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Neoplasie uroteliali 2017 Highlights

Andrea Necchi Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

Disclosures

Available from the ASCO COI website

Consulting or Advisory Role:

• Company: Roche, Bayer, Merck & Co. Inc., Astra Zeneca

Travel, Accommodations, Expenses:

• Company: Roche, Merck & Co. Inc., Pierre Fabre

Research Funding (Institution):

• Company: Merck & Co. Inc., Astra Zeneca, Amgen

Presentation topics & objectives

• Bladder and urinary tract tumors

• Review current translational data from clinical trials/retrospective studies

• Gain insights on the impact of the latest data and future developments of immunotherapy in UBC

From 2016 White Paper of Bladder Cancer

Little progress in UBC therapeutic paradigm with the use of “old” pathological and clinical aids in the last 20 years

Hall et al, Lancet, 1999; updated: J Clin Oncol 2011 Grossman et al, N Engl J Med, 2003

Burger M et al, Eur Urol 2012 Meeks JJ et al, Eur Urol 2012

Grey zone of High Risk NMIBC ± BCG-failure

Perioperative (neoadjuvant) systemic therapy is underutilized worldwide

Little progress in UBC therapeutic paradigm with the use of “old” pathological and clinical aids in the last 20 years

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24 30 36

Months

Surv

ival P

roba

bility

Carboplatin

Cisplatin

381 260 132 74 47 33 23

639 515 349 225 152 118 79

No. pts at risk

Carboplatin

Cisplatin

P < 0.0001

A

Necchi A et al, Eur Urol 2016

+2.3 months

VFL+BSC (N=253)

BSC (N=117)

No. of events 237 115

No. censored (%) 16 (6.3) 2 (1.7)

Median in months (95% CI) 6.9 (5.7 - 8.0) 4.6 (4.1 - 6.6)

Hazard ratio (95% CI) 0.88 (0.70 -1.10)

p-valuea 0.2613 aStratified log-rank test

The salvage chemotherapy landscape

Mean c-index across bootstrap samples of 0.646

Bellmunt J et al, Ann Oncol 2013 Sonpavde G et al, J Urol 2015

Presented By Elizabeth Plimack at 2017 Genitourinary Cancers Symposium

Presented By David McConkey and Roland Seiler at 2017 Genitourinary Cancers Symposium

Presented By Roland Seiler at 2017 Genitourinary Cancers Symposium

N=343 Discovery: 250 Validation: 93

Time Tumor site

“Waves” of CT-induced clonal

tumor evolution

Even mutations in previously reported driver genes, including PIK3CA, KMT2D (MLL2), ATM and TP53, were not consistently shared by matched pre-CT and post-CT tumors

Faltas BM et al, Nat Genet 2016

Liu D et al, ASCO 2016 Jones S et al, Sci Transl Med 2015

Genomic evolution in MIBC after neoadjuvant chemotherapy

New neoantigens are detected in post-CT samples 32% of pts had gain or loss in targetable mutations

Targeted drug class-1 in the neoadjuvant setting

Targeted drug class-2 in the adjuvant setting

Any driver of chemoresistance?

• High-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB

• However, there were significant differences in the prevalence of several recurrently mutated genes including FGFR3, HRAS, TP53, and RB1

Genomic Characterization of Upper Tract Urothelial Carcinoma

Sfakianos JP et al, Eur Urol 2016

PURE01: an open label, single-arm, phase 2 study of the anti-programmed death (PD)-1 monoclonal antibody (moAb) Pembrolizumab for neoadjuvant therapy of muscle-invasive urothelial bladder carcinoma (miUBC)

ClinicalTrials.gov NCT02736266

Future development of PD-L1/PD-1 inhibitors in UC 1

st li

ne

Low grade High grade

In development

BCG-unresponsive

Pembrolizumab Atezolizumab

Neoadjuvant Adjuvant

Trimodality

Cisplatin-eligible

Maintenance

Cisplatin-ineligible

Platinum-refractory

Pembrolizumab±CarboG

Atezolizumab±CarboG

Immuno-Oncology Combinations

Personalized medicine

Atezolizumab Ph III

Nivolumab Ph III

Avelumab (Ph III)

Pembrolizumab

Durvalumab +

Tremelimumab (Ph III)

Pembro+GC

Atezo+GC

Pembrolizumab + RT (Atezolizumab+RT)

Atezolizumab Pembro + Chemo Pembrolizumab

Non-muscle-invasive bladder

cancer

Muscle-invasive bladder cancer

Metastatic urothelial

cancer

2n

d li

ne

an

d b

eyo

nd

Pembrolizumab + BCG

Modified from Bellmunt J et al, ESMO 2016

• Key cohort 1 inclusion criteria:

– No prior treatment for mUC (> 12 months since perioperative chemotherapy) – ECOG PS 0-2 – Cisplatin ineligibility based on ≥ 1 of the following:1 GFR < 60 and > 30 mL/min (Cockcroft-

Gault), Grade ≥ 2 hearing loss (25 dB at 2 contiguous frequencies) or peripheral neuropathy, ECOG PS 2

• Cohort 1–specific endpoints:

– Primary: confirmed ORR per RECIST v1.1 (central IRF) – Key secondary: DOR, OS, safety

Phase II IMvigor210 Study Design and Objectives

Balar AV et al, Lancet 2017

• Inoperable locally advanced or metastatic UC

• Predominantly UC histology

• Tumor tissue evaluable for PD-L1 testinga

Cohort 1 (N = 119): 1L cisplatin ineligible

Cohort 2: Platinum-treated mUC

Atezolizumab 1200 mg IV q3w until RECIST v1.1 progression

Atezolizumab 1200 mg IV q3w until loss of clinical benefit

IMvigor210 Study (Cohort 1): OS by PD-L1 Status in Cisplatin-Ineligible Patients

• NE, not estimable. Patients at risk of an event are displayed at indicated time points below plot. Censored values are indicated with a plus (+) symbol. Data cut-off: 4 July 2016.

Noteworthy survival was observed in octogenarians, those with SD as best RECIST v1.1 response and patients with poor prognostic factors

Balar AV et al, Lancet 2017

Pembrolizumab 200 mg Q3W

Primary Endpoints

•ORR in all patients

•ORR in patients with

PD-L1–positive tumors

Patients (N = 350)

•Advanced urothelial cancer

•No prior chemotherapy for

metastatic disease

•ECOG PS 0-2

•Ineligible for cisplatin based

on ≥ 1 of the following: – CrCl <60 mL/min

– ECOG PS 2

– ≥ grade 2 neuropathy or

hearing loss

– NYHA class III CHF

Phase 2 KEYNOTE-052 Study Design: Pembrolizumab as First-Line Therapy for Cisplatin-Ineligible Advanced/Metastatic Urothelial Cancer

Results from an interim analysis of the first 100 patients were presented at the 2016 ESMO. Results from the total study population (N = 370) are presented herein (from GU-ASCO 2017 poster)

• The primary end point was confirmed ORR per RECIST v1.1 by central imaging vendor review

• Secondary efficacy end points included duration of response, OS, and progression-free survival (PFS) per RECIST v1.1

• Safety and tolerability and determination of a cut point for PD-L1 expression were secondary objectives

• Efficacy and safety were assessed in all patients who received ≥1 dose of pembrolizumab

Presented By Arjun V Balar at 2017 Genitourinary Cancers Symposium

KEYNOTE-052: ORR by PD-L1 Status

Presented By Arjun V Balar at 2017 Genitourinary Cancers Symposium

MK3465-361 (Pembro vs Pembro+CT* vs CT)

IMvigor130 (Atezo vs Atezo+CT* vs CT)

DANUBE (Durva vs Durva+Treme vs CT*)

Ongoing trials in the first-line metastatic setting

*Consisting of Cis or Carboplatin and Gemcitabine

1. Loriot Y et al. ESMO 2016; Abstr 783P. 2. Petrylak DP et al. ASCO 2015. 3. Patel MR et al. ESMO 2016; Abstr. 777PD. 4. Massard C et al. J Clin Oncol 2016;34:3119-25. 5. Sharma P et al. Lancet Oncol 2016;217:1590-1598. 6. Galsky MD et al. Lancet Oncol 2017;doi: http://dx.doi.org/10.1016/S1470-2045(17)30065-7.

7. Plimack ER et al. Lancet Oncol 2017;doi: 10.1016/S1470-2045(17)30007-4. 8. Bellmunt J et al. J Clin Oncol 2009;27:4454-4461. 9. Sonpavde G et al. Lancet Oncol 2010;11:861-870. 10. Choueiri TK et al. J Clin Oncol 2012;30:507-512. 11. Agarwal N et al. Clin Genitourin Cancer 2014;12:130-137.

Single-Arm Trials of Salvage Immunotherapy Targeting the PD-1/PD-L1 pathway – Pre ASCO-GU17 landscape

Phase N Population

Atezolizumab IMvigor 2101 2 310 All comers

PCD4989g2 1a 48 PD-L1+

Avelumab JAVELIN3 1b 109 All comers

Durvalumab Study 11084 1 40 PD-L1+

Nivolumab

CheckMate 0325 1/2 78 All comers

CheckMate 2756 2 265 All comers

Pembrolizumab KEYNOTE-0127 1b 33 PD-L1+

Not reported

Not reported

Not reported

*Historical ORR for chemotherapy.8-10 †Historical 1-y OS for chemotherapy.11

ORR 1-year OS

0 20 40 60 80

% (95% CI)

10* 0

% (95% CI)

20† 40 60 80

Updated Durvalumab results from MEDI1108 trial

Presented By Thomas Powles at 2017 Genitourinary Cancers Symposium

Overall Survival

Data cutoff date: Sep 7, 2016.

Events, n HR (95% CI) P

Pembro 155 0.73 (0.59-0.91)

0.0022

Chemo 179

43.9% 30.7%

Median (95% CI) 10.3 mo (8.0-11.8) 7.4 mo (6.1-8.3)

0 2 4 6 8 10 12 14 16 18 20 22 24

10

20

30

40

50

60

70

80

90

100

Time, months

OS,

%

270 226 194 169 147 131 87 54 27 13 4 0 0

272 232 171 138 109 89 55 27 14 3 0 0 0

No. at risk

Events, n HR (95% CI) P

Pembro 44 0.57 (0.37-0.88)

0.0048

Chemo 60

Total Population

0

0 2 4 6 8 10 12 14 16 18 20 22 24

0

10

20

30

40

50

60

70

80

90

100

Time, months

OS,

%

74 60 51 42 35 31 18 12 7 3 0 0 0

90 76 51 36 28 24 16 8 4 1 0 0 0

No. at risk

Median (95% CI) 8.0 mo (5.0-12.3) 5.2 mo (4.0-7.4)

CPS ≥10% Population

39.8% 26.9%

0

Confirmed Objective Response Rate

0

5

10

15

20

25

30

35

40

OR

R, %

(9

5%

CI)

0

5

10

15

20

25

30

35

40

OR

R, %

(9

5%

CI)

No alpha allocated to the comparison of ORR in the CPS ≥10% population. Assessed per RECIST v1.1 by blinded, independent central review.

Data cutoff date: Sep 7, 2016.

21.1%

11.4%

Δ9.6% P = 0.0011 PR

CR

Total Population

21.6%

6.7%

CPS ≥10% Population

7.0%

14.1%

3.3%

8.1%

6.8%

14.9%

2.2%

4.4%

Pembrolizumab (N = 270)

Chemotherapy (N = 272)

Pembrolizumab (N = 74)

Chemotherapy (N = 90)

1. Galsky MD et al. Lancet Oncol 2017;doi: http://dx.doi.org/10.1016/S1470-2045(17)30065-7.

2. Rosenberg JE et al. Lancet 2016;387:1909-1920. 3. Sharma P et al. Lancet Oncol 2016;17:1590-1598.

RE Model

Median OS, months

Pembrolizumab Phase 3, ECCO 2017

Nivolumab Phase 1-2, Sharma, 2016 [3]

Atezolizumab Phase 2, Rosenberg, 2016 [2]

Nivolumab Phase 2, Galsky, 2016 [1]

10.30 [8.44, 12.16]

9.70 [5.34, 14.06]

7.90 [6.58, 9.22]

8.74 [6.05, not reached]

8.96 [7.54 , 10.37]

Meta-Analysis of OS in Studies of Second-Line Immunotherapy For Advanced Urothelial Carcinomaa

aPembrolizumab phase 1 study by Plimack et al (Lancet Oncol 2017;doi: 10.1016/S1470-2045(17)30007-4) not included because only patients with PD-L1+ tumors were enrolled.

4.00 8.00 12.00 16.00

Necchi A, et al. Poster Board #: G5 Abstract ID: 341

Presented By Vaughn DJ at 2017 Genitourinary Cancers Symposium

Presented By Andrea Apolo at 2017 Genitourinary Cancers Symposium

Patient Characteristics N = 48

Age

Median 58

Range (35-77)

Sex

Male 41 Female 7

Tumor type

Urothelial carcinoma 19 Castration-resistant prostate cancer 9 Urachal adenocarcinoma 4 Germ cell tumor 4 Penile 4 Squamous cell carcinoma of the bladder or urethra

2

Renal cell carcinoma—clear cell 2

Renal cell carcinoma—sarcomatoid 2

Trophoblastic 1

Sertoli Cell carcinoma 1

Presented By Andrea Apolo at 2017 Genitourinary Cancers Symposium

Adverse Event CaboNivo N=30 CaboNivoIpi N=18

Any Grade*

N (%)

Grade 3

N (%)

Grade 4

N (%)

Any Grade

N (%)

Grade 3

N (%)

Grade 4

N (%)

Alanine Aminotransferase Increased 20 (67) 0 0 8 (44) 1 (6) 0

Fatigue 19 (63) 2 (7) 0 13 (72) 2 (13) 0

Diarrhea 18 (60) 2 (7) 0 11 (61) 0 0

Hypothyroidism 17 (57) 0 0 5 (28) 0 0

Aspartate aminotransferase increased 15 (50) 0 0 4 (22) 0 0

Anorexia 14 (47) 0 0 11 (61) 1 (6) 0

Hoarseness 12 (40) 0 0 4 (22) 0 0

Mucositis 12 (40) 0 0 6 (33) 0 0

Hypocalcemia 12 (40) 0 0 4 (22) 0 0

Hyponatremia 11 (37) 1 (3) 0 5 (28) 2 (13) 0

Hypophosphatemia 11 (37) 4 (13) 0 8 (44) 3 (17) 0

Palmar plantar erythrodysesthesia 11 (37) 0 0 5 (28) 0 0

Thrombocytopenia 11 (37) 1 (3) 1 (3) 6 (33) 0 0

Dysgeusia 9 (30) 0 0 8 (44) 0 0

Hypoalbuminemia 9 (30) 0 0 3 (17) 0 0

Myalgia 9 (30) 0 0 3 (17) 0 0

Nausea 9 (30) 0 0 7 (39) 2 (13) 0

Rash€ 8 (27) 0 0 6 (33) 1 (6) 0

Neutropenia 8 (27) 5 (17) 0 4 (22) 0 0

Dry mouth 7 (23) 0 0 6 (33) 0 0

Dry skin 7 (23) 0 0 4 (22) 0 0

Vomiting 7 (23) 1 (3) 0 4 (22) 0 0

Hypertension 7 (23) 3 (10) 0 3 (17) 3 (17) 0

Hypomagnesemia 7 (23) 0 0 2 (11) 0 0

Proteinuria 7 (23) 1 (3) 0 2 (11) 0 0

Headache 7 (23) 0 0 0 0 0

Anemia 6 (20) 1 (3) 0 4 (22) 0 0

Weight loss 6 (20) 0 0 5 (28) 0 0

Abdominal Pain 5 (17) 0 0 3 (17) 0 0

Hypokalemia 5 (17) 0 0 4 (22) 0 0

Lipase increase 5 (17) 2 (7) 2 (7) 8 (44) 2 (13) 1 (6)

Cough 3 (10) 0 0 5 (28) 0 0

Dehydration 3 (10) 2 (7) 0 3 (17) 0 0

Hyperthyroidism 3 (10) 1 (3) 0 2 (11) 0 0

Amylase increase 4 (13) 1 (3) 0 1 (6) 0 0

Thromboembolic event 1 (3) 1 (3) 0 0 0 0

Colitis 0 0 0 1 (6) 1 (6) 0

Aseptic meningitis 1 (3) 1 (3) 0 0 0 0 *Reported in at least 10% of patients or > grade 2; €Rash includes abdomen/chest rash, acneiform, and maculo-papular Apolo AB, et al. GU ASCO 2017 abstract 293

Sharma P et al, SITC 2016

Sharma P et al, SITC 2016

Sharma P et al, SITC 2016

Ipilimumab/Nivolumab in mUC: Overall Survival

0 3 6 9 12 15 18 21 24 27 0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Ove

rall

Surv

ival

(P

rob

abili

ty)

Months No. at risk

NIVO 1 + IPI 3 26 21 17 7 3 3 3 2 1 0

NIVO 3 + IPI 1 104 84 59 45 38 27 8 0 0 0

Median OS, months (95% CI)

NIVO 1 + IPI 3 10.2 (4.5–NR)

NIVO 3 + IPI 1 7.3 (5.6–11.4)

NIVO 1 + IPI 3

NIVO 3 + IPI 1

Sharma P et al, SITC 2016

What is needed by the bladder cancer patient community The case of second-line therapy

Vinflunine ….

Atezolizumab in 1L and 2L, Nivolumab 2L (Durvalumab and Avelumab granted breakthrough therapy designation) …Pembrolizumab

andrea.necchi@istitutotumori.mi.it @AndreaNecchi