolumab was consistent across subgroups and irrespective of PD‐L1 expression.
• Nivolumab was associated with a higher objective response rate
24
Conclusions (2)
• Nivolumab was associated with fewer grade 3 and 4 treatment‐related AEs and fewer TRAEs leading to discontinuation that Everolimus.
• FKSI‐DRS results demonstrated a consistent improvement in QOL with Nivolumab compared to Everolimus.
• These results led to the approval of Nivolumab in December 2015 for use in advanced RCC patients who had received VEGF TKI in the past.
25
Checkpoint inhibitor, Nivolumab; A drug with a novel mechanism of action
• Mechanism of action
• Data from Checkmate 025 trial
• Treatment beyond progression data 025
• Challenges with the response evaluation
• Unique Toxicities and implications
• Possible novel endpoints or radiographic assessments
26
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• With immunotherapy, tumor flare (growth of existing lesions or the appearance of the new lesions) may precede antitumor effects1
• This phenomenon may result in RECIST–defined progression leading to premature discontinuation of therapy
Tumor flare with immunotherapy
T cells infiltrating the
tumor site
Immune therapy
Tumor cells
1. Wolchok JD et al. Clin Cancer Res. 2009;15:7412-7420.
T cells infiltrating the
tumor site
Immune therapy
Tumor cells
27
Introduction
• Response patterns of immunotherapies like nivolumab differ from those seen with other approved targeted therapies1,2
– Immune cell infiltration into the tumor or tumor growth that can occur as the immune system is priming for a responsemakes interpretation by Response Evaluation Criteria in Solid Tumors (RECIST) more challenging and may result in patients discontinuing therapy prematurely3
• In a phase II study, 69% (25/36) of previously treated patients with advanced renal cell carcinoma (aRCC) who were treated beyond progression experienced tumor burden reduction or stabilization in the size of target lesions after first progression4
• We investigated nivolumab treatment beyond RECIST progression in the large, randomized, phase III study of previously treated patients with aRCC (NCT01668784; Figure 1)
4. George S, Motzer R, et al., Safety and efficacy of Nivolumab TBP in RCC patients. JAMA Oncol. 2016 May 28
MethodsFigure 1. Study design, subgroup definitions, and disposition
Study Design and Patients
Nivolumab 3 mg/kg
intravenously every 2 weeksN=406 treated
Everolimus10 mg orally once daily
N=397 treated
Ran
do
miz
e 1:
1
ORR = objective response rate; OS = overall survival
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Methods (cont’d)Assessments for subgroup analysis
• Efficacy:
– Baseline to first RECIST‐defined progression
• Disease characteristics, duration of treatment, ORR, best overall response, time to response
– At first progression
• Disease characteristics
– From first progression to death or study discontinuation
• Duration of treatment, ≥30% tumor burden reduction, OS
• Safety
– Baseline to first RECIST‐defined progression
– After first progression
• This analysis primarily focuses on the nivolumab arm of the study
31Motzer et al. ASCO 2016
Demographics and baseline characteristicsa
Patients treated beyond progression(n = 153)
Patients not treated beyond progression(n = 145)
Median age (range), years 62 (29–85) 63 (23–85)
Sex, n (%)MaleFemale
116 (76)37 (24)
116 (80)29 (20)
MSKCC risk groupb, n (%)FavorableIntermediatePoor
58 (38)70 (46)25 (16)
44 (30)75 (52)26 (18)
KPS, n (%)70 or 80≥90
43 (28)110 (72)
54 (37)90 (62)
Tumor burden5, n (%)Small (<13 cm)Bulky (≥13 cm)
126 (82)27 (18)
108 (74)37 (26)
Prior radiotherapy, n (%) 39 (25) 42 (29)
Number of prior systemic antiangiogenicregimensb, n (%)12
113 (74)38 (25)
118 (81)27 (19)
Quality of life score (FKSI-DRS), median (Q1, Q3)c
31.5 (27.0–34.0) 31.0 (26.0–33.0)
aPatients who did not have a progression event or who were treated briefly beyond progression (<4 weeks) were excluded from analysis; bResults based on case report form data; Cn = 135 treated beyond progression and n = 52 not treated beyond progression. FKSI‐DRS = Functional Assessment of Cancer Therapy–Kidney Symptom Index–Disease Related Symptoms; KPS = Karnofsky performance status; MSKCC = Memorial Sloan Kettering Cancer Center; Q1 = first quartile; Q3 = third quartile 32
Patient disposition and duration of treatment
Patients treated beyond progression
(n = 153)
Patients not treated beyond progression
(n = 145)
Discontinued treatment, n (%) 134 (88) 145 (100)
Reasons for discontinuation, n (%)Disease progression Study drug toxicity AE unrelated to study drug Other
123 (80)8 (5)1 (1)2 (1)
122 (84)13 (9)6 (4)4 (3)
Median duration of treatment, months (95% CI)
OverallRandomization to first progressionPost-progression
8.8 (7.4–10.2)2.7 (1.9–3.8)3.4 (3.0–5.1)
2.3 (1.7–3.3)2.3 (1.8–3.3)
Not applicable
Continue to be followed, n (%) 92 (60) 50 (34)AE = adverse event; CI = confidence interval
33
Anti‐tumor activity of Nivolumab from Randomization to First Progression
Patients treated beyond progression
(n = 153)
Patients not treated beyond progression(n = 145)
ORR, % (95% CI) 20 (14‒28) 14 (9‒21) Best overall response, n (%)
Complete responsePartial responseStable diseaseProgressive diseaseUnable to determine
031 (20)51 (33)70 (46)
1 (1)
1 (1)20 (14)55 (38)58 (40)11 (8)
Median time to response, months (range)
1.9 (1.7‒9.2) 3.7 (1.4‒11.1)
Median duration of response, months (95% CI)
5.6 (3.9‒7.5) 7.0 (2.2‒7.9)
34
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Results: At First ProgressionPatients treated beyond
progression(n = 153)
Patients not treated beyond progression(n = 145)
KPS, n (%)a
<7070 or 80≥90
1 (1)41 (27)111 (73)
3 (2)72 (50)70 (48)
Quality of life score (FKSI-DRS), median (range)b
31.0 (28.0–33.0) 27.0 (24.0–32.5)
Change in KPS, n (%)DeteriorationImprovement
26 (17)24 (16)
39 (27) 11 (8)
Target lesion status at progression, n (%)Increase in target lesionsc
Appearance of new lesionsIncrease in target lesions and appearance of new lesions
84 (55)63 (41)18 (12)
62 (43)64 (44)22 (15)
Site of new lesions, n (%)d
LungLymph node BoneLiver
21 (14)15 (10)8 (5)8 (5)
17 (12)14 (10)21 (14)11 (8)
Change in tumor burden, n (%)Bulky (≥13 cm) to small (<13 cm)5
Small (<13 cm) to bulky (≥13 cm)56 (4)
10 (7)5 (3)
19 (13)
aDefined as the performance status at or prior to and closest to the time of progression; bn = 135 treated beyond progression and n = 52 not treated beyond progression; cAt least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; d% based on all patients treated and not treated beyond progression. FKSI‐DRS = Functional Assessment of Cancer Therapy–Kidney Symptom Index–Disease Related Symptoms 35
Tumor burden change post‐progression
Figure 2. Best reduction in target lesions
Plus signs represent responders before first progression
• 142 of 153 patients treated beyond progression had tumor measurements pre‐ and post‐progression• Of these 142 patients,15% (n=21) had ≥30% tumor burden reduction post‐progression (Figure 2)
36Motzer et al. ASCO 2016
Overall survival
Treated beyond progression
Not treated beyond progression
Median OS, months (95% CI)Treated beyond progression
28.1 (23.2–NE)
Not treated beyond progression
15.0 (12.1–18.2)
HR (95% CI), 0.41 (0.29–0.57)
37Motzer et al. ASCO 2016
Landmark Analysis of OS
Treated beyond progression
Not treated beyond progression
Median OS, months (95% CI)
Treated beyond progression
20.4 (17.3–NE)
Not treated beyond progression
11.4 (9.4–14.6)
HR (95% CI), 0.42 (0.30–0.59)
38Motzer et al. ASCO 2016
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Tumor burden change post‐progression based on best overall response
41
N≥30% tumor burden
reduction post‐progression, n (%)
Best response prior to progression
Complete or partial response
Stable diseaseProgressive disease
29
47
66
8 (28)
3 (6)
9 (14)
39Motzer et al. ASCO 2016
Tumor burden change based on best overall response
(CA209374) A Phase 3b/4 Safety Trial of Nivolumab (BMS‐936558) in Subjects with Advanced or Metastatic Renal Cell Carcinoma
George, Saby
Treatment naive
A Phase III Randomized Open‐label Study to Evaluate Efficacy and Safety of Pembrolizumab (MK‐3475) in Combination with Axitinib versus Sunitinib Monotherapy as a First‐line Treatment for Locally Advanced or Metastatic Renal Cell Carcinoma (mRCC)
George, Saby
Treatment refractory (post checkpoint inhibitor)
2 B0001014; A MULTI CENTER, MULTI COHORT, OPEN LABEL PHASE 2 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF AVELUMAB* (MSB0010718C)