integrating immunotherapy into management of advanced ... · – atezolizumab in platinum...

Integrating Immunotherapy into Management of Advanced Bladder Cancer Tian Zhang, MD Assistant Professor of Medicine Genitourinary Oncology Duke Cancer Institute March 10th, 2017

All Rights Reserved, Duke Medicine 2011

Disclosures

• Research Funding – Janssen – Pfizer

• Consultant – Acerta – G1 Therapeutics


Outline

• Approved systemic therapies in metastatic urothelial cancer

• Immunotherapies in urothelial cancer – Atezolizumab and nivolumab in platinum

refractory disease – Atezolizumab in platinum-ineligible first line

setting • PD-L1 as biomarker • Unanswered questions and ongoing trials


Evolution of Systemic Therapy for Urothelial Cancer

2017

/ Today

1997 1999 2001 2003 2005 2007 2009 2011 2013 2015

Docetaxel

Standard MVAC 1989

Gemcitabine + Cisplatin

Accelerated MVAC

Paclitaxel Vinflunine

Atezolizumab

Cisplatin USFDA

Approved 1978

Gemcitabine EMA Approved

Vinflunine EMA Approved

Atezolizumab USFDA Approved for post-platinum

advanced UC May 18, 2016

Durvalumab breakthrough

therapy designation Feb 17, 2016

Adapted from Elizabeth Plimack, ASCO 2016

Sternberg CN, Yagoda A, et al. Cancer 1989; 64(12): 2448-58. McCaffrey JA, et al. J Clin Oncol 1997; 15(5): 1853-7 von der Maase H, et al. J Clin Oncol 2005; 23(21): 4602-8. Sternberg CN, et al. J Clin Oncol 2001; 19(10): 2638-46. Vaughn DJ, et al. J Clin Oncol 2002; 20(4): 937-40. Bellmunt J, et al. J Clin Oncol 2009; 27(27): 4454-61. Rosenberg JE, et al. Lancet 2016. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. http://www.ema.europa.eu/ema/

Pub

licat

ion

Age

ncy

Act

ion

2017

Nivolumab Approval for

post-platinum advanced UC Feb 2, 2017


Chemotherapy for Bladder Cancer

Non-Muscle Invasive

Neoadjuvant Adjuvant

1st Line Metastatic

Next Line Metastatic

No systemic therapy

Gem + Cisplatin or A-MVAC (Cisplatin)

Gem + Cisplatin A-MVAC (Cisplatin) or Gem + Carbo

• Paclitaxel/Docetaxel • Vinflunine*

Cisplatin: ORR 50-60%

median OS 15 mo. 1 year OS 60%

Carboplatin ORR 36%


ORR: 12% Median OS 7 mo. 1 year OS 26%*

NCCN Guidelines. Bladder Cancer. Version 1.2016.



Integrated immunotherapy for urothelial cancer

Non-Muscle Invasive


1st Line Metastatic

2nd Line Metastatic


No systemic therapy



Atezolizumab Nivolumab

• Paclitaxel/Docetaxel • Vinflunine*

Cisplatin: ORR 50-60%


Carboplatin ORR 36%


ORR: 15% (atezo) 19.6% (nivo)

ORR: 12% ? Median OS 7 mo. ? 1 year OS 26%* ?



PD-1/PD-L1 inhibitors

MPDL3280A/Atezolizumab (Genentech) – Durvalumab (MedImmune/AZ) – Avelumab (Pfizer)

Nivolumab (BMS) Pembrolizumab (Merck) Pidilizumab (CureTech)


Atezolizumab Phase 2 Baseline characteristics

Characteristic Atezolizumab

(N=310) Median age, years (range) 66 (32‒91) Male, % 78% Race, Caucasian % 92% Site of primary, %

Bladder 74% Renal pelvis 14%

Ureter 7% Urethra 2% ECOG PS

0 38% 1 62%

# previous systemic regimens in metastatic setting 0 19% 1 40% 2 21% Previous platinum-based regimen

Cisplatin-based 73% Carboplatin-based 26% Neoadjuvant/adjuvant chemo 18%

Rosenberg JE et al, Lancet, 2016, 387:1909-20


Atezolizumab Phase 2 Overall response rate



Atezolizumab Phase 2


310 patients Single arm study Analyzed PD-L1 status on TILs

Primary endpoint: ORR Secondary endpoints: Duration of response, PFS, OS, safety

Median OS: 7.9 months (95% CI 6.6-9.3)


Atezolizumab Phase 2 Response by CD8% and TCGA type



150 samples with mutation analysis Subtyped into TCGA clusters Grouped by CR/PR vs SD/PD

Atezolizumab Phase 2 Response by mutational burden



Nivolumab phase 2 Checkmate 275

Sharma P et al, Lancet Oncol, 2017, Epub

Primary endpoint: Overall response in all and in PD-L1 positive patients Secondary endpoints: PFS, OS


Nivolumab phase 2 Checkmate 275

Sharma P et al, Lancet Oncol, 2017, Epub


0%

10%

20%

30%

40%

50%

60%

Phase I Basket Studies

Nivolumab Phase II n=270

Atezolizumab N=87

Avelumab n=44

Durvalumab n=42

Nivolumab n=78

Pembrolizumab n=29

Overall Response Rates: Post-Platinum

Historical Control w Chemo ~ 12%

Rosenberg Lancet 2016 Sharma Lancet Oncol 2017 Powles Nature 2014 Apolo GUASCO 2016 Massard ASCO 2016 Sharma ASCO 2016 Plimack ASCO 2015

Atezolizumab Phase II n=310


Drug Antibody Target Setting Phase Total n

Atezolizumab humanized IgG1 PD-L1 First line

cis-ineligible Phase II 119

Atezolizumab humanized IgG1 PD-L1 Post platinum Phase II 310

Nivolumab human IgG4 PD-1 Post platinum Phase I

basket 78

Nivolumab Human IgG4 PD-1 Post platinum Phase II 270

Durvalumab Human IgG1 PD-L1 Post platinum Phase I

basket 42

Is Earlier Better? Single arm, single agent PD1 pathway inhibitors



IMvigor210 Atezolizumab Platinum ineligible

Balar AJ et al, Lancet, 2017, 389: 67-76

Primary endpoint: Objective response rate Secondary endpoints: Duration of response PFS, OS


22




24






Adverse event Any grade (n=119)

Grade 3-4 (n=119)

Overall 66% 16% Fatigue 30% 3% Diarrhea 12% 2% Pruritus 11% 1%

Decreased appetite 9% 1% Hypothyroidism 7% --

Anemia 5% 1% Rash 5% 1%

ALT increased 4% 3% AST increased 3% 3%

Total bilirubin increased 3% 2%


Frontline Therapy for UC: Cis-Ineligible

ORR: 36%

mOS:

9.3 mo.

1-year OS: 37%

5-year OS:

~ 0

ORR: 23%

mOS:

15.9 mo.

1-year OS: 57%

5-year OS:

?

All Patients (N = 119)

ORRa (95% CI) 23% (16, 32)

CR 9%

PR 13%

Gem Carbo Atezolizumab

Balar A, et al. IMvigor210. Lancet 2017.



Challenge of PD-L1 assays

NSCLC: Comparison of Dako 28-8 & Ventana SP263 showed 96% concordance (91% for positive and 98% for negative)

Hansen AR & Siu LL, JAMA Oncol, 2016 Ratcliffe MJ et al, Proceedings of 107th AACR Annual Meeting


PD-L1 Status as Biomarker

Author Phase Drug Setting Total n Definition of PDL1 +

% of patients PDL1 "high" or

"positive"

ORR in favorable biomarker group ORR - all

Balar Lancet 2017 II Atezolizumab First line cis

ineligible 119 IC 2/3 27% 28% 23%

Rosenberg Lancet Oncol 2016

II Atezolizumab Post platinum 310 IC 2/3 32% 28% 16%

Sharma ASCO 16 I basket Nivolumab Post platinum 78 >=1% TC 37% 24% 24%

Massard ASCO 16 I basket Durvalumab Post platinum 42 >25% in TC or IC 67% 46% 31%

Plimack ASCO 15 I basket Pembrolizumab Post platinum 29 ≥1% tumor or stroma 100% 28% 28%

Apolo GUASCO 2016 I basket Avelumab Post platinum 44 ≥5% tumor cells* 16% 40% 16%

Petrylak ASCO 15 I basket Atezolizumab pre/post

platinum 87 IC 2/3 45% 50% 34%



PD-L1 Testing (IC 2/3 vs. 1/2) Loses Ability to Enrich for Response Across Atezolizumab Studies

Res

pons

e R

ate

0%

10%

20%

30%

40%

50%

60%

Phase IPetrylak ASCO 15

Phase II Post PlatinumDreicer ASCO 16

Phase II First lineBalar ASCO 16

PDL1 "high" (IC 2/3)PDL1 "low" (IC 0/1)

Relevance of a dynamic marker in archival tissue? Adapted from Elizabeth Plimack, ASCO 2016


Novel Biomarkers: Beyond PD1

Early data suggests the following may enrich for response to PD1 pathway inhibition: •Higher mutational load •TCGA Subtype (Luminal II) •CD8 infiltration •Immune related gene expression signatures (Nanostring) •Peripheral expansion of certain TCR clones


PD-1 Pathway Inhibitors: Progression after Response Seems to Occur Outside of Target Lesions

Time on Study, Weeks

Cha

nge

in S

LD

from

Bas

elin

e, %

0

100

–100 0 18 36 54 72 90

ATEZOLIZUMAB Post Platinum Patients With CR or PR

ATEZOLIZUMAB First Line NIVOLUMAB

DURVALUMAB

First occurrence of new lesion Occurrence of CR or PR

Non-responder Responder



Chemotherapy/Targeted Therapy: Progression After Response Commonly Occurs in Target Lesions

Cha

nge

From

Bas

elin

e %

Data from paclitaxel + cetuximab responders (Wong et al. Phase II trial of cetuximab with or without paclitaxel in patients with advanced urothelial tract carcinoma. JCO 2012)

-1

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

00 20 40 60 80 100 120

PD with new lesion only

CR

PD with new lesion only

CR

PD in target lesions




Time (weeks)



What is the optimal duration of therapy?

Author Phase Drug Setting Total n TBP allowed

Maximum treatment

duration on study

Balar ASCO 16 II Atezolizumab First line cis

ineligible 119 no indefinite

Dreicer ASCO 16 II Atezolizumab Post platinum 310 yes indefinite

Sharma ASCO 16 I basket Nivolumab Post platinum 78 yes indefinite

Massard ASCO 16 I basket Durvalumab Post platinum 42 yes 1 year*

Plimack ASCO 15 I basket Pembrolizumab Post platinum 29 yes 2 years*

Apolo GUASCO 2016 I basket Avelumab Post platinum 44 no indefinite

Petrylak ASCO 15 I basket Atezolizumab pre/post platinum 87 yes 1 year*

* Retreatment permitted if PD after cessation Balar ASCO 2016 #4500, Dreicer ASCO 2016 #4515, Petrylak ASCO 2015, Apolo GU ASCO 2016, Massard #4502 ASCO 2016, Sharma #4501 ASCO 2016, Plimack ASCO 2015


Unanswered questions


Can Response be Maintained Off Therapy?

Sharma P, et al. CheckMate 032 : Nivolumab monotherapy in metastatic urothelial cancer. ASCO 2016


Unanswered questions


Future development of PD1 inhibitors in UC

1st l

ine Low grade High grade

In development

BCG-unresponsive

Pembrolizumab


Trimodality

Cisplatin-eligible

Maintenance

Cisplatin-ineligible

Platinum-refractory

Pembrolizumab

Pembrolizumab (Ph III vs chemo) Atezolizumab (Ph III vs chemo)

Pembrolizumab + acalabrutinib (Ph II) Schema adapted from: Fakhrejahani F et al. Curr Opin Urol 2015

Atezolizumab Ph III

Nivolumab Ph III

Avelumab (Ph III) Pembrolizumab

Durvalumab + Tremelimumab (Ph III)

Pembrolizumab + RT

Atezolizumab

Pembro + Chemo

Nivo + Urelumab

Non-muscle-invasive bladder

cancer

Muscle-invasive bladder cancer

Metastatic urothelial cancer

2nd l

ine

and

beyo

nd

Pembrolizumab + BCG



Improving immunotherapy

• 15-25% overall response rate in early clinical trials. – Quick and durable responses: rare patients respond

for >1 year on PD-1 inhibitors • What about the other 75%? • Can we improve these immunotherapy strategies?

• Other strategies for T cell activation?

– Inhibiting Myeloid-Derived Suppressor Cells (MDSC) • Acalabrutinib (ACP-196):

– BTK inhibitor, potential MDSC inhibitor


RAPID CHECK study

Key criteria: • Metastatic urothelial carcinoma • Pathology-proven • Progression on or after platinum-based chemotherapy • Radiographically measurable disease • ECOG PS 0-1 • Adequate organ/marrow function

• No prior exposure to PD-1, PD-L1 or CTLA-4 inhibition

R A N D O M I Z E

Pembrolizumab 200mg IV every 3 weeks

+ acalabrutinib 100mg PO BID

Pembrolizumab 200mg IV every 3 weeks

DISEASE

PROGRESSION

Add ACP-196

STOP

Primary endpoints: Overall response rate Safety of combination

Secondary endpoints: PFS and OS

Multicenter study Enrolled 78 patients between May 2015 and Jan 2016 Expect results later this year


A new space: Post PD1 pathway inhibition Non-Muscle Invasive


1st Line Metastatic

2nd Line Metastatic


No systemic therapy



Atezolizumab Nivolumab

• Paclitaxel/Docetaxel? • Vinflunine? • Combination immunotherapy? • Clinical trials needed!!



Conclusions

• Metastatic urothelial cancer can be treated by inhibiting the PD1 pathway, with favorable response rates, survival and toxicity.

• Atezolizumab and nivolumab now approved for treatment in the post-platinum setting

• Atezolizumab has promising data in platinum-ineligible patients as first-line therapy

• Data thus far does not support PD-L1 staining as a useful biomarker for treatment selection.

• All trials have been single arm phase I/II. Randomized phase 3 trials are ongoing. Unanswered questions: – Are patterns of response or progression different with

immunotherapy vs. chemotherapy? – Optimal duration of therapy?

• Unmet needs include better biomarkers and clinical trials after checkpoint blockade


Acknowledgments

• GU Oncology team Urology team – Dan George - Mike Ferrandino – Andy Armstrong - Brant Inman – Mike Harrison - Judd Moul – Megan McNamara - Tom Polascik

- Ed Rampersaud • Tumor immunology

– Kent Weinhold

integrating immunotherapy into management of advanced ... · – atezolizumab in platinum...

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