Revisión de IO en cáncer de vejiga, desde NMIBC de alto riesgo, hasta líneas avanzadas. Basada en la evidencia.

1. IO en cáncer de vejiga
Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA, Medellín
27.07.2020

2. After a long drought,<br />novel therapies for <br />metastatic urothelial cancer <br />emerge
Presented By Elizabeth Plimack at TBD

3. FDA-Approved Checkpoint Inhibitors for UC
1. Atezolizumab [package insert]. July 2018. 2. Avelumab [package insert]. October 2017.
3. Durvalumab [package insert]. February 2018. 4. Nivolumab [package insert]. July 2018.
5. Pembrolizumab [package insert]. June 2018. Slide credit: clinicaloptions.com
Agent Target Schedule FDA Approval Type by Setting
Post-Platinum Frontline Cisplatin Ineligible
Atezolizumab[1] PD-L1 Q3W Accelerated Accelerated
Avelumab[2] PD-L1 Q2W Accelerated --
Durvalumab[3] PD-L1 Q2W Accelerated --
Nivolumab[4] PD-1 Q4W Accelerated --
Pembrolizumab[5] PD-1 Q3W Level 1 Accelerated

4. Immune Checkpoint Inhibitors Currently FDA Approved
for Urothelial Carcinoma
Agent
Ab
Inhibits
Schedule
Post
Platinum
Frontline
Cis-Ineligible
Atezolizumab PD-L1 Q3W Accelerated Accelerated
Nivolumab PD-1 Q2W Accelerated --
Durvalumab PD-L1 Q2W Accelerated --
Avelumab PD-L1 Q2W Accelerated --
Pembrolizumab PD-1 Q3W Level 1 Accelerated
June 2018:
Use of atezo and
pembro was
restricted to
PD-L1–positive
patients
only
Slide credit: clinicaloptions.com

5. PD(L)1 Inhibitors in the Bladder Cancer Spectrum
Presented By Daniel Heng at TBD

6. NMIBC – refractaria a BCG

7. KEYNOTE-057: Pembrolizumab in Patients With
High-Risk NMIBC Unresponsive to BCG
 Single-arm, open-label, phase II study
 Primary endpoint: CR (absence of HR NMIBC) in Cohort A; DFS in Cohort B
 Secondary endpoints: CR (absence of any disease, high or low risk NMIBC) in cohort A, DoR
in cohort A, safety
De Wit. ESMO 2018. Abstr. Balar ASCO 2020. Abstr 5041. Slide credit: clinicaloptions.com
Patients with high-risk NMIBC who are
unresponsive to BCG who are ineligible
for or refuse cystectomy
Cohort A: CIS with or without papillary
disease* (high-grade Ta or T1) (n = 130)
Cohort B: papillary disease* (high grade
Ta or any T1) without CIS (n = 130)
Pembrolizumab
200 mg Q3W for up to 24 mos
*Patients with papillary disease must have fully resected disease at study entry.
Eval with cystoscopy,
cytology with or
without biopsy
Q12W x 2 yrs, then
Q24W x 2 yrs and
once yrly thereafter
CT urogram Q24W x
2 yrs or more
frequently as
clinically indicated
If no persistence or
recurrence of HR
NMIBC, treat until
PD, toxicity, death or
completion of 2 yrs
of treatment
OR
Discontinue if HR
NMIBC present at
any assessment

8. De wit. ESMO 2018. Abstract 3575. Slide credit: clinicaloptions.com
Characteristic, n (%)
Patients
(N = 103)
Median prior BCG instillations, n (range)
12.0
(6.0-45.0)
PD-L1 status
 CPS ≥ 10
 CPS < 10
 NE/NA
39 (37.9)
59 (57.3)
5 (4.9)
Urothelial (transitional cell) histology, n
(%)
103 (100)
Pretreatment bladder cancer stage, n
(%)
 CIS w/T1
 CIS (TIS) w/high-grade Ta
 CIS (TIS) alone
13 (12.6)
16 (15.5)
74 (71.8)
Characteristic
Patients
(N = 103)
Median age, yrs (range)
 ≥ 65, n (%)
 < 65, n (%)
73 (44-92)
72 (69.9)
31 (30.1)
Male/Female, n (%) 86 (83.5) / 17 (16.5)
Race, n (%)
 White
 Asian
 Missing
70 (68.0)
27 (26.2)
6 (5.8)
ECOG PS, n (%)
 0
 1
76 (73.8)
27 (26.2)
KEYNOTE-057, Pembrolizumab in NMIBC:
Baseline Characteristics

9. KEYNOTE-057: ORR at First Evaluable Assessment
 Of 96 patients, 86 discontinued study
therapy, most due to persistent
disease (n = 38) or recurrent
disease/stage progression (n = 33)
DoR in Patients With CRResponse (N = 96) N % 95% CI
CR 39 40.6 30.7-51.1
Non-CR
 Persistent
 Recurrent
 NMIBC stage progression
 Non-bladder malignancy
 Progression to T2
56
40
6
9
1
0
58.3
41.7
6.3
9.4
1.0
0
47.8-68.3
31.7-52.2
2.3-13.1
4.4-17.1
0.0-5.7
NA
Nonevaluable 1 1.0 0.0-5.7
Balar ASCO 2020. Abstr 5041. Slide credit: clinicaloptions.com

10. Characteristic Patients (N = 74)
Median age, yrs (range) 73.4 (47.4-90.8)
Male, % 85
White race, % 95
ECOG PS 0/1, n (%)
77 / 23
Median BCG instillations, n (range) 12 (6-29)
Median days since last BCG dose, n
(range)
154 (5-346)
Histology, %
 TIS
 TIS/Ta
 TIS/T1
 TIS/Ta/T1
58
19
18
5
Phase II SWOG S1605 Study: Atezolizumab in
BCG-Unresponsive NMIBC
 Single arm phase II registration
trial of atezolizumab (1200 mg IV)
every 3 wks for 1 yr
 BCG-unresponsive high risk
NMIBC; unfit for or declined
radical cystectomy
 This report includes patients with
CIS (with or without concomitant
Ta/T1)
 Primary endpoint: pCR at 6 Mos
Black. ASCO 2020. Abstr 5022. Slide credit: clinicaloptions.com

11. Phase II SWOG S1605 Study: Atezolizumab in
BCG-Unresponsive NMIBC
 CIS efficacy population N = 74  pCR at 3 mos: 42%
(95% CI: 31-54)
 pCR at 6 mos: 27%
(95% CI: 17-39)
 At 3 mos, 32 pts had recurrence
(HG Ta or CIS, n = 28; T1, n = 3;
T2, n = 1)
‒ 9 of 28 with HG Ta/CIS stayed
on therapy and 2 experienced
CR at 6 mos
Event, n 3-Mo 6-Mo
CR 31 20
Persistent CIS 22 31
CIS + Ta/T1 5 0
Recurrent Ta/T1 4 14
Recurrent T2 1 0
Recurrent,
unknown stage
3 3
Recur, positive
cytology only
2 0
Not assessable 6* 6§
*Due to death (n = 1), site error (n = 2), declining PS from brain tumor (n = 1), grade 3 AE (n = 1).
§Due to death (n = 1), declining PS from brain tumor (n = 1), physician choice (n = 1), withdrew
consent (n = 1), grade ≥ 2 AE (n = 2).
Black. ASCO 2020. Abstr 5022. Slide credit: clinicaloptions.com

12. Adyuvante

13. IMvigor010 Study Design
Presented By Daniel Heng at TBD

14. DFS in ITT Population
Presented By Daniel Heng at TBD

15. DFS by PD-L1 Status
Presented By Daniel Heng at TBD

16. DFS by Clinical Subgroup
Presented By Daniel Heng at TBD

17. Imvigor 010 Discussion
Presented By Daniel Heng at TBD

18. NeoAdjuvant or
preoperative CT
Radical
Cystectomy +
Bilateral Pelvic
LND
Cure
Relapsed

19. Metastásicos candidatos a
platino

20. Gemcitabine and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin,
and Cisplatin in Advanced or Metastatic Bladder Cancer: Results of a Large,
Randomized, Multinational, Multicenter, Phase III Study
Von der Maase, J Clin Oncol (2000)
GC: Gemcitabine 1,000 mg/m2 over 30 to 60 minutes on
days 1, 8, and 15 plus cisplatin 70 mg/m2 on day 2.
GC provides a similar survival advantage to MVAC with a
better safety profile and tolerability.

21. Response Rates to First-line Therapy for Metastatic
Urothelial Carcinoma
CISPLATIN ELIGIBLE
1. Sternberg. Eur J Ca. 2006;42:50. 2. Von Der Masse. JCO. 2000;18:3068.
100
90
80
70
60
50
40
30
20
10
0
DD MVAC[1]
Sternberg
2006
Gem/cis[2]
Vonder Masse
2000
ResponseRate(%)
CR
PR
Slide credit: clinicaloptions.com

22. OS(%)
100
80
60
40
20
0
0 2 4 6 8 10 12
Yrs
32
45
15
29
11
23
4
8
2
0
DD MVAC
mOS, mos
DD MVAC
15.1
MVAC
14.9
Patients at Risk, n
MVAC (n = 129)
DD MVAC (n = 134)
MVAC
Log-rank test P = .042
HR: 0.76
Cisplatin-Based CT for UC Yields Durable Responses:
The Original “Tail on the Curve”
ORR 36%
CR 3%
mOS 9.3 mos
Dose-Dense MVAC[2]
ORR 72%
CR 25%
mOS 15.1 mos
Gemcitabine Carboplatin[3]Cisplatin Eligible
Gemcitabine Cisplatin[1]
ORR 49%
CR 12%
mOS 14 mos
OS(%)
100
80
60
40
20
0
0 1 2 3 4 5 6 7
Yrs
MCAVI
Gem/carbo
Log-rank test P = .64
Patients at Risk, n
MCAVI (n = 119)
Gem/carbo (n = 119)
37
44
13
15
7
5
3
2
1
2
1
1
1. Von Der Masse. JCO. 2005;23:4602. 2. Sternberg. Eur J Ca. 2006;42:50. 3. De Santis. JCO. 2012;30:191.
OS(%)
100
80
60
40
20
0
0 12 24 36 48 60 72
Mos
203
202
118
125
52
62
36
40
30
34
Patients at Risk, n
84
23
29
7
9
0
1
HR: 1.09 (95% CI: 0.88-1.34)
Log-rank P = .44, Wald’s P = .66
GC 14.0 (12.3-15.5)
MVAC 15.2 (13.2-17.3)
GC
MVAC
mOS, mos (95% CI)
Chemo

23. Chemotherapy - before the checkpoint era<br />Note the “tail” on the curve for cisplatin
Presented By Elizabeth Plimack at TBD

24. Atezo más quimioterapia en 1L
Atezo
Atezo – quimio
quimio
IMvigor130

25. Phase III IMvigor130: Atezolizumab ± Platinum-Based
CT for First-line Patients
Grande. ESMO 2019. Abstr LBA14_PR. Slide credit: clinicaloptions.com
 Coprimary endpoints: investigator-assessed PFS and OS (Arm A vs C); OS (Arm B vs C; hierarchical approach)
 Key secondary endpoints: ORR, DoR, PFS, and OS (Arm B vs C; PD-L1 subgroups), safety
Patients with locally advanced or
mUC and no prior systemic therapy
for metastatic disease; ECOG PS ≤ 2;
1L platinum eligible:
cisplatin or carboplatin
(N = 1200) Placebo + Platinum/Gemcitabine
(n = 362)
Atezolizumab Monotherapy
(n = 400)
Atezolizumab + Platinum/Gemcitabine
(n = 451)
Stratified by PD-L1 status (IC0 vs IC1 vs IC2/3); Bajorin risk factor score* (0 vs 1 vs 2 and/or patients with liver metastases);
Investigator choice of plt/gem (cisplatin + gem or carboplatin + gem)
*Including KPS < 80% vs ≥ 80% and presence of visceral metastases.
Arm
A
Arm
B
Arm
C
Atezolizumab Chemo

26. IMvigor130: Confirmed ORR and DoR
0
10
20
30
40
50
60
47%
23%
44%
35%
17%
37%
13%
7% 6%
CR:
PR:
Median DoR,*
mos (95% CI)
8.5
(7.2-10.4)
7.6
(6.3-8.5)
NE
(15.9-NE)
Atezolizumab
+ Plt/Gem
(n = 447)
Placebo
+ Plt/Gem
(n = 397)
Atezolizumab
(n = 359)
ORR(%)
Grande. ESMO 2019. Abstr LBA14_PR. Slide credit: clinicaloptions.com
*n = 212 in atezo + plt/gem, n = 174 in placebo + plt/gem, n = 82 in atezo.
Atezolizumab Chemo

27. IMvigor130: Platinum-Based CT ± Atezolizumab in
Advanced UC
Grande. ESMO 2019. Abstr LBA14_PR. Slide credit: clinicaloptions.com
Atezolizumab Chemo
Final PFS (ITT) Interim OS (ITT)
PFS(%)
OS(%)
Atezo + plt/gem
Placebo + plt/gem
334 (74)
326 (82)
PFS Events, n (%)
HR: 0.82 (95% CI: 0.70-0.96)
P = .007 (one-sided)
Atezo + plt/gem
Placebo + plt/gem
235 (52)
228 (57)
OS Events, n (%)
HR: 0.83 (95% CI: 0.69-1.00)
P = .027 (one-sided)
Co-primary endpoint of OS not (yet) met based on stats design, alpha spend
100
80
60
40
20
0
Mos
0 3 6 9 12 15 18 21 24 27 30 33
Atezo + plt/gem
Placebo + plt/gem
Patients atRisk, n
451 345 282 160 111 74 42 22 10 4 2 NE
400 317 246 116 73 40 18 11 4 NE NE NE
6.3 mo
(6.2-7.0)
8.2 mo
(6.5-8.3)
Mos
0 3 6 9 12 15 18 21 24 27 30 33
451 408 360 301 229 163 117 72 36 16 3 NE
400 359 308 255 182 123 79 49 25 8 NE NE
13.4 mo
(12.0-13.2)
16.0 mo
(13.9-18.9)
100
80
60
40
20
0
Atezo + plt/gem
Placebo + plt/gem
Patients atRisk, n
Co-primary endpoint of PFS met

28. IMvigor130: Interim OS for Atezo Monotherapy vs
Platinum-Based CT
Data cutoff 31 May 2019; median survival follow-up 11.8 months (all patients). a Comparison only includes patients concurrently enrolled with Arm B.
Patients atRisk, n
100
80
60
40
20
0
OS(%)
0 3 6 9 12 15 18 21 24 27 30 33
Mos
Atezo 360 285 245 216 173 120 72 42 16 NE NE NE
Placebo + plt/gem 359 322 274 224 158 103 62 35 15 3 NE NE
Grande. ESMO 2019. Abstr LBA14_PR. Slide credit: clinicaloptions.com
Atezo monotherapy
Placebo + plt/gem
191 (53)
198 (55)
OS Events, n (%)
HR: 1.02 (95% CI: 0.83-1.24)
15.7 (13.1-17.8)
13.1 (11.7-15.1)
Median OS, Mos (95% CI)
Atezolizumab Chemo

29. IMvigor130: Interim OS (Atezo vs Platinum CT)
by PD-L1 Status
PD-L1 IC0/1
OS(%)
Mos Mos
Atezo
Placebo +
plt/gem
Patients atRisk, n
272 210 175 152 124 85 48 28 11 NE NE NE
274 246 212 173 116 73 41 21 10 2 NE NE
PD-L1 IC2/3
88 75 70 64 49 35 24 14 5 NE NE NE
85 76 62 51 42 30 21 14 5 1 NE NE
12.9 mo
(11.3-15.0)
13.5 mo
(11.1-16.4)
0 3 6 9 12 15 18 21 24 27 30 33
17.8 mo
(10.0-NE)
NE
(17.7-NE)
100
80
60
40
20
0
0 3 6 9 12 15 18 21 24 27 30 33
Atezo monotherapy
Placebo + plt/gem
158 (58)
156 (57)
OS Events, n (%)
HR: 1.07 (95% CI: 0.86-1.33)
Atezo monotherapy
Placebo + plt/gem
OS Events, n (%)
HR: 0.68 (95% CI: 0.43-1.08)
33 (38)
42 (49)
Grande. ESMO 2019. Abstr LBA14_PR. Slide credit: clinicaloptions.com
Atezolizumab Chemo

30. IMvigor130: OS by Patient Subgroups
Grande. ESMO 2019. Abstr LBA14_PR. Slide credit: clinicaloptions.com
Characteristic
All patients
ECOG PS
PD-L1 status
Bajorin risk
factor score
Investigator choice
of chemo
0
1
2
0
1
2/3
0
1
2 and/or liver mets
Cisplatin
Carboplatin
851
355
396
100
278
374
199
338
318
195
273
578
16.0
22.0
14.2
7.4
14.2
14.9
23.6
24.5
15.8
9.5
21.7
14.2
13.4
18.2
10.8
9.3
12.8
13.4
15.9
18.2
12.6
9.5
13.4
13.4
0.83 (0.69-1.00)
0.83 (0.60-1.15)
0.78 (0.60-1.01)
0.99 (0.62-1.57)
0.82 (0.60-1.12)
0.87 (0.66-1.15)
0.74 (0.49-1.12)
0.79 (0.57-1.11)
0.80 (0.60-1.08)
0.94 (0.68-1.31)
0.66 (0.47-0.94)
0.91 (0.74-1.14)
Arm A (Atezo + Plt/Gem) Better Arm A (Placebo + Plt/Gem) Better
v
Patients,
n
Arm A
mOS, Mos
(n = 451)
Arm C
mOS, Mos
(n = 400)
0.3 1.0 3
HR (95% CI)
Atezolizumab Chemo

31. IMvigor130: Safety
 AEs requiring use of systemic corticosteroids:
atezo + plt/gem, 12%; placebo + plt/gem, 6%;
atezo alone, 8%
Slide credit: clinicaloptions.com
AE, n (%)
Atezo +
Plt/Gem
(n = 453)
Placebo +
Plt/Gem
(n = 390)
Atezo
(n = 354)
Any AE
 Grade 3/4
 Grade 4
451 (100)
383 (85)
29 (6)
386 (99)
334 (86)
20 (5)
329 (93)
148 (42)
28 (8)
Any Tx-related AE
 Grade 3/4
 Grade 4
434 (96)
367 (81)
9 (2)
373 (96)
315 (81)
4 (1)
211 (60)
54 (15)
3 (1)
AE leading to Tx d/c
 Atezo/placebo
 Cisplatin
 Carboplatin
 Gemcitabine
156 (34)
50 (11)
53 (12)
90 (20)
117 (26)
132 (34)
27 (7)
52 (13)
79 (20)
100 (26)
22 (6)
21 (6)
0
1 (< 1)
1 (< 1)
AE leading to dose
reduction/interruption
363 (80) 304 (78) 112 (32)
Any-Gr AE of Special
Interest in ≥ 1% of
Patients, n (%)
Atezo +
Plt/Gem
(n = 453)
Placebo +
Plt/Gem
(n = 390)
Atezo
(n = 354)
Rash 137 (30) 74 (19) 45 (13)
Hepatitis*
 Lab abnormalities
 Diagnosis
82 (18)
79 (17)
6 (1)
49 (13)
44 (11)
8 (2)
50 (14)
46 (13)
6 (2)
Hypothyroidism 48 (11) 15 (4) 36 (10)
Hyperthyroidism 31 (7) 7 (2) 15 (5)
Pneumonitis 12 (3) 6 (2) 12 (3)
Infusion-related rxn 6 (1) 3 (1) 5 (1)
Pancreatitis 3 (1) 2 (1) 6 (2)
*Some patients are included in both categories.
Atezolizumab Chemo
Grande. ESMO 2019. Abstr LBA14_PR.

32. Mantenimiento con IO luego de
quimio 1L
Continuar con IO en pacientes que no progresan
luego de quimioterapia 1L

33. Maintenance avelumab + best supportive care (BSC)<br />versus BSC alone after platinum-based first-line<br />chemotherapy in advanced urothelial carcinoma:<br /> JAVELIN
Bladder 100 phase III results
Presented By Thomas Powles at TBD

34. Background
Presented By Thomas Powles at TBD

35. Background
Presented By Thomas Powles at TBD

36. JAVELIN Bladder 100 study design (NCT02603432)
Presented By Thomas Powles at TBD

37. Statistical design
Presented By Thomas Powles at TBD

38. Select baseline characteristics
Presented By Thomas Powles at TBD

39. Patient disposition at the time of analysis
Presented By Thomas Powles at TBD

40. OS in the overall population
Presented By Thomas Powles at TBD

41. OS in the PD-L1+ population
Presented By Thomas Powles at TBD

42. Subgroup analysis of OS in the overall population
Presented By Thomas Powles at TBD

43. PFS by independent radiology review in the overall population
Presented By Thomas Powles at TBD

44. PFS by independent radiology review in the PD-L1+ population
Presented By Thomas Powles at TBD

45. Confirmed objective response
Presented By Thomas Powles at TBD

46. Subsequent anticancer therapy
Presented By Thomas Powles at TBD

47. Treatment-emergent AEs (any causality)
Presented By Thomas Powles at TBD

48. Immune-related AEs
Presented By Thomas Powles at TBD

49. Conclusions
Presented By Thomas Powles at TBD

50. HCRN GU14-182: Maintenance Pembrolizumab After
First-line Platinum-Based CT for mUC
 Double-blind, randomized phase II trial
 Primary endpoint: PFS (irRECIST)
 Secondary endpoints: restricted mean PFS, PFS in PD-L1high, PFS by RECIST 1.1, OS, ORR, and AEs
Galsky. ASCO 2019. Abstr 4504. Slide credit: clinicaloptions.com
Patients with metastatic UC and
at least stable disease after
≤ 8 cycles of first-line platinum-
based chemotherapy
(N = 107)
Crossover to
pembrolizumab
permitted
Pembrolizumab 200 mg IV
Q3W x up to 24 mos
(n = 55)
Placebo Q3W x up to 24 mos
(n = 52)
Stratified by lymph-node only metastases (Y/N),
response to 1st line chemo (CR/PR vs SD)
Pembrolizumab

51. HCRN GU14-182: Progression-Free Survival
 Median PFS, mos (95% CI)
‒ Pembrolizumab: 5.4 (3.6-9.2)
‒ Placebo: 3.2 (2.8-5.5)
 HR: 0.64 (95% CI: 0.41-0.98)
 Log rank P = .038
Pembrolizumab
Galsky. ASCO 2019. Abstr 4504. Slide credit: clinicaloptions.com
100
80
60
40
20
0
PFS(%)
0 6 12 18 24 30
Mos
Pembrolizumab (n = 55)
Placebo (n = 52)
Patients at Risk, n
Pembrolizumab
Placebo
55
52
20
12
12
4
7
1
3
0
2
0

52. Switch maintenance in mUC:<br />Phase II trial<br />HCRN GU14-182
Presented By Elizabeth Plimack at TBD

53. Slide 13
Presented By Elizabeth Plimack at TBD

54. Switch Maintenance in mUC: PFS
Presented By Elizabeth Plimack at TBD

55. Switch Maintenance in mUC: OS
Presented By Elizabeth Plimack at TBD

56. Switch Maintenance Approach vs Second Line
Presented By Elizabeth Plimack at TBD

57. Post platinum, is switch maintenance checkpoint inhibition preferred over a treatment break followed by second line?
Presented By Elizabeth Plimack at TBD

58. Metastásicos no candidatos a
platino

59. Response Rates to First-line Therapy for Metastatic
Urothelial Carcinoma
CISPLATIN ELIGIBLE CISPLATIN IN-ELIGIBLE
1. Sternberg. Eur J Ca. 2006;42:50. 1. Von Der Masse. JCO. 2000;18:3068. 3. De Santis. JCO. 2012;30:191.
4. O’Donnell. ASCO 2019. Abstr 4546. 5. Grande. ESMO 2019. Abstr LBA14_PR.
100
90
80
70
60
50
40
30
20
10
0
DD MVAC[1]
Sternberg
2006
Gem/cis[2]
Vonder Masse
2000
Gem/carbo[3]
De Santis
2012
ResponseRate(%)
CR
PR
Slide credit: clinicaloptions.com

60. IMvigor 210: Atezolizumab for First-line Cisplatin-
Ineligible Patients
Atezolizumab OS: Cohort 1
100
80
60
40
20
0
0 4 8 12 16 20 24
Mos
Patients at Risk, n
119
28 32
89 73 65 57 51 45 30 10
OS(%)
36
1-yr OS: 58% (95% CI: 49-67)
2-yr OS: 41% (95% CI: 32-50)
Median OS: 16.3 mos (95% CI: 10.4-24.5)
Balar. ASCO 2018. Abstr 4523.
IMvigor 210 Update: 2018
N = 119 patients
Median f/up: 29.3 mos
Overall response rate: 24%
Median OS: 16.3 mos
58% alive at 12 mos
Slide credit: clinicaloptions.com
Atezolizumab

61. KEYNOTE 052: Pembrolizumab for First-line
Cisplatin-Ineligible Patients
KEYNOTE 52 UPDATE 2019[1]
N = 370 patients
24-mo follow-up (median: 15.3 mos)
Objective response rate: 29%
Median OS: 11.3 mos
47% alive at 12 mos
Pembrolizumab
1. O’Donnell. ASCO 2019. Abstr 4546. 2. Vuky. ASCO 2018. Abstr 4524. Slide credit: clinicaloptions.com
OS (Overall Population)[1]
Best Change From Baseline[2]
100
80
60
40
20
0
OS(%)
0 4 8 12 16 20 24 28 32 36 40 44
Mos
Patients at Risk, n
370 284 223 173 147 127 113 80 41 15 1
Median, Mos
(95% CI)
12-Mo OS,
%
24-Mo OS,
%
11.3 (9.7-13.1) 46.9 31.2
100
80
60
40
20
0
-20
-40
-60
-80
-100
ChangeinTumorSizeFromBaseline(%)
20% increase
in tumor size
30% decrease
in tumor size
58% experience a
decrease in target lesions

62. KEYNOTE 052: Improved OS in PD-L1 Positive (CPS ≥ 10)
First-line Cisplatin-Ineligible Patients
PDL1-
O’Donnell. ASCO 2019. Abstr 4546. Slide credit: clinicaloptions.com
CPS Median OS,
mos (95% CI)
24-Mo OS,
%
≥ 10 18.5 (12.2-28.5) 47.0
< 10 9.7 (7.6-11.5) 24.0
OS(%)
100
80
60
40
20
0
00 4 8 12 16 20 24 28 32 36 40 44
Mos
CPS ≥ 10
CPS < 10
Patients at Risk, n
CPS ≥ 10
CPS < 10
110
251
96
179
79
140
66
103
59
84
52
71
50
59
39
37
21
17
8
6
1
1
-
-
Pembrolizumab

63. Response Rates to First-line Therapy for Metastatic
Urothelial Carcinoma
CISPLATIN ELIGIBLE CISPLATIN IN-ELIGIBLE
All Comers
PD-L1
positive
1. Sternberg. Eur J Ca. 2006;42:50. 1. Von Der Masse. JCO. 2000;18:3068. 3. De Santis. JCO. 2012;30:191.
4. O’Donnell. ASCO 2019. Abstr 4546. 5. Grande. ESMO 2019. Abstr LBA14_PR.
100
90
80
70
60
50
40
30
20
10
0
DD MVAC[1]
Sternberg
2006
Gem/cis[2]
Vonder Masse
2000
Gem/carbo[3]
De Santis
2012
Pembrolizumab[4]
KN052 (CPS ≥ 10)
O’Donnell
2019
Pembrolizumab[4]
KN052 (all)
O’Donnell
2019
Atezolizumab[5]
IMvigor 130 (all)
Grande
2019
ResponseRate(%)
CR
PR
Slide credit: clinicaloptions.com

64. Immune Checkpoint Inhibitors Currently FDA Approved
for Urothelial Carcinoma
Agent
Ab
Inhibits
Schedule
Post
Platinum
Frontline
Cis-Ineligible
Atezolizumab PD-L1 Q3W Accelerated Accelerated
Nivolumab PD-1 Q2W Accelerated --
Durvalumab PD-L1 Q2W Accelerated --
Avelumab PD-L1 Q2W Accelerated --
Pembrolizumab PD-1 Q3W Level 1 Accelerated
June 2018:
Use of atezo and
pembro was
restricted to
PD-L1–positive
patients
only
Slide credit: clinicaloptions.com

65. 2L
Progresión después de quimioterapia basada en
platino

84. Powles T, IMvigor211 - Lancet, 2018
FDA approved

85. Post-Platinum Urothelial Carcinoma: ORR
Slide credit: clinicaloptions.com
CT: ~ 10%
1. Powles T, et al. Lancet. 2018;391:748-757. 2. Apolo AB, et al. J Clin Oncol. 2017;35:2117-2124.
3. Powles T, et al. JAMA Oncol. 2017;3:e172411. 4. Sharma P, et al. Lancet Oncol. 2017;18:312-322.
5. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026.
Atezolizumab[1]
ORR(%,95%CI)
Data from separate studies. Not head-to-head comparisons.
13.4 18.2 17.8 19.6 21.1
0
10
20
30
40
50
60
70
Pembrolizumab[5]Nivolumab[4]Durvalumab[3]Avelumab[2]

86. Post-Platinum Urothelial Carcinoma: OS at 12 Mos
1. Powles T, et al. Lancet. 2018;391:748-757. 2. Apolo AB, et al. J Clin Oncol. 2017;35:2117-2124.
3. O’Donnell P, et al. AACR 2018. Abstract CT031. 4. Sharma P, et al. AACR 2018. Abstract CT178.
5. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026. Slide credit: clinicaloptions.com
CT: ~ 26%
Atezolizumab[1]
OS(%,95%CI)
Data from separate studies. Not head-to-head comparisons.
39.2 54.3 46.6 40.3 43.9
0
10
20
30
40
50
60
70
Pembrolizumab[5]Nivolumab[4]Durvalumab[3]Avelumab[2]

87. Postplatinum Urothelial Carcinoma: Safety
1. Powles T, et al. Lancet. 2018;391:748-757. 2. Apolo AB, et al. J Clin Oncol. 2017;35:2117-2124.
3. Powles T, et al. JAMA Oncol. 2017;3:e172411. 4. Sharma P, et al. Lancet Oncol. 2017;18:312-322.
5. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026. Slide credit: clinicaloptions.com
Agent Phase Median
F/U, Mos
Patients,
n
Treatment-Related AEs, %
Any Grade 3/4 Death None
Atezolizumab[1] III 17.3 459 70 20 < 1 30
Avelumab[2] Ib 16.5 44 66 7 0 34
Durvalumab[3] I/II 5.78 191 61 7 1 39
Nivolumab[4] II 7.0 270 64 18 1 36
Pembrolizumab[5] III 14.1 266 61 15* 2 39
*Reported as grade 3-5.

88. Pembrolizumab[1]
pCR: 42%
Atezolizumab[2]
pCR: 29%
Durvalumab +
tremelimumab[3]
pCR: 42%
cT3-4aN0
50%
cT1-2N0
50%cT3N0*
54%
cT2N0
42%
cT2N0
73%
cT3-4aN0
27%
cN+
4%
Ipilimumab +
Nivolumab[4]
pCR: 46%
cTanyN+
42%
cT3-4aN0
58%
Substantial Heterogeneity in Baseline Clinical Stages
Complicates Comparisons Across Neoadjuvant Trials
1. Necchi. J Clin Oncol 2018;36:3353. 3. Gao. ASCO 2019. Abstr 4551. 4. Van der Heijden. ESMO 2019. Abstr 904PD. Slide credit: clinicaloptions.com

89. What sequence yields the longest median overall survival?
Presented By Elizabeth Plimack at TBD

90. Adyuvancia No röle (IMvigor010 negativo)
1L post platino
Mantenimiento con avelumab (JAVELIN
100 Bladder positivo) vASCO2020
Platino inelegible
Atezolizumab (IMvigor210+, fase II)
(más barato que pembro)
IO en cáncer urotelial
Mi opinión
2L
Pembrolizumab
(KN45 positivo con OS)
NMIBC – refractario a BCG
Pembro x24 meses
(KN-057 positivo – Fase 2)
IMvigor211 no OS, ni PFS
07.2020