01%$2*)%' 3%).'45676'' - oncoconferences.ch · – Does not kill tumor cells directly, but rather,...

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•  63yearoldwhitefemale•  ECOGPS0•  Adenocarcinoma,noEGFR,BRAF,HER2,KRAS,NRAS,ALKalteraVon;T4N3M1b(mediasVnallymphnodes,boneandretroperitonealmets)diagnosedinJanuary2013.

•  4linesofsystemictherapy(carbo/pemetrexed&maintenance,taxotere,gemzar/vinorelbine)anderloVnib.

•  Pulmonary,adrenal,boneandnodalprogressioninApril2014

Casepresenta8on

April2014 August2014

PD-1directedtherapy

Pulmonary,adrenalandboneprogressioninApril2015=1yearaGerbeginning

June2015:onsetofboneradiotherapyandongoingimmunotherapyNewbrainlesions,pulmonaryembolism.Death08/15

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1°endpoint irPFSOther PFS,BORR,irBORR,OS,safety

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CA184-104: Randomized, Multicenter, Double-Blind, Phase 3 Trial Comparing the Efficacy of Ipilimumab with Paclitaxel/Carboplatin versus Placebo with Paclitaxel/Carboplatin in Patients with Stage IV/Recurrent Non-Small Cell Lung Cancer of Squamous Histology

Background • Years of research in advanced non-small cell lung cancer (NSCLC) have

not improved outcomes for the squamous cell subtype beyond those of standard platinum doublets

• Increasing evidence of responses to immune therapies in NSCLC of squamous cell histology support continued clinical development of immunotherapy in this subtype

• Ipilimumab – A fully human, IgG1 monoclonal antibody which blocks cytotoxic T-

lymphocyte antigen-4 (CTLA-4) and augments antitumor T-cell responses

– CTLA-4 is a negative regulator of T-cell activation – Blockade of CTLA-4 on T cells—which allows CD28 to interact with

B7—can augment T-cell activation, proliferation, and infiltration into tumors, leading to cell death1 (Figure 1)

– Does not kill tumor cells directly, but rather, causes tumor cell death indirectly via activated T cells

• Ipilimumab in metastatic melanoma – Demonstrated overall survival (OS) benefit in two phase 3 trials for

advanced melanoma1-3

– Manageable adverse event (AE) profile using product-specific guidelines1,3

– Approved in many countries at a dose of 3 mg/kg for treatment of patients with unresectable or metastatic melanoma3+reference ex-US labels

~254 sites in 35 countries

53E

CA184-104* trial design and endpoints • Randomized, double-blind, phase 3 trial (Table 1)

• Patients with Stage IV or recurrent†/squamous NSCLC

• Phased schedule of first-line P (175 mg/m2 q3w x 2) / C (AUC = 6 q3w x 2) followed by ipilimumab (10 mg/kg q3w x 4 � q12w) and P (175 mg/m2 q3w x 4) / C (AUC = 6 q3w x 4) vs placebo plus PC

CT = paclitaxel (175 mg/m2) plus carboplatin (AUC = 6) or carboplatin (AUC 5); Ipi = ipilimumab (10 mg/kg)

CA184-104 inclusion and exclusion criteria • Patient population: Stage IV or recurrent†/squamous NSCLC (Tables 2a and 2b)

– Per the 7th edition of the TNM classification of malignant tumors, Stage IV NSCLC is classified as any T, any N, and M1

– Diagnosis of squamous NSCLC was histologically or cytologically confirmed from brushing, washing or needle aspiration of a defined lesion, but not from sputum cytology alone

• Targeted enrollment: 920 patients

• Argentina • Australia • Austria • Belgium • Brazil • Canada • Chile • Colombia • Czech

Republic • Denmark • France • Germany

• Hong Kong • Hungary • Ireland • Israel • Italy • Korea • Mexico • Netherlands • Peru • Poland • Portugal • Romania • Russian

Federation

Table 2a. Inclusion criteria

Squamous cell NSCLC

Stage IV or recurrent† NSCLC

ECOG Performance Score of 0 or 1

Table 2b. Exclusion criteria

Brain metastases

Autoimmune disease

Presented at the American Society of Clinical Oncology 2012 Annual Meeting, June 1–5, 2012; Chicago, IL, USA

• Singapore • South Africa • Spain • Sweden • Switzerland • Taiwan • Thailand • Turkey • United

Kingdom • United States

CA184-104 study design • Induction phase

– Two cycles of chemotherapy (PC; paclitaxel [175 mg/m2] plus carboplatin [AUC = 6], followed by PC plus ipilimumab (10 mg/kg) or PC plus placebo every 3 weeks

� 4 cycles of ipilimumab or placebo

� Up to 6 total cycles of PC

– Randomized 1:1 PC/ipilimumab or PC/placebo

• Maintenance phase

– Patients without progressive disease after the induction phase offered ipilimumab (10 mg/kg) or placebo q12w starting at Week 25 until progressive disease, per mWHO

Current as of April 11, 2012 (www.clinicaltrials.gov)

Treatment stopping criteria • Unacceptable toxicity

• Clinical deterioration

• Confirmed disease progression

References 1. Hodi FS, et al. N Engl J Med. 2010;363:711–23. 2. Robert C, et al. N Engl J Med. 2011;364:2517–25. 3. YERVOY™ (ipilimumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2011. 4. Fong L, et al. J Clin Oncol. 2008;26:5275–83. 5. Lynch T, et al. Presented at the 2010 European Society for Clinical Oncology Annual Meeting;

October 8–12, 2010; Milan, Italy. Abstract 375PD. 6. Lynch T, et al. Presented at the 2011 World Congress for Lung Cancer; July 3–7, 2011;

Amsterdam, Netherlands. Abstract 701. 7. Reck M, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in

extensive-disease small cell lung cancer: results from a phase II trial. Presented at the 2011 World Congress of Lung Cancer; July 3–7; Amsterdam, Netherlands. Abstract 1365.

8. Hoos A, et al. Semin Oncol. 2010;37:533–546. 9. Wolchok JD, et al. Clin Cancer Res. 2009;15:7412–7420. 10.Eisenhauer EA, et al. Eur J Cancer. 2009;45:228–247. 11. Miller AB, et al. Cancer. 1981;47:207–214.

Martin Reck,1 Haolan Lu,2 Greta Gribkoff,2 Sabine Maier,2 Rachel McGovern,2 Jean-Marie Cuillerot,2 Thomas Lynch3

1Hospital Grosshansdorf, Grosshansdorf, Germany; 2Bristol-Myers Squibb Company, Wallingford, CT, USA; 3Yale Cancer Center and Smilow Cancer Hospital, New Haven, CT, USA

Acknowledgments • The patients and their families • The study sites enrolling patients to the trial • StemScientific, for providing support services for writing, editorial, studio, and production; funded by Bristol-Myers

Squibb

Clinical support • Prior data from a phase 2 study in advanced NSCLC and extensive-disease

small cell lung cancer (CA184-041)5-7 showed activity of ipilimumab and support ongoing phase 3 (CA184-104) evaluation in squamous NSCLC

– CA184-041 utilized a phased schedule of ipilimumab and paclitaxel/carboplatin (PC) (ipilimumab started after 2 cycles of PC)

– Study endpoints were assessed using both modified WHO (mWHO) and immune-related response criteria (irRC)

� irRC evolved from WHO criteria to capture outcomes of patients treated with ipilimumab1,8-11

– Primary endpoint, immune-related progression-free survival (irPFS), was met for phased ipilimumab administration in patients with NSCLC

� Addition of ipilimumab to PC significantly prolonged irPFS, but not mWHO-PFS

� Clinically relevant prolongation of OS with addition of ipilimumab

� Activity appeared to be most pronounced in patients whose NSCLC was of squamous histology

– Addition of ipilimumab did not worsen toxicity associated with PC, and irAEs were managed using protocol-specific guidelines

– Absolute lymphocyte count was not affected by PC, suggesting that PC has no effect on ipilimumab activity

Mechanism of action

Table 1. Endpoints‡ Primary outcome measure:

OS§,ll

Secondary outcome measures: OS in patients who receive at least one dose of blinded study drug

PFS (mWHO)

Best Overall Response Rate (mWHO)

!"

Ipilimumab 10 mg/kg every 12 wks

Placebo every 12 wks

Tumor assessment: Every 12 weeks

Randomization to Wk 24

NSCLC stage IV

squamous PS ��

SCREENING INDUCTION MAINTENANCE FOLLOW-UP

Day -28 to randomization

2 cycles PC Wks 1, 4

Ipilimumab 10 mg/kg + PC Wks 7, 10, 13, 16

Placebo + PC Wks 7, 10, 13, 16

Tumor assessment: Wks 7, 13, 19, and 25

Wk 25*

Follow-up every 12 wks for survival

CA184-104 study design: treatment flow

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Figure 1. Mechanism of action for ipilimumab

A, co-stimulation via CD28 ligation transduces T-cell activating signals; B, CTLA-4 ligation on activated T cells downregulates T-cell responses; C, blocking CTLA-4 ligation enhances T-cell responses4

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ECOG = Eastern Cooperative Oncology Group; TNM = tumor, node, and metastasis; M1 = distant metastasis

* Further information on enrolling in this trial and participating study sites is available on www.clinicaltrials.gov, identifier: NCT01285609.

† Recurrent disease after patient received curative surgery. ‡ Exploratory endpoints included immune-related PFS, best overall response, and disease-control rate.

§ Assessed until 705 death events have occurred; an interim analysis at 528 events is planned. ll705 events out of 920 randomized patients will be needed to ensure 90% power to detect a statistically significant difference in OS between treatment arms with a Type I error rate of 5% based on a 2-sided log-rank test.

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ClinicalDevelopmentofInhibitorsofPD-1ImmuneCheckpoint

PD-1 NivolumabBMS-936558

FullyhumanIgG4mAb Bristol-MyersSquibb PhaseIII

PidilizumabCT-011

HumanizedIgG1mAb CureTech PhaseII

PembrolizumabMK-3475

HumanizedIgG4mAb Merck PhaseIII

AMP-224 RecombinantPD-L2-Fcfusionprotein

GlaxoSmithKline PhaseI

PD-L1 BMS-936559 FullyhumanIgG4mAb Bristol-MyersSquibb PhaseII

DurvalumabMedI-4736

EngineeredhumanIgG1mAb

MedImmune PhaseIII

AtezolizumabMPDL-3280A


Genentech PhaseIII

AvelumabMSB0010718C


EMDSerono PhaseIII

PD-1axisimmunotherapyforNSCLC

1.  Alookatdatafromearlytrials

2.  Evidence-baseddataforan8-PD-1monotherapy

3.  Currentevidenceforbiomarker-basedselec8on

4.  Upfrontperspec8vesforan8-PD-1therapy

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PrimaryObjec8ve• Overallsurvival(OS)SecondaryObjec8ves• ORR• PFS• ORRandOSbyPD-L1status• Dura8onofOR• TimetoOR• Propor8onofpa8entsexhibi8ngdisease-relatedsymptomprogression(LungCancerSymptomScale)

Docetaxel

Nivolumab

Docetaxel

Nivolumab

CA209-017NCT01642004

(Phase3;N=264)

PaVentswithstageIIIb/IVsquamous

cellNSCLC

CA209-057NCT01673867

(Phase3;N=574)

PaVentswithstageIIIb/IVnon-squamouscell

NSCLC

NivolumabphaseIIItrial

Squamous&non-squamous-2ndlinevsdocetaxel

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Docetaxel 18-month OS rate=13%

OS

(%)

Time (months)

0 6 14 25 37 51 57 69 86 113 135 0 Nivolumab Number of Patients at Risk

0 4 7 11 17 22 33 46 69 104 137 Docetaxel 1

Nivolumab 18-month OS rate=28%

100 90 80 70 60 50 40 30

10 0

20

33 27 24 21 18 15 12 9 6 3 0 30

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10 0

20

27 18 15 9 6 21 12 3 0 24 30

Nivolumab Docetaxel

Number of patients at risk (18-mo OS)b 292 233 195 171 148 128 107 55 4 27 290 244 194 150 111 89 61 23 4

0 0 6

Nivolumab Docetaxel

Nivolumab Docetaxel

Number of patients at risk (12-mo OS)a 292 232 194 169 146 123 62 32 0 9 290 244 194 150 111 88 34 10 0 5

18-mo OS rate = 23%

18-mo OS rate = 39%

1-yr OS rate = 39%

1-yr OS rate = 51%

Time (Months)

OS

(%)

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Areweeverreadytoselectpa8ents?

ComplexityofimmunesurveillanceandescapemightpreventusfromidenFfyingasimple&uniquepredicFvebiomarker.

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BIRCH:AtezolizumabinPD-L1+pa8ents

Besse,ESMO2015

0

10

20

30

1L 2L 3L+

26% 24%

27%

19% 17% 17%

TC2/3 or IC2/3 TC3 or IC3

OR

R, %

N=115 N=253 N=267 N=139 N=65 N=122

BIRCH:ObjecFveResponseRateTC3orIC3SubgroupvsTC2/3orIC2/3SubgroupbyCohort

PhaseIIItrialsin1st-lineadvancedNSCLC(selected)

Nivolumab

Pembrolizumab

MEDI4736

SOC=standard of care. ClinicalTrials.gov. http://www.clinicaltrials.gov/. Accessed August 2015.

KEYNOTE-042 Pembrolizumab

SOC chemotherapy Primary endpoint: OS PD-L1+ NSCLC

N = 1240

Primary endpoints: OS, PFS

Treatment-naïve or recurrent NSCLC N = 1980 CheckMate 227

Nivolumab

Nivolumab + ipilimumab

Platinum-based chemotherapy

Primary endpoint: PFS Treatment-naïve or recurrent PD-L1+ NSCLC N = 535 CheckMate 026

Nivolumab

Investigator’s choice chemotherapy

KEYNOTE-024 Pembrolizumab

Platinum-based chemotherapy Primary endpoint: PFS PD-L1 strong NSCLC

N = 300

Atezolizumab

IMpower 111 Atezolizumab

Gemcitabine + cisplatin or carboplatin Primary endpoint: PFS Stage IV squamous PD-L1+ NSCLC

N = 400

IMpower 150

Atezolizumab + carboplatin + paclitaxel

Bevacizumab + paclitaxel + carboplatin

Primary endpoint: PFS Stage IV non-squamous NSCLC N = 1200 Atezolizumab + bev. + paclitaxel + carboplatin

IMpower 130 Atezolizumab + carboplatin + nab-paclitaxel

Carboplatin + nab-paclitaxel Primary endpoint: PFS Stage IV non-squamous NSCLC

N = 550

IMpower 110 Atezolizumab

Carboplatin or carboplatin + pemetrexed Primary endpoint: PFS Stage IV non-squamous PD-L1+ NSCLC

N = 400

IMpower 131

Atezolizumab + carboplatin + nab-paclitaxel

Carboplatin + nab-paclitaxel

Primary endpoint: PFS Stage IV squamous NSCLC N = 1200 Atezolizumab + carboplatin + paclitaxel

Primary endpoint: PFS Advanced NSCLC N = 675

MYSTIC

MEDI4736

MEDI4736 + tremelimumab

SOC chemotherapy

IPI + Paclitaxel/Carboplatinà IPI

Pbo + Paclitaxel/Carboplatin à Pbo Primary endpoint: OS Squamous NSCLC

N = 920 CA184-104

IPI + Paclitaxel/Carboplatinà IPI

Pbo+ Paclitaxel/Carboplatin à Pbo Primary endpoint: OS Squamous NSCLC

N = 867 CA184-153

Ipilimumab

Ant

i-PD

-1/P

D-L

1 A

nti-

CTL

A-4

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TumorImmuneProfiletounderstandtheimmunemodeofac8onofPD-1/PD-L1blockade

•  Serialon-treatmentbiopsies•  Neoadjuvanttrials(worldwide)

•  DurvalumabinNSCLCstageIIIA(SAKK16/14)•  mRNAvaccineinresectableNSCLC(Basel)•  NivolumabinStageII-IVRCC•  PembrolizumabinTNBC•  PembrolizumabinStageIII/IVmelanoma•  Pembrolizumabinrectalcancer

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TakeHomeMessages

•  RemarkablyexciVngandeffecVvedrugs!

•  IsitrighttoexcludePD-L1negaVvepaVents?

•  Biomarker–complex,needsmoreresearch

•  Datafromlargephase3studiesareawaited

•  CureinNSCLC–haveprogressed,butnotthereyet!

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01%$2*)%' 3%).'45676'' - oncoconferences.ch · – Does not kill tumor cells directly, but rather,...

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