Inmunoterapia: Presente y futuro. Cáncer de vejiga · Inmunoterapia: Presente y futuro. Cáncer de vejiga Enrique Grande Jefe de Servicio de Oncología Médica y Director de Investigación

Inmunoterapia: Presente y futuro.

Cáncer de vejiga

Enrique Grande Jefe de Servicio de Oncología Médica y Director de Investigación Clínica

MD Anderson Cancer Center Madrid

Does it make sense to use Immunotherapy in

Urothelial Tumours?

Proposed Model of BCG Therapy in Bladder Cancer

Clinical Care Options slide deck

Tcells

NeutrophilsMonocytes

Bladderurothelium

BCG Tumorcells

1.Attachmentandinvasionoftheurothelium

4.CytolysisofbladdertumorcellsbyCD8+Tcells

3.AttractionandactivationofTcells2.Attractionofinnateimmunecellsandreleaseofcytokines/chemokines

BCG in Superficial Bladder Cancer (SWOG 8216)

Lamm DL, et al. N Engl J Med 1991

100

80

60

40

20

0 6 0 12 18 24 30

BCG

Doxorubicin

Months from Registration

Dis

ease F

ree S

urv

ival

%

At Risk

28

26

Relapses

6

16

Somatic mutations can be used to indirectly estimate neoantigen burden

Alexandrov LB, et al. Nature 2013

From Chemo-based treatments to Immuno-

sensitive disease

Atezolizumab está autorizado por la Comisión Europea para el tratamiento de pacientes adultos con carcinoma urotelial localmente avanzado o metastásico (CU) después de quimioterapia previa que

contenga platino o que no son considerados aptos para el tratamiento con cisplatino. En España se encuentra pendiente del acuerdo del Precio & Reembolso con el Sistema Nacional de Salud.

Evolving Regulatory Field in Urothelial Tumors

BLA, Biologics License Application http://www.accessdata.fda.gaov/scripts/cder/drugsatfda/index.cfm; http://www.ema.europa.eu/ema/ 1. Sternberg et al. Cancer 1989;64:2448–58; 2. McCaffrey et al. J Clin Oncol 1997;15:1853–7 3. von der Maase et al. J Clin Oncol 2005;23:4602–8; 4. Sternberg et al. J Clin Oncol 2001;19:2638–46 5. Vaughn et al. J Clin Oncol 2002;20:937–40; 6. Bellmunt et al. J Clin Oncol 2009;27:4454–61 7. Rosenberg et al. Lancet 2016;387:1909–20; 8. Balar et al. Lancet 2017;389:67–76 9. Sharma et al. Lancet Oncol 2017; doi: 10.1016/S1470-2045(17)30065-7 10. Bellmunt et al. N Engl J Med 2017; doi: 10.1056/NEJMoa1613683 11. Balar et al. J Clin Oncol 2017;35(suppl 6S):Abstract 284

1998 2000 2002 2004 2006 2008 2010 2012 2014 20161996 2017

Pub

licat

ions

Reg

ulat

ory

stat

us

Cisplatin FDA

approval

1978

Gemcitabine EU approval

Vinflunine EU approval

Atezolizumab FDA approval prior platinum

18 May 2016

AtezolizumabFDA BLA 1L cis-ineligible

09 January 2017

Docetaxel2

Standard MVAC1

1989

HD-MVAC4

Paclitaxel5

Vinflunine6

Atezolizumab

(prior platinum)7

Gemcitabine

+ cisplatin3 Pembrolizumab

(prior platinum)10

Nivolumab

(prior platinum)9

Atezolizumab

(1L cis-ineligible)8

Durvalumab FDA BLA prior platinum

09 December 2016

NivolumabFDA approval prior platinum

02 February 2017

PembrolizumabFDA BLA 1L cis-ineligible

AND prior platinum

03 February 2017

AvelumabFDA BLA prior platinum

28 February 2017

Pembrolizumab

(1L cis-ineligible)11

EMA approved drugs in 2017

1. Platinum-refractory

2. Unfit for chemo (1st Line)



ESMO Guidelines for Metastatic Bladder Cancer

Adapted from Bellmunt J, et al. Ann Oncol 2014

Setting Treatment Level ofEvidence

First Line

Cisplatin +Gemcitabine IA

MVAC(methotrexate,vinblastine, adriamycinand

cisplatin)IA

Cisplatin +Gemcitabine +Paclitaxel IB

Carboplatin +Gemcitabine IA

M-CAVI(Methotrexate/carboplatin/vinblastin)orTaxane or Gemcitabine

IIA

Second Line Vinflunine IB

Fit

UnfitLonge

r-term

survival

Role of vinflunine in 2nd line

Bellmunt , et al. J Clin Oncol 2009

OS in the eligible population*

Time (months)

1.0

0.8

0.6

0

0.2

Ov

era

ll s

urv

iva

l (p

rob

ab

ilit

y)

VFL + BSC

BSC

0.4

2510 3530200 155

OS in the ITT population

Time (months)

1.0

0.8

0.6

0

0.2

Ov

era

ll s

urv

iva

l (p

rob

ab

ilit

y)

VFL + BSC

BSC

0.4

2510 3530200 155

Median OS (ITT)

6.9 months with VFL + BSC (n=253) versus 4.6 months with BSC (n=117)

HR=0.88 (log rank p=0.2868)

Median OS (eligible)


HR=0.78 (log rank p=0.0403)


Time (years)

1.0

0.8

0.6

0

0.2

Ov

era

ll s

urv

iva

l (p

rob

ab

ilit

y)

VFL + BSC

BSC

0.4

2510 3530200 155


Time (months)

1.0

0.8

0.6

0

0.2

Ov

era

ll s

urv

iva

l (p

rob

ab

ilit

y)

VFL + BSC

BSC

0.4

2510 3530200 155

Median OS (ITT)


HR=0.88 (log rank p=0.2868)



HR=0.78 (log rank p=0.0403)

Urothelial tract carcinoma: an unmet medical need

Pal, et al. PLoS One 2015

Disease specific survival (months)

1.0

0.8

0.2

0

Su

rviv

al

pro

ba

bilit

y

0.4

48246 543630180 60

0.6

4212

Survival in 2nd Line

n

Median (months) 1-year 2-year 3-year

1990–2000 810 4.0 21% 10% 8%

2001–2010 2,300 4.0 23% 11% 8%

Log-rank p-value: 0.1328

Not exactly the same indications by EMA

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003985/WC500189765.pdf http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/004143/WC500231701.pdf

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003820/smops/Positive/human_smop_001170.jsp&mid=WC0b01ac058001d127

• OPDIVO as monotherapy is indicated for the treatment of locally advanced unresectable or metastatic urothelial carcinoma in adults after failure of prior platinum-containing therapy

Nivolumab

• Tecentriq as monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma after prior platinum-containing chemotherapy or who are considered cisplatin ineligible

Atezolizumab

• Keytruda as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy.

• Keytruda as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy.

Pembrolizumab

Checkmate 275: Nivolumab in metastatic urothelial carcinoma after platinum therapy phase 2 trial

Sharma P, et al. Lancet Oncol 2017

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months

Pro

gre

ss

ion

-Fre

e S

urv

iva

l(P

rob

ab

ilit

y)

0 3 6 9 12No. at Risk

All treated patients 265 110 48 17 0

Median PFS, Months (95% CI)a

All treated 2.00 (1.87–2.63)

All treated

patients

PD-L1 <1%

PD-L1 <1% 1.87 (1.77–2.04)

143 49 21 9 0PD-L1 <1%

PD-L1 ≥1% 3.55 (1.94–3.71)

122 61 27 8 0PD-L1 ≥1%

PD-L1 ≥1%

Keynote 045: Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma

Bellmunt J, et al. N Engl J Med 2017

Pembrolizumab

200 mg Q3W

(N = 270)

Investigator’s Choice

Paclitaxel 175 mg/m2 Q3W or

Docetaxel 75 mg/m2 Q3W or

Vinflunine 320 mg/m2 Q3W

(N = 272)

Treated up to 24 mos or until

CR, PD, unacceptable AE, or

investigator decision*†

Treated until PD, unacceptable

AE, or patient withdrawal of

consent

Primary endpoints: OS, PFS in overall and in PD-L1 CPS ≥ 10% populations

Secondary endpoints: ORR, DoR in overall and in PD-L1 CPS ≥ 10% populations; safety

Patients with metastatic or locally

advanced UC after recurrence or

progression following platinum-based

chemotherapy;

ECOG PS ≤ 2; evaluable tumor tissue

for PD-L1 testing

(N = 542)

Keynote 045: PFS and OS of Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma

Bellmunt J, et al. N Engl J Med 2017

Keynote 045: OS benefit over each of the individual agents

Petrylak D, et al. ESMO 2017

Imvigor 210: Atezolizumab in Urothelial Cancer

Rosenberg J, et al. Lancet 2016


Rosenberg J, et al. Lancet 2016

Imvigor 210: Overall Response Rate - primary endpoint (platinum resistant)

Dreicer et al. ASCO 2016

IC2/3n = 100

IC1/2/3n = 207

Alla

N = 310

ORR: confirmed IRF RECIST v1.1 (95% CI)

28%(19, 38)

19%(14, 25)

16%(12, 20)

CR rate: confirmed IRF RECIST v1.1 (95% CI)

15%(9, 24)

9%(6, 14)

7%(4, 10)

IC1n = 107

IC0n = 103

11%(6, 19)

9%(4, 16)

4%(1, 9)

2%(0, 7)

• ResponseswereseeninallICsubgroups,butORRwasenrichedwithhigherPD-L1status• Completeresponsesaccountedfornearlyhalfoftheobservedresponses

– CRswereobservedinallPD-L1subgroups,withthehighestrateinIC2/3patients

• ORRsperimmune-modifiedRECISTwereconcordant

Imvigor 210: Overall Response Rate - primary endpoint (platinum resistant)

• Median time to first

responsea

was 2.1 mo

‒ Range, 1.6 to 8.3 mo

• Additional CRs and PRs

were observed with

longer follow-up

‒ 5 PR-to-CR and 2 SD-to-

PR conversions

Months

0 2 4 6 8 10 12 14 16 18 20

Pa

tien

ts W

ith C

R o

r P

R a

s B

est

Re

spo

nse

Median follow-up: 17.5 months

(range, 0.2 to 21.1+ mo)

CR as Best Response

PR as Best Response

First CR/PR

Treatment Discontinuationb

Ongoing Responsec

First Responses

a Per IRF RECIST v1.1 b Discontinuation

symbol does not indicate timing. c No PD or death only. Data cutoff: March 14,

2016.

Dreicer et al. ASCO 2016

Imvigor 210: PFS data from Atezolizumab in UBC

Rosenberg J, et al. ECCO 2015

IC2/3 (n=100)

IC0/1 (n=211)

All (n=311)

Median PFS,* months (95% CI) 2.1 (2.1, 4.1) 2.1 (2.0, 2.1) 2.1 (2.1, 2.1)

PF

S e

stim

ate

2 6 113 8 9

2.1

4 5 7 10

2.1

0

1.0

0.8

0.6

0.4

0.2

0

Time (months)

1

IC2/3 (n=100)

IC0/1 (n=211)

Imvigor 210: OS data from Atezolizumab in UBC

Oral presentation of Dr. D. Petrylak at 17th Annual Meeting of the Society of Urologic Oncology (SUO 2016) – November 30-December 2, 2016, San Antonio, TX

IMvigor211: A Phase III Randomized Study Examining Atezolizumab vs. Chemo for Platinum-Treated adv. UC

Powles T, et al. EAS 2017, IMvigor211

Key Eligibility Criteriaa

• mUC with progression during or

following platinum-based chemotherapy

– ≤ 2 prior lines of therapy

• Measurable disease per RECIST v1.1

• ECOG PS 0-1• Evaluable sample for PD-L1 testing

• TCC histology as primary component

(N = 931)

§ Primary endpoint

– OS, tested hierarchically

in pre-specified populations

Atezolizumab 1200 mg q3w

R

1:1No crossover permitted

per protocolSurvival

follow-up

Loss of clinical benefit

RECIST v1.1

progression

Stratification Factors• No. of risk factorsb (0 vs. 1/2/3)

• Liver metastases (yes vs. no)

• PD-L1 status (0/1 vs. 2/3)

• Chemotherapy (vinflunine vs. taxanes)

§ Additional endpoints

– Efficacy: RECIST v1.1 ORR, PFS and DORc

– Safety

– PROs: EORTC QLQ-C30

Chemotherapy (investigator ’s choice)

• Vinflunine q3w

• Docetaxel q3w

• Paclitaxel q3w

IMvigor211: OS Analysis in the Intention to Treat (ITT) Population

Powles T, et al. EAS 2017, IMvigor211 § Median follow-up duration in ITT population: 17.3 mo (range, 0 to 24.5 mo)

Events/Patients

Median OS(95% CI)

12-mo OS Rate(95% CI)

Atezolizumab 324/467 8.6 mo (7.8, 9.6) 39% (35, 44)

Chemotherapy 350/464 8.0 mo (7.2, 8.6) 32% (28, 37)80

60

0

10 12 14 16 18 202 4 6 80 2422

20

40

Ove

rall

Su

rviv

al

100

Months

80

60

0

10 12 14 16 18 202 4 6 80 2422

20

40

Ove

rall

Su

rviv

al

100

Months

HR = 0.85 (95% CI: 0.73, 0.99)

P = 0.038

No. at Risk

Atezolizumab 467 405 327 280 245 201 177 138 90 59 34 13 1

Chemotherapy 464 397 330 268 219 175 140 99 60 42 17 7 1

Key secondary endpoints: ORR, then PFS

Primary endpoint:

OS

OS: IC2/3

OS: IC1/2/3

OS: ITT

PFS: IC2/3

PFS: IC1/2/3

PFS: ITT

ORR: IC2/3

ORR: IC1/2/3

ORR: ITT

2-sided = 0.05

IMvigor211: Study Design


IMvigor211: OS Analysis in IC2/3 Population


HR = 0.87 (95% CI: 0.63, 1.21)

P = 0.41

Events/Patients

Median OS(95% CI)

12-mo OS Rate(95% CI)

Atezolizumab 72/116 11.1 mo (8.6, 15.5) 46% (37, 56)

Chemotherapy 88/118 10.6 mo (8.4, 12.2) 41% (32, 50)

No. at Risk

Atezolizumab 116 100 85 77 71 58 51 39 27 19 11 6 0

Chemotherapy 118 100 91 82 71 61 47 32 24 15 9 5 1

80

60

0

10 12 14 16 18 202 4 6 80 2422

20

40

Ove

rall S

urv

iva

l100

Months

Diferencia no significativa: no se alcanzó el objetivo primario del estudio.

IMvigor211: OS by Chemotherapy Type


§ OS was also examined in subgroups based on chemotherapy

type at randomization

– Improved OS was observed

with atezolizumab vs. taxanes

ITT With Taxane

SubgroupMedian OS

(95% CI)

Atezolizumab 9.2 mo (7.9, 10.4)

Vinflunine 8.3 mo (6.9, 9.6)

SubgroupMedian OS

(95% CI)

Atezolizumab 8.3 mo (6.6, 9.8)

Taxane 7.5 mo (6.7, 8.6)

No. at Risk

Atezolizumab 215 186 153 125 106 89 81 66 45 34 19 7 0

Taxane 214 179 147 122 94 74 58 35 20 16 4 3 1

80

60

0

10 12 14 16 18 202 4 6 80 2422

20

40

Ove

rall

Su

rviv

al

100

Months

No. at Risk

Atezolizumab 252 219 174 155 139 112 96 72 45 25 15 6 1

Vinflunine 250 218 183 146 125 101 82 64 20 26 13 4 0

80

60

0

10 12 14 16 18 202 4 6 80 2422

20

40

Ove

rall

Su

rviv

al

100

Months

HR = 0.97 (95% CI: 0.78, 1.19)

ITT With Vinflunine

HR = 0.73 (95% CI: 0.58, 0.92)

Resultados exploratorios al no haberse alcanzado el objetivo primario del estudio.

IMvigor211: Responses by PDL1 subgroup and Duration of Response


12 14

Months

Confirmed ORRa

IC2/3 IC1/2/3 ITT

Atezo (n = 113)

Chemo (n = 116)

Atezo (n = 312)

Chemo (n = 306)

Atezo (n = 462)

Chemo (n = 461)

Responders, n (%) 26 (23%) 25 (22%) 44 (14%) 45 (15%) 62 (13%) 62 (13%)

95% CI, % 16, 32 15, 30 10, 19 11, 19 11, 17 11, 17

CR, n (%) 8 (7%) 8 (7%) 11 (4%) 13 (4%) 16 (3%) 16 (3%)

§ Objective response was similar between arms

§ Responses to atezolizumab were durable

regardless of PD-L1 status

– 63% of patients in the

atezolizumab arm and

21% in the chemotherapy

arm had ongoing responses

at data cutoff

DOR in ITT Population

No. at Risk

Atezolizumab 62 61 56 50 42 35 23 14 9 5 2 0

Chemotherapy 62 62 59 40 28 23 16 8 5 4 0 0

Events/Patients mDOR (95% CI)

Atezolizumab 23/62 21.7 mo (13.0, 21.7)

Chemotherapy 49/62 7.4 mo (6.1, 10.3)

80

60

0

10 12 14 16 18 202 4 6 80 22

20

40O

bje

ctiv

e R

esp

on

se

100

Months

IMvigor211: Treatment Related Adverse Events


Treatment-Related AEs in ≥ 10% (All Grade) or ≥ 4% (Grades 3-4) for Either Arm

ChemotherapyAtezolizumab

Proportion of Patients (%)

30% 30%10%10% 0%40% 40%20%20%

■■ All Grade

■■ Grade 3-4

IMvigor211: Patient Related Outcomes


EORTC QLQ-C30 Scales: Change From C1D1

Better

Worse

Better

Worse

n = 385 329 254 223 201 162 157 144 122 107 105 91 91 84 79 73 72 67 69 65 56 46 38 32 25 22 19 16 13 10 9 8 4 1

n = 350 302 202 186 169 107 92 83 56 43 39 33 31 24 18 16 14 12 11 9 8 6 5 5 4 5 5 3 2 1 1 1 1

Cycle No.

n = 379 328 250 222 197 162 156 143 120 106 104 90 90 82 78 71 71 66 68 64 55 45 37 31 23 21 19 16 13 10 9 8 4 1

n = 349 299 203 185 169 106 90 82 55 42 38 32 30 24 17 15 13 12 11 9 8 6 5 5 4 5 5 3 2 1 1 1 1

What’s behind the curves?

Enrique Grande

• 64 y.o. male

• Cystectomy for Urothelial Bladder Carcinoma in 2011 pT2N0

• Lung and Lymph nodes mets. October 2014

• Cisplatin + Gemcitabine x 6 (ends April 2015)

• Liver, lung and lymph progression July 2015

• We recruited the patient for the IMvigor210 trial

July 2015

Sept 2015

Oct 2015


Enrique Grande

July 2015

Sept 2015

Oct 2015


Enrique Grande

Oct 2015

Sept 2015

July 2015



ESMO Guidelines for Metastatic Bladder Cancer

Adapted from Bellmunt J, et al. Ann Oncol 2014

Setting Treatment Level ofEvidence

First Line

Cisplatin +Gemcitabine IA

MVAC(methotrexate,vinblastine, adriamycinand

cisplatin)IA

Cisplatin +Gemcitabine +Paclitaxel IB

Carboplatin +Gemcitabine IA

M-CAVI(Methotrexate/carboplatin/vinblastin)orTaxane or Gemcitabine

IIA

Second Line Vinflunine IB

Fit

UnfitLonge

r-term

survival

Urothelial tract carcinoma: 1st Line Outcome

von der Maase, et al. J Clin Oncol 2005 De Santis, et al. J Clin Oncol 2012

Galsky, et al. Lancet Oncol 2011

‘Fit’ for Cisplatin Cisplatin ineligible (unfit)

Median OS 8.1m 9.3m

Treatment of Elderly or Unfit Patients with Urothelial Tumors: the Biggest Challenge and Opportunity

Bellmunt J, et al. Eur J Cancer 2016

Keynote 052: Pembrolizumab as First-Line Therapy in Cisplatin-ineligible Advanced Urothelial Cancer

Balar AV, et al. Lancet Oncol 2017



Imvigor 210: First-line Atezolizumab in Cisplatin-Ineligible Metastatic Urothelial Carcinoma (Cohort 1)


Imvigor 210 Cohort 1: Overall Response Rate


Imvigor 210 Cohort 1: Change in tumor burden in patients with objective response

Bellmunt J; et al. Poster presentation at NCRI 2016



NCCN Guidelines 2017 v.5

https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf


Enrique Grande

• 62 y.o male

• Morbid obesity

• DM type II under insulin treatment

• Renal impairment: creatinine clearance 43 ml/min

• Cystectomy due to uncontrolled bladder bleeding in July 2015

• Staging CT scan: liver and lymph nodes metastasis (Aug 2015)


Enrique Grande

Aug 2015


Enrique Grande

Aug 2015 Nov 2015


Enrique Grande

Aug 2015


Enrique Grande

Aug 2015 Nov 2015


Enrique Grande Aug 2015


Enrique Grande Aug 2015 Nov 2015

IMvigor 210 (Cohort 1): Monitoring of Renal Function in Patients Treated with Atezolizumab

Bellmunt J; et al. Poster presentation at NCRI 2016

Phase III: avelumab (EudraCT 2015-003262-86)

Phase II: regorafenib (NCT02459119)

Phase II: pembrolizumab

• Atezo + BCG

• Pembrolizumab

• Everolimus + intravesical GEM (NCT01259063)

Pembrolizumab + RT (NCT02560636)

PURE01: pembrolizumab>cystectomy (EudraCT: 2015-002055-10)

ABACUS: atezolizumab>cystectomy

Phase III: atezolizumab (NCT02450331)

Phase III: avelumab (EudraCT 2015-003262-86)

Phase III: nivolumab (CA209-274)

Neoadjuvant Adjuvant

BCG refractory

Phase II: KEYNOTE-052, pembrolizumab

(NCT02335424)

Phase III: KEYNOTE-045, pembrolizumab vs chemo

(NCT02256436)

Phase III: (GO29294), atezolizumab vs chemo, (NCT02302807)

Phase III: DANUBE: MEDI4736 vs MEDI4736 + tremelimumab vs chemo(NCT02516241)

Maintenance Tx

Refractory

Phase III: Ramucirumab + docetaxel

(NCT02426125)

Phase III: IMVIGOR 130: atezolizumab vs chemo + atezolizumab vs chemo

Phase III: MK3475-361: pembrolizumab vs chemo + pembrolizumab vs chemo

A continuous evolving field

Sources: http://ClinicalTrials.gov Usos experimentales, no autorizados.

This is a matter of opportunity

Rosemberg JE, et al. Lancet 2016 Bellmunt , et al. J Clin Oncol 2009


Time (months)

1.0

0.8

0.6

0

0.2

Ov

era

ll s

urv

iva

l (p

rob

ab

ilit

y)

VFL + BSC

BSC

0.4

2510 3530200 155


Time (months)

1.0

0.8

0.6

0

0.2

Ov

era

ll s

urv

iva

l (p

rob

ab

ilit

y)

VFL + BSC

BSC

0.4

2510 3530200 155

Median OS (ITT)


HR=0.88 (log rank p=0.2868)



HR=0.78 (log rank p=0.0403)

?

Conclusions and Remaining Challenges

• Atezolizumab, pembrolizumab and nivolumab are now approved by EMA for the

treatment of platinum-resistant urothelial carcinomas

• Atezolizumab and pembrolizumab are also approved but patients ‘unfit’ for

cisplatinum in 1st line

• Unfortunately, there’s a clear lack of reliable Biomarkers

• We still don’t know the future and synergy of novel combinations

o Chemo

o Other IOs like CTLA4, IDO1, LAG3, TIGIT, etc

o Targeted agents

• We need experience for the assessment of response/clinical benefit in daily practice

[email protected]

@drenriquegrande

Documents

Inmunoterapia: Presente y futuro. Cáncer de vejiga · Inmunoterapia: Presente y futuro. Cáncer de vejiga Enrique Grande Jefe de Servicio de Oncología Médica y Director de Investigación