2015 ASCO Genitourinary Cancers Update

2015 ASCO Genitourinary Cancers Update

June 13, 2015

Amir Mortazavi, MD

Clinical Assistant Professor of Internal Medicine

Prostate Cancer

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

RANDOMIZE

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

Pro

babi

lity

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

Pro

babi

lity

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

Pro

ba

bili

ty

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 Presented by: Christopher J. Sweeney, MBBS

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.

N = 742

Urothelial Carcinomas

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


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.


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


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


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%)


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%)


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 status

a

* * * *

* * * * *

IC0

IC1 IC2 IC3

Max

imum

SLD

Red

uctio

n

From

Bas

elin

e, %

b


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


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)


• 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.

Kidney Cancer

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 OM 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)

Prog

ress

ion-

free

Sur

viva

l

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


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)

Ove

rall

Surv

ival

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 Lenvatinib/Everolimus

(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


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

RadiographicPFS 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)

0.0

0.2

0.4

0.6

0.8

1.0

Prog

ress

ion-

Free

Sur

viva

l (p

roba

bilit

y)

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 sunitinib favors 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


0.0

0.2

0.4

0.6

0.8

1.0

Ove

rall

Surv

ival

(p

roba

bilit

y)

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


Prog

ress

ion-

Free

Sur

viva

l pr

obab

ility

0 1-2 3+

MSKCC Risk Criteria

0 6 12 18 24 30 36

0.0

0.2

0.4

0.6

0.8

1.0

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+

Number of Patients at Risk Time since randomization (months)

Prog

ress

ion-

Free

Sur

viva

l pr

obab

ility

Papillary Chromophobe Unclassified

Histology

0 6 12 18 24 30 36

0.0

0.2

0.4

0.6

0.8

1.0

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: Disease-Free Survival 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 Sunitinib Sorafenib Placebo

Grade (%) 4 5 4 5 4 5 Thrombocytopenia 1 - <1 - - - Myelosuppression <1 - - - - - Anemia <1 <1 - - -


Sunitinib Sorafenib Placebo 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

Disease-Free Survival


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


Events

Patients

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


Events

Patients

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


Thank You

109

2015 ASCO Genitourinary Cancers Update

Health & Medicine

Transcript of 2015 ASCO Genitourinary Cancers Update