2015 ASCO Genitourinary Cancers Update

2015 ASCO
Genitourinary Cancers Update
June 13, 2015
Amir Mortazavi, MD
Clinical Assistant Professor of Internal Medicine

E3805
CHAARTED: ChemoHormonal Therapy
versus Androgen Ablation Randomized Trial
for Extensive Disease in Prostate Cancer
3
ASCO 2014
Christopher Sweeney, MBBS, et al.

E3805 – CHAARTED Treatment
STRATIFICATION
Extent of Mets
-High vs. Low
Age
≥70 vs < 70yo
ECOG PS
- 0-1 vs 2
CAB> 30 days
-Yes vs. No
SRE Prevention
-Yes vs. No
Prior Adjuvant ADT
≤12 vs. > 12 months
R
A
N
D
O
M
I
Z
E
ARM A:
ADT + Docetaxel
75mg/m2 every 21
days for maximum
6 cycles
ARM B:
ADT (androgen
deprivation therapy
alone)
Evaluate
every 3 weeks
while
receiving
docetaxel and
at week 24
then every 12
weeks
Evaluate
every 12
weeks
Follow for time
to progression
and overall
survival
Chemotherapy
at investigator’s
discretion at
progression
Presented by: Christopher J. Sweeney, MBBS
• ADT allowed up to 120 days prior to randomization.
• Intermittent ADT dosing was not allowed
• Standard dexamethasone premedication but no daily prednisone
(N = 790)

Primary endpoint: Overall survival
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
OS (Months)
0 12 24 36 48 60 72 84
Probability
HR=0.61 (0.47-0.80) p=0.0003
Median OS:
ADT + D: 57.6 months
ADT alone: 44.0 months

Causes of Death
ADT + Doc (N=397) ADT alone (N=393)
N % N %
Due to prostate cancer 84 83.2 112 82.6
Due to protocol Rx 1 1.0 0 0.0
Other cause 8 7.9 11 8.2
Unknown 8 7.9 11 8.2
Missing 0 2
Total 101 136

0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
OS (Months)
0 12 24 36 48 60 72 84
Probability
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
OS (Months)
0 12 24 36 48 60 72 84
Probability
In patients with high volume metastatic disease, there is a 17 month
improvement in median overall survival from 32.2 months to 49.2 months
OS by extent of metastatic disease at start of ADT
High volume Low volume
p=0.0006
HR=0.60 (0.45-0.81)
Median OS:
ADT + D: 49.2 months
ADT alone: 32.2 months
p=0.1398
HR=0.63 (0.34-1.17)
Median OS:
ADT + D: Not reached
ADT alone: Not reached

ADT + Docetaxel
benefited all
subgroups

Secondary Endpoints
ADT + Doc
(N=397)
ADT alone
(N=393)
P-value
Hazard Ratio
(95%CI*)
PSA <0.2 ng/mL at 6 months 27.5% 14.0% <0.0001
PSA <0.2 ng/mL at 12 months 22.7% 11.7% <0.0001
Median time to CRPC
- biochemical, symptoms, or
radiographic (months)
20.7 14.7 <0.0001 0.56 (0.44, 0.70)
Median time to clinical
progression
- symptoms or radiographic
(months)
32.7 19.8 <0.0001 0.49 (0.37, 0.65)
*CI: confidence intervals

Conclusion
• The combination of standard ADT and 6 cycles of
docetaxel significantly improved overall survival
compared to standard ADT alone in men with hormone
sensitive prostate cancer
• The benefit in patients with a high volume of
metastases is clear and justifies the treatment burden
– longer follow-up is required for patients with low volume
metastatic disease

Docetaxel and/or zoledronic acid for
hormone-naïve prostate cancer:
First survival results from STAMPEDE
12
Abstract # 5001
Nicholas James, MD, PhD, et al.

• Setting
 Hormone therapy the mainstay of treatment since 1940s
 Addition of radiotherapy to N0M0 disease improves
outcomes
• Hypothesis
 Early use of active therapies (e.g. docetaxel, zoledronic
acid, abiraterone, enzalutamide, etc.) may give a larger
absolute benefit in overall survival
Setting and hypothesis

Inclusion criteria
Newly-diagnosed
Any of:
• Metastatic
• Node-Positive
• ≥2 of: Stage T3/4
PSA≥40ng/ml
Gleason 8-10
Relapsing after previous RP or
RT with ≥1 of:
• PSA ≥4ng/ml and rising with
doubling time <6m
• PSA ≥20ng/ml
• Node-positive
• Metastatic
All patients
WHO performance status 0-2

Outcome measures
Primary outcome measure
Overall survival
Secondary outcome measures
Failure-free survival (FFS)
Toxicity
Quality of life
Skeletal-related events
Cost effectiveness
FFS definition
First of:
PSA failure
Local failure
Lymph node failure
Distant metastases
Prostate cancer death
PSA failure definition
PSA fall >= 50%
 24wk nadir + 50% and
 >4ng/ml
PSA fall of <50%
 failure at t=0

Multi-arm multi-stage (MAMS) design
For each research comparison
• Allocation ratio of 2 control to 1 research
• Target 25% relative improvement in overall survival
 HR=0.75
• Interim analysis
 3 lack-of-benefit analyses on failure-free survival
• Main analysis on primary outcome measure
 Requires ~400 control arm deaths
 Power and alpha 90% and 0.025, 1-sided
Over all original comparisons
 Power and alpha 83% and 0.013, 1-sided
 Familywise error rate ~5%

Docetaxel & ZA comparisons: patients

Accrual
Comparison
Open: Oct-2005
Closed: Mar-2013
Accrual: 2962
Number of patients
1184 A Standard-of-care (SOC)
593 B SOC + zoledronic acid
592 C SOC + docetaxel
593 E SOC + zoledronic acid + docetaxel

Patient characteristics
1% WHO PS 2 [s]
21% WHO PS 1 [s]
65yr Median age [s]
(min 40, max 84)
61% Metastatic [s]
(85% Bony mets)
15% N+M0
24% N0M0
98% LHRH analogues [s]
29% Planned for RT [s]
(72% of N0M0 pts)
6% Previous local therapy
Balanced by arm
[s] Stratification factors + hospital + NSAID/aspirin

SOC 750 FFS events
SOC+ZA 371 FFS events
HR (95%CI) 0.93 (0.82, 1.05)
P-value 0.26
Zoledronic acid: Failure-free survival
Median FFS (95% CI)
SOC 21m (18, 24m)
SOC+ZA 21m (18, 25m)

Zoledronic acid: Survival
SOC 405 deaths
SOC+ZA 197 deaths
HR (95%CI) 0.93 (0.79, 1.11)
P-value 0.44
Median OS (95% CI)
SOC 67m (60, 91m)
SOC+ZA 80m (70, NR)

Docetaxel: Failure-free survival
SOC 750 FFS events
SOC+Doc 371 FFS events
HR (95%CI) 0.62 (0.54, 0.70)
P-value <0.0000000001*
Median FFS (95% CI)
SOC 21m (18, 24m)
SOC+Doc 37m (33, 42m)

Docetaxel: Survival
SOC 405 deaths
SOC+Doc 165 deaths
HR (95%CI) 0.76 (0.63, 0.91)
P-value 0.003
Median OS (95% CI)
SOC 67m (60, 91m)
SOC+Doc 77m (70, NR)

Zoledronic acid + docetaxel: Failure-free survival
SOC 750 FFS events
SOC+ZA+Doc 371 FFS events
HR (95%CI) 0.62 (0.54, 0.71)
P-value <0.0000000001*a
Median FFS (95% CI)
SOC 21m (18, 24m)
SOC+ZA+Doc 37m (31, 42m)

Zoledronic acid + docetaxel: Survival
SOC 405 deaths
SOC+ZA+Doc 181 deaths
HR (95%CI) 0.81 (0.68, 0.97)
P-value 0.02
Median OS (95% CI)
SOC 67m (60, 91m)
SOC+ZA+Doc 72m (63, 90m)

Consistency of treatment effect
• Subgroups included:
 Metastatic status (M0, M1)
 Nodal status (N0, N+, NX)
 Gleason sum score (≤7, 8+, unknown)
 PSA pre-hormone therapy (0-20ng/ml, 20-40, 40-100, 100+)
 Age at randomisation (under 70, 70 or over)
 WHO PS (0, 1-2)
 NSAID/Aspirin use (no use, uses either)
• No good evidence of heterogeneity

Treatment effect by metastatic status: FFS
+ZA
+Doc
+ZA+Doc
Pre-planned analysis

+ZA
+Doc
+ZA+Doc
Pre-planned analysis
Treatment effect by metastatic status: Overall survival

Docetaxel: Survival – M1 Patients
SOC 343 deaths
SOC+Doc 134 deaths
HR (95%CI) 0.73 (0.59, 0.89)
P-value 0.002
Median OS (95% CI)
SOC 43m (24, 88m)
SOC+Doc 65m (27, NR)

Target Dose: 75mg/m2, every 3 weeks for 6 cycles (+prednisolone 10mg daily)
Doc ZA+Doc
Report receiving 6 cycles 76% 69%
Report receiving ≥5 cycles 80% 74%
Docetaxel treatment

Grade 3+ adverse events ever reported
A
SOC
B
SOC+ZA
C
SOC+Doc
E
SOC+ZA+Doc
Patients randomised 1184 593 592 593
Patients with adverse event data 1174 587 579 564
Grade 3-5 AE (G5) N 363 (3) 185 (1) 291 (3) 294 (7)
% 31% 31% 51% 52%
Endocrine disorder 12% 12% 10% 12%
Blood and lymphatic (febrile neutropenia) 1% 2% 12% 12%
Blood/bone marrow (neutrophils) 1% 1% 12% 11%
General disorder 4% 5% 8% 11%
Musculo-skeletal 5% 5% 6% 8%
Gastrointestinal disorder 3% 3% 7% 7%
Renal 5% 4% 4% 6%
- Early peak in toxicity during chemotherapy seems to settle by 1 year

• Docetaxel improves survival for hormone-naive prostate cancer
• Zoledronic acid does not improve survival
• Adding both improves survival but offers no obvious benefit
over adding just docetaxel
• Multi-arm, multi-stage trials are practicable and efficient
• Docetaxel should be:
 Considered for routine practice in suitable men with
newly-diagnosed metastatic disease
 Considered for selected men with high-risk non-metastatic disease
in view of substantial prolongation of failure-free survival
Conclusions

A phase III protocol of androgen suppression and
radiotherapy vs AS and RT followed by
chemotherapy with docetaxel and prednisone for
localized, high-risk prostate cancer
(NRG Oncology/RTOG 0521)
33
Abstract # LBA 5002
Howard Sandler, MD, et al.

Background
• Locally advanced or high-risk localized prostate
cancer has a relatively poor prognosis.
• Standard management often uses radiotherapy and
long term (2-3 years) hormonal treatment.
• Improvements in local and systemic treatment are
likely to beneficial.
• Hypothesis: chemotherapy (docetaxel) known to be
beneficial in metastatic, hormone-resistant cancer
would improve outcome in non-metastatic, hormone-
sensitive prostate cancer

RTOG 0521
Stage
Gleason
score PSA
Any T
stage
≥9 <150
7-8 ≥20-150
≥T2 8 <20
Arm 1
Androgen
Suppression (24 mos)
+
External RT (8 wks)
High
Risk
R
a
n
d
o
m
i
z
e
Arm 2
Androgen
Suppression (24 mos)
+
External RT (8 wks)
+
Docetaxel beginning 4 wks after RT (6 cycles)

Characteristic
Arm 1 and Arm 2
(N=563)
Risk Category (stratification) (%)
Gleason ≥9, PSA ≤150, Any T-stage 53
Gleason 8, PSA <20, ≥T2 21
Gleason 8, PSA≥20-150, Any T-stage 10
Gleason 7, PSA≥20-150, Any T-stage 16
Gleason score, no. (%)
7 16
8 31
9-10 53
Serum PSA, ng/mL, Median (Q1-Q3) 15 (7-34)
Age, Median 66
cT3-T4 27%
pN0 33%

Overall Survival
4 yr OS 93% vs. 89%
HR 0.70 (90%CI: 0.51-0.98)

Biochemical Failure
6 yr BF 74% vs. 66%
HR 0.81 (95%CI: 0.58-1.11)

Disease-Free Survival
6 yr DFS 65% vs. 55%
HR 0.76 (95%CI: 0.58-0.99)

Distant Metastasis at Any Time

Cause of Death*
AS+RT
(n=59)
AS+RT+CT
(n=43)
Death due to cancer under study 23 16
Death due to protocol treatment 0 2
Death due to other cause 24 16
Death due to second primary 12 5
Unknown cause of death 0 4
*Based on central review blinded to treatment arm

Adverse Events Definitely, Probably, or
Possibly Related to Treatment
Grade
AS+RT
(%)
AS+RT+CT
(%)
Worst overall 1 17 3
2 53 29
3 21 38
4 1 26
5 0 1

Conclusions
• For the first time, improvement in overall survival observed with
(tolerable) adjuvant chemotherapy for localized, high-risk,
hormone-sensitive prostate cancer.
• Cumulative incidence of distant metastasis was reduced
• The potential role of docetaxel in hormone-sensitive prostate
cancer is consistent with and supported by our data and other
studies, such as STAMPEDE and CHAARTED.
• This analysis is relatively early and additional follow-up will likely
be enlightening.

Interest of short hormonotherapy (HT) associated
with radiotherapy (RT) as salvage treatment for
biological relapse (BR) after radical prostatectomy
(RP): Results of the GETUG-AFU 16 phase III
randomized trial
44
Abstract # 5006
Christian Carrie, MD, et al.

A Phase Ia Study of Atezolizumab
(MPDL3280A/Anti-PDL1):
Updated Response and Survival Data
in Urothelial Bladder Cancer (UBC)
52
Abstract # 4501
Daniel Petrylak, MD, et al.

Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC
53
References: 1. Bellmunt et al. J Clin Oncol. 2009. 2. The Cancer Genome Atlas Research Network. Nature. 2014. 3. Kandoth C, et al. Nature. 2013.
4. Lawrence MS, et al. Nature. 2013. 5. Rizvi et al. Science. 2015.
• Metastatic UBC is associated with poor outcomes
• There are no FDA-approved therapies for patients who relapse after platinum-based
therapy
– OS ≈ 5-7 months in the second-line setting1
• UBC has a high mutational load due to tobacco/environmental carcinogen exposure2-4
– In other cancers,4,5 high somatic non-synonomous mutational burden has been associated with
durable clinical benefit of PD-L1/PD-1–directed therapy5
Metastatic UBC: Unmet Need and Potential for
Cancer Immunotherapy

54
Atezolizumab (MPDL3280A) Is a Humanized Anti-PDL1 Anti-
body That Inhibits the Binding of PD-L1 to PD-1 and B7.1
• Inhibiting PD-L1/PD-1 and PD-L1/B7.1
interactions can restore antitumor T-cell activity
and enhance T-cell priming
• Targeting PD-L1 leaves the PD-L2/PD-1
interaction intact, thereby potentially preserving
peripheral immune homeostasis1,2
• PD-L1 is expressed in many cancers3,4
References: 1. Akbari et al. Mucosal Immunol. 2010; 2. Matsumoto et al. Biochem Biophys Res
Commun. 2008. 3. Brown et al. J Immunol. 2003. 4. Latchman et al. Nat Immunol. 2001.

55
a Safety-evaluable UBC population. b The UBC cohort originally enrolled patients with PD-L1 IC2/3 but was then expanded to include all-comers,
primarily recruiting PD-L1 IC0/1 patients.
References: Powles et al. ASCO, 2014; Powles et al. Nature, 2014; Bellmunt et al. ESMO, 2014; Xiao et al. SITC, 2014; Kim et al. ASCO-GU, 2015.
• Atezolizumab (MPDL3280A) administered IV Q3W 15 mg/kg or 1200 mg flat dose
Atezolizumab (MPDL3280A): Phase Ia Study
Ongoing dose-expansion phase
RCC
1. All-
comers
2. PD-L1
selected
Melanoma
All-comers
NSCLC
1. All-
comers
2. PD-L1
selected
Other Tumor
Types
1. PD-L1
selected
2. All-
comers
UBC
N = 92a
1. PD-L1
selected
2. All-
comersb
TNBC
1. PD-L1
selected
2. All-
comers
Key Eligibility Criteria:
• Measurable disease per RECIST v1.1
• ECOG PS 0 or 1

56
a Safety-evaluable patients received at least 1 dose of atezolizumab. b Includes lung, liver, non-lymph or soft tissue. c n = 89. Data cutoff, Dec 2, 2014.
References: 1. Bellmunt et al J Clin Oncol. 2010. 2. Pond et al BJU Int. 2014.
Atezolizumab (MPDL3280A): Baseline Characteristics
in UBC (safety evaluable)
Characteristic
Patients
N = 92a
Median age, y (range) 66 (36-89)
Male, n (%) 69 (75%)
ECOG PS, n (%)
0 37 (40%)
1 55 (60%)
Site of primary tumor
Bladder 73 (79%)
Renal pelvis 5 (5%)
Ureter 9 (10%)
Urethra 5 (5%)
Site of metastases at baseline, n (%)
Visceralb 73 (79%)
Liver 34 (37%)
Characteristic
Patients
N = 92a
Prior treatments, n (%)
Cystectomy or
nephroureterectomy
56 (61%)
Platinum-based chemotherapy 86 (94%)
Cisplatin-based 69 (75%)
Carboplatin-based 35 (38%)
≥ 2 prior systemic therapies
(metastatic
66 (72%)
≤ 3 months from last chemotherapy 37 (42%)c
Hemoglobin levels < 10 g/dL 16 (17%)
GFR < 60 mL/min 38 (41%)
• Poor prognostic factors included visceral
mets, low hemoglobin levels, ECOG PS 1 and
short time (≤ 3 months) from prior chemo1,2

57
Atezolizumab (MPDL3280A): Treatment-Related AEs
in UBC
• Atezolizumab was generally well tolerated
– Median safety follow-up was 16+ wk (range, 3
to 86+ wk)
• Median duration of treatment was 3 mo
(range, 0 to 19 mo)
– No treatment-related deaths
– 1 discontinuation due to a treatment-related AE
– 5% of patients had a Grade 3-4 immune-
mediated AE per investigator assessment
• Grade 3 AEs: increased AST (n = 3);
increased ALT (n = 2); increased blood
bilirubin (n = 1); hypophysitis (n = 1)
– 37 patients (40%) had a Grade 3-4 AE of
any causec
a Safety-evaluable patients received at least 1 dose of atezolizumab. b Additional Gr 3-4 AEs (1% each) included anemia, confusional state, decreased
blood phosphorus, hypophysitis, increased ALT, increased GGT and thrombocytopenia. c In addition, 2 Grade 5 AEs not related to treatment were seen
(acute respiratory failure and alcohol overdose). Data cutoff, Dec 2, 2014.
Treatment-Related AEs
Occurring in ≥ 5% of Patients (All Grade)
or in ≥ 2 Patients (Grade 3-4)
N = 92a All Grade Grade 3-4b
Any AE 60 (65%) 7 (8%)
Fatigue 15 (16%) 0
Asthenia 12 (13%) 1 (1%)
Nausea 10 (11%) 0
Decreased appetite 9 (10%) 0
Pruritus 9 (10%) 0
Pyrexia 6 (7%) 0
Rash 7 (8%) 0
Diarrhea 5 (5%) 0
Increased AST 2 (2%) 2 (2%)

58
PD-L1 IHC
n = 87b
ORR
(95% CI), %a
IC3 (n = 12) 67% (35%-90%)
50% (35, 65)
IC2 (n = 34) 44% (27%-62%)
IC1 (n = 26) 19% (7%-39%)
17% (7, 32)
IC0 (n = 15) 13% (2%-40%)
a Efficacy-evaluable patients with measurable disease at baseline per RECIST v1.1. Responses are investigator assessed (unconfirmed); of 30 unconfirmed
responses, 24 have been confirmed by the cutoff date. b 4 IC2/3 patients and 7 IC0/1 patients missing or unevaluable. Data cutoff, Dec 2, 2014.
• Responses were observed all PD-L1 subgroups, with higher ORRs associated with higher
PD-L1 expression in IC
• Responders also included patients with visceral metastases at baseline: 38% ORR (95% CI,
21%-56%) in 32 IC2/3 patients and 14% (95% CI, 5%-30%) ORR in 36 IC0/1 patients
Atezolizumab (MPDL3280A): ORR in UBC by IC Status
CR,
n (%)
PR,
n (%)
4 (33%)
9 (20%)
4 (33%)
14 (30%)
5 (15%) 10 (29%)
-
-
5 (19%)
7 (17%)
- 2 (13%)

59
a Change in SLD > 100%. b Seven patients without post-baseline tumor assessments not included. Asterisks denote 9 CR patients, 6 of whom have been
confirmed by data cutoff date (Dec 2, 2014) and 7 of whom had < 100% reduction due to lymph node target lesions. All lymph nodes returned to normal
size per RECIST v1.1.
• Forty-four of 80 patients (55%) with post-baseline tumor assessments experienced a
reduction in tumor burden
• Decreased circulating inflammatory marker (CRP) and tumor markers (CEA, CA-19-9)
were also observed in patients responding to atezolizumab
Atezolizumab (MPDL3280A): Response in UBC
by IC statusa
* *
* *
*
*** *
IC0
IC1
IC2
IC3MaximumSLDReduction
FromBaseline,%b

60
Atezolizumab (MPDL3280A): Duration of Treatment
and Response in UBC
• Median duration of response has not
yet been reached in either IC group
(range, 0+ to 43 mo)
• Median time to response was 62 days
– IC2/3 patients: range, 1+ to 10+ mo
– IC0/1 patients: range, 1+ to 7+ mo
• 20 of 30 responding patients had
ongoing responses at the time of
data cutoff
• 10 patients have been treated for over
1 year, including 3 retreated following
protocol amendment
a Discontinuation and ongoing response status markers have no timing implication. 4 patients discontinued treatment after cycle 16 prior to 1 year per original protocol.
Responses plotted are investigator assessed and have not all been confirmed by the data cutoff (Dec 2, 2014).
Patients with UBC and CR or PR as best response

61
Median OS 7.6 mo
(95% CI, 4.7 mo-NE)
Median OS Not Reached
(95% CI, 9.0 mo-NE)
___ IC2/3
___ IC0/1
+ Censored
• PD-L1 IC status appeared to be predictive of benefit from atezolizumab treatment
– mPFS and 1-year PFS rates were higher in atezolizumab-treated patients with higher PD-L1 IC expression
– The same association was observed for 1-year OS rates, and mOS for IC2/3 patients was not yet reached
• Preliminary analysis using SP142 from an independent sample set (n = 110) suggests that
PD-L1 IC status is not prognostic for OS in UBC1
Data cutoff, Dec 2, 2014. Reference: 1. Genentech, unpublished data.
Atezolizumab (MPDL3280A): Survival in UBC
Survivala
N = 92
IC2/3
n = 48
IC0/1
n = 44
PFS
Median PFS
(range)
6 mo
(0+ to 18)
1 mo
(0+ to 14+)
1-y PFS
(95% CI)
39%
(24-54)
10%
(0-21)
OS
Median OS
(range)
Not reached
(1 to 20+ mo)
8 mo
(1 to 15+ mo)
1-y survival
(95% CI)
57%
(41-73)
38%
(19-56)
Median survival follow-up: 14 mo (IC2/3)
12 mo (IC0/1)

62
• Atezolizumab has demonstrated promising clinical activity in a heavily pre-treated
metastatic UBC cohort with encouraging survival and clinically meaningful response data
– 1-year OS rates were 57% and 38% for IC2/3 and 0/1 patients, respectively
– ORRs were 50% and 17% in IC2/3 and 0/1 patients, respectively
– Median time to response was 62 days, and median DOR was not reached
• Atezolizumab has been well tolerated with manageable side effects
– No treatment-related deaths
– Grade 3-4 immune-mediated AE rate was 5%
• The highly sensitive and specific SP142 IHC assay measures PD-L1 expression on IC,
which may be a predictive biomarker for atezolizumab response
• Phase II and III studies in UBC are ongoing (NCT02108652 [IMvigor 210] and
NCT02302807 [IMvigor 211]), with Phase II data expected later this year
Atezolizumab (MPDL3280A): Phase Ia UBC Summary

Pembrolizumab (MK-3475) for advanced
urothelial cancer: Updated results and
biomarker analysis from KEYNOTE-012.
63
Abstract # 4502
Elizabeth Plimack, MD, et al.

Randomized phase 2 three-arm trial of
lenvatinib (LEN), everolimus (EVE), and
LEN+EVE in patients with metastatic renal
cell carcinoma
76
Abstract # 4506
Robert Motzer, MD, et al.

Introduction
 There is an unmet need for improved
treatment outcome of metastatic RCC
patients to standard VEGF-targeted
therapies and mTOR inhibitors
 Fibroblast Growth Factor (FGF) pathway
activation has been proposed as a
mechanism of escape from
VEGF-targeted therapies1
 Lenvatinib is a highly potent tyrosine
kinase inhibitor of VEGFR1–3 and
FGFR1–42-4
Kinase inhibitory profile of lenvatinib5
1. Casanovas O, Cancer Cell. 2005; 2. Matsui J, Int J Cancer 2008; 3. Matsui J, Clin Cancer Res 2008; 4. Okamoto K, Cancer Lett 2013; 5. Eisai data on file.

Study Design
Stratification factors:
• Hemoglobin (normal vs low)
• Corrected serum calcium
(≥ vs < 10 mg/dL)
Key eligibility criteria:
•Advanced or metastatic RCC
•Measurable disease
•Progression on/after 1 prior
VEGF-targeted therapy
•Progression within 9 mos of
stopping prior treatment
•ECOG PS ≤1 Everolimus
10 mg PO qd
Lenvatinib
18 mg PO qd
+
Everolimus
5 mg PO qd
Lenvatinib
24 mg PO qd
Patients were treated until:
• Disease progression
• Unacceptable toxicity
R
A
N
D
O
M
I
Z
E

Patient Characteristics and Prior Therapy
Lenvatinib/Everolimus
(n = 51)
Lenvatinib
(n = 52)
Everolimus
(n = 50)
MSKCC risk group, %
Favorable 24 21 24
Intermediate 37 35 38
Poor 39 44 38
Prior VEGF-targeted therapy*, %
Sunitinib 71 67 56
Pazopanib 18 25 26
Sorafenib 2 0 4
Other 10 8 14
*Lenvatinib/Everolimus total sum exceeds 100% due to rounding
In total, 5 patients had prior checkpoint inhibitor therapy and 14 patients had prior cytokine therapy

Treatment Administration
Lenvatinib/Everolimus Lenvatinib Everolimus
Patients Treated, n 51 52 50
Treatment Ongoing at Data Cut-off* 13 7 3
Duration of treatment, mos
Median 7.6 7.4 4.1
Range 0.7–22.6 0.1–23.0 0.3–20.1
Dose reductions, %
Lenvatinib 71 62 -
Everolimus 2 - 26
Primary Reason for Discontinuation, n
Adverse Events 9 11 5
Patient Choice 3 0 0
Progression 19 29 35
Other 7 5 7

Primary Endpoint: Progression-free Survival
Number at risk
Lenvatinib/Everolimus 51 41 27 23 16 10 5 1 0
Lenvatinib 52 41 29 20 11 6 4 1 0
Everolimus 50 29 15 11 7 3 1 0 0
Median, mos (95% CI)
Lenvatinib/Everolimus 14.6 (5.9–
20.1)
Lenvatinib 7.4 (5.6–
10.2)
Everolimus 5.5 (3.5–
7.1)
0.8
1.0
0.6
0.4
0.2
0.0
Time (mos)
Progression-freeSurvival
0 3 6 9 12 15 18 21 24
Lenvatinib/Everolimus vs Everolimus
HR 0.40 (95% CI 0.24–0.68); P < 0.001
Lenvatinib vs Everolimus
HR 0.61 (95% CI 0.38–0.98); P = 0.048

Objective Response
(n = 51)
Lenvatinib
(n = 52)
Everolimus
(n = 50)
Objective response rate, % 43 27 6
95% CI 29–58 16–41 1–17
Best overall response, %
Complete 2 0 0
Partial 41 27 6
Stable disease 41 52 62
Progression 4 6 24
Not evaluated 12 15 8
Median duration of objective
response, (months)
13.0 7.5 8.5
95% CI 3.7–NE 3.8–NE 7.5–9.4
NE, not estimable.

Overall Survival (Updated Analysis)
0.8
1.0
0.6
0.4
0.2
0.0
Time (mos)
OverallSurvival
0 3 6 9 12 15 18 21 24 27
Median, mos (95% CI)
Lenvatinib/Everolimus 25.5 (16.4–NE)
Lenvatinib 19.1 (13.6–26.2)
Everolimus 15.4 (11.8–19.6)
Lenvatinib/Everolimus vs Everolimus
HR 0.51 (95% CI 0.30–0.88); P = 0.024
Lenvatinib vs Everolimus
HR 0.68 (95% CI 0.41–1.14); P = 0.118
Number at risk:
Lenvatinib/Everolimus 51 48 46 44 38 35 29 21 14 6
Lenvatinib 52 50 45 42 37 31 26 16 7 4
Everolimus 50 46 42 38 30 27 20 14 8 2

Selected Treatment-emergent Adverse Events
(n = 51)
Lenvatinib
(n = 52)
Everolimus
(n = 50)
Adverse event, % Any grade Grade 3 (4) Any grade Grade 3 (4) Any grade Grade 3 (4)
Any TEAE 100 71 (14) 100 83 (10) 100 52 (12)
Diarrhea 84 20 71 12 34 2
Fatigue/Asthenia 59 14 50 8 38 0 (2)
Vomiting 45 8 39 4 10 0
Nausea 41 6 62 8 16 0
Hypertension 41 14 48 17 10 2
Decreased weight 31 2 48 6 8 0
Stomatitis 29 0 25 2 42 2
Dyspnea 24 0 (2) 21 2 22 8
Dysphonia 20 0 37 0 4 0
Rash 18 0 17 0 22 0
Grade 5 TEAEs
Lenvatinib/Everolimus (n = 1): Cerebral hemorrhage*; Lenvatinib (n = 3): Myocardial infarction*; Intracranial hemorrhage; Sepsis;
Everolimus (n = 2): Acute respiratory failure; Sepsis
*Treatment-related as per investigator’s assessment

Summary of Efficacy
(n = 51)
Lenvatinib
(n = 52)
Everolimus
(n = 50)
Progression-free survival
Median (mo) 14.6 7.4 5.5
95% CI 5.9–20.1 5.6–10.2 3.5–7.1
Benefit vs everolimus P < 0.001 P = 0.048 NA
Objective response rate, % 43 27 6
95% CI 29–58 16–41 1–17
Benefit vs everolimus P < 0.001 P = 0.007 NA
Overall survival (updated)
Median (mo) 25.5 19.1 15.4
95% CI 16.4–NE 13.6–26.2 11.8–19.6
Benefit vs everolimus P = 0.024 P = 0.118 NA
NA, not applicable; NE, not estimable.

Conclusions
 Progression-free survival was longer for lenvatinib/everolimus
and lenvatinib compared with everolimus
 Response rate was higher in both lenvatinib-containing arms
 The highest rate and longest duration of response was observed with
the combination
 Study results suggest an overall survival benefit for
lenvatinib/everolimus over everolimus

Conclusions
 Adverse events were generally higher for the lenvatinib-
containing arms compared with everolimus
 Adverse events were predictable, and generally managed with
dose modifications
 Further study of lenvatinib therapy is warranted in RCC

Final clinical results of a randomized
phase 2 international trial of everolimus vs.
sunitinib in patients with metastatic non-
clear cell renal cell carcinoma (ASPEN)
88
Abstract # 4507
Andrew Armstrong, MD, MSc, et al.

Rationale for the ASPEN Trial
• Current NCCN guidelines
provide little clinical guidance
around the optimal front line
therapy for non-clear cell RCC
• ASPEN is the largest
randomized trial conducted to
date in non-clear cell RCC and is
intended to inform on clinical
practice and to develop
predictive biomarkers NCCN RCC guidelines version 2015

ASPEN Trial Schema
Metastatic RCC
• Non-clear cell pathology:
papillary, chromophobe,
unclassified
• No prior therapy
• Measurable disease
Stratified by Histology, MSKCC
Risk Group
Everolimus 10 mg
orally once daily
Days 1-42
Cycle = 6 weeks
Sunitinib 50 mg orally
Days 1-28
Cycle = 6 weeks
n=108
R
A
N
D
O
M
I
Z
E
Radiographic
PFS Primary
Endpoint
NCT01108445
18 global
sites: 10
USA, 5 UK,
3 in Canada
Duke Cancer Institute was coordinating center and central biorepository for this
multinational randomized open label trial, monitoring by inVentiv Health clinical
No planned
crossover

Baseline Characteristics
Characteristic
Sunitinib
(n=51)
Everolimus
(n=57)
Years of age, median (range) 59 (24-100) 64 (29-90)
Gender (male %) 73 77
Race, Caucasian [white/black %] 82/14 91/9
Papillary histology, n (%)
type 1 papillary, n (%)
65
8
65
4
Chromophobe, n (%)
Unclassified histology, n (%)
Translocation carcinoma, n (%)
20
16
12
11
23
4
Sarcomatoid differentiation (%) 11 27
Prior nephrectomy (%) 80 79
Elevated LDH (%) 27 25
Liver/lung/bone metastases, (%) 31 / 59 / 24 26 / 44 / 26
MSKCC Risk Group (%)
0
1-2
≥ 3
29
63
8
25
56
19

Primary Endpoint: PFS
0 6 12 18 24 30 36
Time since randomization (months)
0.00.20.40.60.81.0
Progression-FreeSurvival
(probability)
Sunitinib, median PFS 8.3 months
Everolimus, median PFS 5.6 months
51 26 17 10 8 4 1
57 21 8 4 3 2 1
Sunitinib
Everolimus
Number of Patients at Risk
Stratified log-rank HR 1.41, p=0.16*
<0.20 boundary p-value level

PFS According to Pre-specified Subgroups
favors sunitinibfavors everolimus
Median PFS
(S vs. E, months)
Hazard Ratio
(80% CI)
8.3 vs. 5.6 1.41 (1.03-1.92)
14 vs. 5.7 3.07 (1.51-6.28)
6.5 vs. 4.9 1.38 (0.96-2.00)
4.0 vs. 6.1 0.21 (0.06-0.69)
8.1 vs. 5.5 1.52 (1.05-2.20)
5.5 vs. 11.4 0.71 (0.31-1.65)
11.5 vs. 5.6 2.55 (1.01-6.45)
Category
Overall
Good risk
Int. Risk
Poor Risk
Papillary
Chromophobe
Unclassified
Hazard Ratio and 80% CI
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Key Secondary Endpoint: Overall Survival
0 6 12 18 24 30 36
0.00.20.40.60.81.0
OverallSurvival
(probability)
Sunitinib: 32 months
(95% CI 15-NR)
Everolimus: 13 months
(95% CI 10-38)
51 40 34 19 14 10 4
57 44 27 15 9 6 2
Sunitinib
Everolimus
Stratified log-rank HR 1.12, p=0.60
Pre-specified two
sided alpha of 0.05

PFS by MSKCC Risk Group and Histologic Subtype
probability
0
1-2
3+
MSKCC Risk Criteria
0 6 12 18 24 30 36
0.00.20.40.60.81.0
29 16 11 6 5 0 0
64 25 14 8 6 6 2
15 6 0 0 0 0 0
0
1-2
3+
probability
Papillary
Chromophobe
Unclassified
Histology
0 6 12 18 24 30 36
0.00.20.40.60.81.0
70 29 15 9 8 6 2
16 8 6 4 2 0 0
22 10 4 1 1 0 0
Papillary
Chromophobe
Unclassified
Motzer Sunitinib PFS
(95% CI)
Everolimus PFS
(95% CI)
0 14.0 (2.9, 25.9) 5.7 (5.5, 11.0)
1-2 6.5 (5.3, 11.1) 4.9 (2.7, 6.1)
3+ 4.0 (0.9, 5.8) 6.1 (2.7, 7.6)
Pathology subtype Sunitinib PFS
(95% CI)
Everolimus PFS
(95% CI)
Papillary 8.1 (5.6, 13.0) 5.5 (3.0, 6.9)
Chromophobe 5.5 (1.7, 19.7) 11.4 (4.2, NA)
Unclassified 11.5 (2.7, NA) 5.6 (1.2, 7.3)

RECIST 1.1 Responses
Sunitinib
Everolimus
Endpoint Sunitinib
(n=51)
Everolimus
(n=57)
RECIST 1.1 Best Overall
Response (%)
CR/PR
SD
PD
NE
Clinical Benefit Response:
CR+PR+SD>24 weeks
18
59
19
4
22
9
53
23
15
11
Best tumor change by
RECIST (median %)
+10.7 +2.1
Median duration of
response in months
5.5 3.3

Summary and Conclusions
• Patients with metastatic NC-RCC treated with sunitinib had
a statistically significantly prolonged PFS duration than
patients treated with everolimus
– Sunitinib resulted in improved PFS in good/intermediate risk,
papillary, and unclassified subtypes
– Everolimus resulted in improved PFS in poor risk and
chromophobe subtypes
• Both agents resulted in short PFS times and low response
rates
• Sunitinib and everolimus resulted in different rates of
expected toxicities; more severe toxicities with sunitinib,
but more discontinuations due to toxicity from everolimus.

Initial results from ASSURE (E2805):
Adjuvant sorafenib or sunitinib for
unfavorable renal carcinoma, an ECOG-
ACRIN-led, NCTN phase III trial
98
ASCO GU 2015
Naomi Haas, MD, et al.

Stratify
Risk
- Intermediate High
- Very High
Histology
- Clear cell
- Non-clear cell
Performance status
- 0 vs. 1
Surgery
- Open
- Laparoscopic
Arm B Sorafenib
Twice daily for 9 cycles
(1 yr)
Arm C Placebo
Daily for 1 year
• Non-
metastatic
Kidney
Cancer
• Resectable
Disease by
scan
• ≥ T1bNany
(resectable)
M0 disease
Arm A Sunitinib
Daily 4 of 6 weeks for 9
cycles (1 yr)
Surgery
Endpoints:
Overall Survival
Side Effects
(Including Cardiac, Fatigue)
Correlatives
Starting Dose Sunitinib Sorafenib
Original 50 mg/day 400 mg twice daily
Revised 37.5 mg/day 400 mg/day
Presented by: Naomi B. Haas, MD
N = 1943

Toxicity Sunitinib Sorafenib Placebo
Grade (%) 3 4 5 3 4 5 3 4 5
Hypertension 16 <1 - 16 <1 - 4 - -
Thrombotic <1 <1 <1 1 1 - <1 <1 -
Bleeding <1 <1 - <1 - - <1 - -
Cardiac ischemia <1 <1 <1 <1 <1 - <1 <1 -
LVEF dysfunction 1 - - 1 - - <1 - -
CNS 1 - - <1 - - <1 <1 -
Adverse Events - Cardiovascular

Sunitinib Sorafenib Placebo
Grade (%) 3 4 5 3 4 5 3 4 5
Fatigue 17 1 - 7 - - 3 - -
Rash 2 - - 15 <1 - <1 - -
Hand-foot 15 - - 33 - - 1 - -
Diarrhea 10 - - 9 - - - - -
Anorexia 2 - - 1 - - - - -
Stomatitis 4 <1 - 2 - - <1 - -
Nausea/vomiting 6 - - 2 - - <1 - -
Neuropathy 1 - - 2 <1 - <1 - -
Pain 7 <1 - 9 <1 - 3 <1 -
Renal failure 1 - <1 1 <1 - - - -
Infection/febrile neutropenia 3 - <` 4 <1 <1 2 - -
Adverse Events - Clinical

Hematologic Adverse Events
Grade (%) 4 5 4 5 4 5
Thrombocytopenia 1 - <1 - - -
Myelosuppression <1 - - - - -
Anemia <1 <1 - - -
Grade 3 4 5 3 4 5 3 4 5
Percent 57 5 1 67 3 <1 20 4 <1
Worst Degree - All Event Types

Events Patients 5-yr DFS 97.5% CI HR 97.5% CI
Sunitinib 265 647 53.8% 49.0 – 59.1% 1.01 0.83 – 1.23
Sorafenib 272 649 52.8% 48.0 – 58.0% 0.98 0.81 – 1.19
Placebo 270 647 55.8% 51.2 – 60.9%
Median 5.8 yrs
Median 5.8 yrs
Median 6.0 yrs

DFS for Clear Cell Population
Event
s
Patient
s
5-yr DFS 97.5% CI HR 97.5% CI
Sunitinib 214 513 52.4% 47.0 – 58.4% 1.01 0.81 – 1.26
Sorafenib 224 519 50.7% 45.4 – 56.7% 1.00 0.81 – 1.24
Placebo 216 509 54.9% 49.7 – 60.6%
Median 5.6 yrs
Median 5.1 yrs
Median 5.7 yrs

Overall Survival
Event
s
Patient
s
5-yr OS 97.5% CI HR 97.5% CI
Sunitinib 138 647 76.9% 72.9 – 81.2% 1.10 0.83 – 1.45
Sorafenib 121 649 80.7% 77.0 – 84.6% 0.93 0.69 – 1.23
Placebo 130 647 78.7% 74.8 – 82.8%

Sunitinib vs. Placebo

Sorafenib vs. Placebo

Conclusions
• First and largest trial reporting on efficacy of VEGF inhibitors
as adjuvant therapy for patients with locally advanced
kidney cancer who are at high risk of recurrence
• Median time to disease recurrence did not differ between
those who received sorafenib or sunitinib after surgery
(median 5.8 years) and those treated with placebo (median
6 years)
• Findings from this study suggest that patients with locally
advanced kidney cancer should not be treated with either
adjuvant sorafenib or sunitinib

2015 ASCO Genitourinary Cancers Update

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2015 ASCO Genitourinary Cancers Update