mariano provencio hospital universitario puerta de hierro- … · 2019. 7. 16. · título de...

InmunoterapiaMariano Provencio

Hospital Universitario Puerta de Hierro-Madrid

InmunoterapiaMariano Provencio

Hospital Universitario Puerta de Hierro-Majadahonda

• Longer follow-up results

•Check-points inhibitors in first line

•Practical approach

Título de diapositivaSubítulo de diapositiva



•/CT

Phase 3, Global, Randomized Trial (CheckMate 017) of Nivolumab vs Docetaxel

in Advanced Squamous (SQ) Cell Non-Small Cell Lung Cancer (NSCLC)

Karen Reckamp,1 David R. Spigel,2 Naiyer Rizvi,3 Elena Poddubskaya,4 Howard West,5

Wilfried Ernst Erich Eberhardt,6 Paul Baas,7 Scott J. Antonia,8 Adam Pluzanski,9 Everett E. Vokes,10

Esther Holgado,11 David Waterhouse,12 Neal Ready,13 Justin Gainor,14 Osvaldo Arén Frontera,15

Leora Horn,16 Luis Paz-Ares,17 Ang Li,18 Mark Lynch,18 Julie Brahmer19

1City of Hope Comprehensive Cancer Center, Duarte, CA, USA; 2Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA; 3Memorial Sloan Kettering Cancer Center, New York, NY, USA; 4N.N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation; 5Swedish Cancer Institute, Seattle, WA, USA; 6University Hospital Essen, West German Cancer Centre, Ruhrlandklinik, University Duisburg-Essen, Essen, Germany; 7The Netherlands Cancer Institute, Netherlands; 8H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA; 9Centrum Onkologii, Instytut Im. Marii

Sklodowskiej-Curie, Warsaw, Poland; 10University of Chicago Medicine & Biological Sciences, Chicago, IL, USA; 11Hospital De Madrid, Norte Sanchinarro, Spain; 12Oncology Hematology Care, Cincinnati, OH, USA; 13Duke University Medical Center, Durham, NC, USA; 14Massachusetts General Hospital, Boston, MA, USA; 15Centro Internacional de Estudios Clinicos, Santiago, Chile; 16Vanderbilt University Medical

Center, Nashville, TN, USA; 17Hospital Universitario Virgen Del Rocio, Seville, Spain; 18Bristol-Myers Squibb, Princeton, NJ, USA; 19The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

CheckMate 017 (NCT01642004) — Study Design

• Updated safety and longer-term survival (18 months) are reported here• At the time of analysis, 13% of patients in the nivolumab arm were continuing treatment vs no patients in the docetaxel arm

5aUpdated based on August 2015 database lock (DBL). bUpdated based on June 2015 DBL

Stage IIIb/IV SQ NSCLC1 prior PT-DC, ECOG PS 0–1, pretreatment (archival or fresh) tumor samples required for PD-L1 analysis

N=272

Nivolumab3 mg/kg IV Q2W

n=135Until PD or unacceptable toxicity

Docetaxel75 mg/m2 IV Q3W

n=137Until PD or unacceptable toxicity

Primary endpoint: OSa

Additional endpoints: ORR (investigator-assessed), PFSa (investigator-assessed), correlation between PD-L1 expression and efficacy, safety,b quality of life (LCSS)

Randomize1: 1

Stratification factors: region, prior

paclitaxel use

Updated Overall Survival

6

Nivolumabn=135

Docetaxel n=137

mOS, mos(95% CI)

9.2(7.33, 12.62)

6.0(5.29, 7.39)

# events 103 122

HR=0.62 (0.48, 0.81); P=0.0004

0614253751576986113135 0NivolumabNumber of Patients at Risk

037111722334669104137Docetaxel 1

Docetaxel18-month OS rate=13%

OS

(%)

Time (mos)

Nivolumab18-month OS rate=28%

100

90

80

70

60

50

40

30

10

0

20

332724211815129630 30

Based on August 2015 DBL.Symbols refer to censored observations.

12-month OS rate=42%

12-month OS rate=24%

Minimum follow-up for survival: 18 months


CheckMate 017

Treatment Effect on OS Across Predefined Subgroups

7

NUnstratified HR (95%

CI)Overall 272 0.59 (0.44, 0.78)Prior paclitaxel vs other prior treatment

Prior paclitaxel 92 0.51 (0.31, 0.83)Another agent 180 0.63 (0.45, 0.90)

RegionUS/Canada 86 0.59 (0.36, 0.98)Europe 155 0.50 (0.34, 0.72)Rest of world 31 1.50 (0.65, 3.60)

Age<65 yrs 152 0.52 (0.35, 0.75)≥65 and <75 yrs 91 0.56 (0.34, 0.91)≥75 yrs 29 1.90 (0.76, 4.50)

ECOG PS0 64 0.48 (0.24, 0.99)1 206 0.54 (0.39, 0.74)

Time from completion of most recent regimen to randomization<3 mos 123 0.56 (0.37, 0.85)3–6 mos 75 0.54 (0.31, 0.95)>6 mos 72 0.64 (0.37, 1.13)

CNS metastasesNo 255 0.60 (0.45, 0.80)

Smoking statusCurrent/Former smoker 250 0.59 (0.44, 0.80)

0 1 2

HR not computed for subset category with <10 patients per treatment group

Nivolumab Docetaxel

CheckMate 017

Updated Progression-free Survival

8

Docetaxel18-month PFS rate=2.7%

PFS

(%)

Time (mos)

2812162024334868135 0NivolumabNumber of Patients at Risk

001138102762137Docetaxel 0

Nivolumab18-month PFS rate=17%

0

100

90

80

70

60

50

40

30

10

20

302724211815129630


Minimum follow-up for survival: 18 months

Nivolumabn=135

Docetaxel n=137

mPFS, mos(95% CI)

3.5(2.14, 5.06)

2.8(2.14, 3.52)

# events 105 122

HR=0.63 (0.48, 0.83); P=0.0008

12-month PFS rate=6.4%

12-month PFS rate=21%

CheckMate 017)

Survival Benefit By PD-L1 Expression

9

PD-L1Expression

Patients, n Unstratified HR (95% Cl)

InteractionP-valueNivoluma

b DocetaxelOS

<1% 54 52 0.58 (0.37, 0.92) 0.56≥1% 63 56 0.69 (0.45, 1.05)<5% 75 69 0.70 (0.47, 1.02) 0.47≥5% 42 39 0.53 (0.31, 0.89)<10% 81 75 0.70 (0.48, 1.01) 0.41≥10% 36 33 0.50 (0.28, 0.89)Not quantifiable 18 29 0.39 (0.19, 0.82)

PFS<1% 54 52 0.66 (0.43, 1.00) 0.70≥1% 63 56 0.67 (0.44, 1.01)<5% 75 69 0.75 (0.52, 1.08) 0.16≥5% 42 39 0.54 (0.32, 0.90)<10% 81 75 0.70 (0.49, 0.99) 0.35≥10% 36 33 0.58 (0.33, 1.02)Not quantifiable 18 29 0.45 (0.23, 0.89)

83% of patients (225/272) had quantifiable PD-L1 expressionBased on December 2014 DBL

PD-L1 negative expression

PD-L1 positive expression

Not quantifiable

0 1 2Nivolumab Docetaxel

• Nivolumab benefit was independent of PD-L1 expressionCheckMate 017

Time to Onset of First Treatment-relatedSelect AE With Nivolumab by Category (Any Grade)

10

Pts still on study, n 131 112 85 52Pts still on treatment, n 131 73 51 25Total pts with first event,a n 24 6 2 1

• The majority of patients who experienced treatment-related select AEs with nivolumab experienced their first event within the first 3 months of treatment

Select AEs: AEs with potential immunologic etiology that require frequent monitoring/intervention.Based on December 2014 DBL. Includes events reported between first dose and 30 days after last dose of study therapy. Within each time interval, patients with ≥1 event were counted only once in each category but could be classified into more than one category

CheckMate 017)

Summary• With longer follow-up, nivolumab continues to demonstrate survival benefit versus

docetaxel in previously treated patients with advanced SQ NSCLC

– 18-month OS: 28% vs 13%– 18-month PFS: 17% vs 2.7%– mOS: 9.2 vs 6.0 mo (HR=0.62; P=0.0004)

• Nivolumab benefit was independent of PD-L1 expression and seen across clinical subgroups

• Safety profile of nivolumab continues to be favorable versus docetaxel and consistent with prior studies

– The majority of patients who developed a treatment-related select AE on nivolumab did so within the first 3 months

11CheckMate 017)

Longer-term Follow-up of a Phase 2Study (CheckMate 063) of Nivolumabin Patients With Advanced Refractory

Squamous (SQ) Non-Small CellLung Cancer (NSCLC)

Leora Horn,1 Naiyer Rizvi,2* Julien Mazières,3 David Planchard,4 Thomas E. Stinchcombe,5 Grace K. Dy,6Scott J. Antonia,7 Herve Lena,8 Elisa Minenza,9 Bertrand Mennecier,10 Gregory A. Otterson,11 Luis T. Campos,12

David R. Gandara,13 Benjamin P. Levy,14 Suresh G. Nair,15 Gérard Zalcman,16 Jürgen Wolf,17 Paul Paik,2 Ang Li,18

Dong Xu,18 Jaclyn Neely,18 Zhenhao Qi,18 Christopher T. Harbison,18 Mark Lynch,18 Suresh S. Ramalingam19

1Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 2Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Hôpital Larrey, Centre Hospitalier Universitaire de Toulouse, Toulouse, France; 4Gustave Roussy, Villejuif, France; 5University of North Carolina School of Medicine, Chapel Hill, NC, USA; 6Roswell Park Cancer Institute, Buffalo, NY, USA; 7H. Lee Moffitt Cancer Center

& Research Institute, Tampa, FL, USA; 8Centre Hospitalier Universitaire de Rennes, Rennes, France; 9Ospedale S. Maria, Terni, Italy; 10Centre Hospitalier Universitaire, Strasbourg, France; 11The Ohio State University Medical Center, Columbus, OH, USA; 12Oncology Consultants, PA, Houston, TX, USA; 13University of California Davis Cancer Center, Sacramento, CA, USA;

14Beth Israel Comprehensive Cancer Center, New York, NY, USA; 15Lehigh Valley Hospital, Allentown, PA, USA; 16Centre Hospitalier Universitaire de Caen, Caen, France; 17Universitaetsklinik Köln, Köln, Germany; 18Bristol-Myers Squibb, Princeton, NJ, USA; 19Winship Cancer Institute, Emory University, Atlanta, GA, USA

*Current affiliation: Columbia University Medical Center, New York, NY, USA

CheckMate 063 (NCT01721759) Study Design

• Assessments (RECIST v1.1) performed at week 8 and Q6W• Tumor PD-L1 expression was retrospectively assessed in pretreatment (archival) tumor samples (baseline

testing not required)• Updated safety and OS are reported as of June 2015

13

Screening

•Stage IIIB/IV SQ NSCLC •≥2 prior systemic therapies•ECOG PS 0–1

(N =140)

Treatment

Nivolumab 3 mg/kg IV Q2W until PD

or unacceptable toxicity

(N=117)

EndpointsPrimarya

• IRC-assessed confirmed ORRSecondaryb

• Investigator-assessed confirmed ORRExploratory• Safety and tolerability• PFSa and OS• Efficacy by PD-L1 expressiona

aBased on July 2014 DBL; bBased on March 2014 DBLIRC = Independent radiology review committee

Efficacy of Nivolumab Monotherapy inPatients With Advanced Refractory SQ NSCLC

• Four of 22 patients treated beyond initial PD demonstrated a non-conventional pattern of benefit

– OS for these patients was 6.6, 11.6+, 12.9+ and 13.5+ mos

14

IRC-assessed (per RECIST v1.1)

ORR, % (n) [95% CI] 15 (17) [9, 22]

Ongoing responders, % (n/N) 76 (13/17)

Median time to response, mos (range) 3.3 (1.7–8.8)

Median duration of response, mos (range) Not reached (1.9+ to 11.5+)

Median PFS, mos (95% CI) 1.9 (1.8, 3.2)

PFS rate at 1-yr, % (95% CI) 20 (13, 29)

July 2014 DBL

Overall Survival (All Treated Patients)

15

DBLMedian follow-up, mos (range)

Median OS, mos (95%

CI)

1-yr OS rate,

% (95% CI)

18-mo OS rate, % (95%

CI)Events,

n/N

July 2014 8.0 (0.0, 17.3) 8.2 (6.1, 10.9) 41 (32, 50) – 72/117

June 2015 8.0 (0.0, 26.8) 8.1 (6.1,

10.9) 39 (30, 48) 27 (19, 35) 90/117

Time Since Treatment Initiation (Months)Number of patients at risk:

OS

(%)

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 243 9 15 21 27

39%

27%

8.1 mos

117 68 28 093 51 5July 2014 DBL

117 69 45 30 693 54 38 24 0June 2015 DBL

41%

8.2 mos

Data are based on July 2014 and June 2015 DBLs. Symbols represent censored observations

0 00

65% 3rd line and beyond61% chemorefractory

Overall Survival by PD-L1 Expression

16

Median OS, mos (95% CI)

Events, n/N

PD-L1 <1% 8.3 (5.6, 15.6) 23/31

PD-L1 ≥1% 10.1 (5.5, 16.8) 32/45

Not evaluable 13.0 (1.1, 20.8) 8/10

Time Since Treatment Initiation (Months)

OS

(%)

0 3 6 9 12 15 18 21 24 27

10

0

20

30

40

50

60

70

80

90

100

<1%≥1%Not evaluable

Based on June 2015 DBL. Symbols represent censored observations

Summary

• With longer follow-up in patients with advanced SQ NSCLC, nivolumab continues to demonstrate clinically meaningful efficacy with no new safety concerns– mOS: 8.1 mos (95% CI: 6.1, 10.9)– 12-mo OS: 39% (95% CI: 30, 48)– 18-mo OS: 27% (95% CI: 19, 35)

• Consistent with randomized phase 3 trials, most treatment-related AEs were oflow grade and manageable with established guidelines– Most patients who experienced a treatment-related select AE reported their first event

within 3–6 months of treatment initiation

• Clinical benefit with nivolumab was observed independent of PD-L1 expression

17

20

Preliminary analysis showed high response rate: 63% Duration response, PFS… immature no unexpected toxities in combination with standart firs-line chemotherapy

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Safety and Efficacy of First-line Nivolumab(Anti-programmed Death-1 [PD 1]) and Ipilimumab in Non-small Cell

Lung Cancer (NSCLC)Naiyer Rizvi,1* Scott N. Gettinger,2 Jonathan Goldman,3 Matthew D. Hellmann,1

Laura Q. Chow,4 Rosalyn Juergens,5 Hossein Borghaei,6 Julie Brahmer,7 Yun Shen,8Christopher Harbison,8 Faith Nathan,8 Neal E. Ready,9 Scott J. Antonia10

1Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2Yale Cancer Center, New Haven, CT, USA; 3University of California, Los Angeles, Los Angeles, CA, USA; 4University of Washington, Seattle, WA, USA; 5Juravinski Cancer Centre at McMaster University, Hamilton, ON, Canada; 6Fox Chase Cancer Center, Philadelphia, PA, USA; 7The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA; 8Bristol-Myers Squibb, Princeton, NJ, USA;

9Duke University Medical Center, Durham, NC, USA; 10H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

*Current affiliation: Columbia University Medical Center, New York, NY, USA

CTLA-4 Blockade (Ipilimumab)

PD-1 Blockade(Nivolumab)

APC – T-cellInteraction

Activation(cytokine secretion, lysis,

proliferation, migration to tumor)

TumorMicroenvironment

Dendriticcell T cell Tumor cell

MHCTCR TCR

PD-L1

PD-L2

MHC

PD-1

PD-1

B7

B7 CD28

CTLA-4

anti-CTLA-4

+++

---+++

T cell+++

---

---anti-PD-1

anti-PD-1

Rationale for Combined CTLA-4 and PD-1 Blockade in NSCLC

• Nivolumab and ipilimumab enhance T-cell antitumor activity through distinct but complementary mechanisms5–8

• Preclinical data suggest synergy with dual CTLA-4 and PD-1 blockade vs either agent alone9

– Increased proliferation of effector CD8+ and CD4+ T cells and decreased intratumoral T-regulatory cells vs single pathway blockade• Clinical experience with nivolumab plus ipilimumab demonstrate

– Deep and durable responses in previously treated advanced MEL and SCLC10,11

– 2-year OS of 79% in patients with previously treated advanced MEL11

PFS with nivo or nivo plus ipi vs ipi alone inpreviously untreated advanced MEL12

Nivo + Ipi (N=314)

Nivo (N=316)

Ipi (N=315)

mPFS, mos 11.5 6.9 2.9

HR vs Ipi 0.42 0.57 --

HR vs Nivo 0.74 -- --

NivoNivo + Ipi

Ipi

0 6 9 12 15 183 21Months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Prop

ortio

n al

ive

and

prog

ress

ion-

free

23

CheckMate 012 Study Design: Nivolumab Plus Ipilimumab in First-line NSCLC

Primary endpoint: safety and tolerabilitySecondary endpoints: ORR (RECIST v 1.1) and PFS rate at 24 wksExploratory endpoints: OS; efficacy by PD-L1 expression

Stage IIIB/IV NSCLC (any histology); no prior chemotherapy for advanced disease; ECOG PS 0 or 1

Nivo 3 mg/kg IV Q2W until disease progression or unacceptable toxicitya

Nivo 1 mg/kg IV Q3W x 4+

Ipi 1 mg/kg IV Q3W x 4

Nivo 1 mg/kg IV Q2W+

Ipi 1 mg/kg IV Q6W


Ipi 1 mg/kg IV Q12W


Ipi 1 mg/kg IV Q6W

Until disease progression or unacceptable toxicitya

• Here, we report results from new cohorts explored to permit synergistic activity and acceptable safety profile of combination treatment with nivolumab and ipilimumab

24

Safety Summary: primary endpoint

25

• There were no treatment-related deaths

Nivo 1 + Ipi 1 Q3W(n = 31)

Nivo 1 Q2W+ Ipi 1 Q6W

(n = 40)


(n = 38)


(n = 39)

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Treatment-related AEs, % 77 29 73 35 74 29 69 28

Treatment-related AEs leading to discontinuation, % 13 10a 8 8b 5 3c 10 10d

NivolumabMedian number of doses(range)Median duration of therapy, wks(range)

4(1–42)12.0

(3.0–92.0)

7(1–26)16.0

(2.0–59.0)

13(1–26)28.7

(2.0–52.0)

8(1–25)18.0

(2.0–53.0)

Ipilimumab Median number of doses(range)Median duration of therapy, wks(range)

NC1–4e

11.6(3.0–24.0)

3(1–9)17.6

(6.0–59.0)

3(1–5)35.7

(12.0–60.0)

2(1–9)15.0

(6.0–54.0)

aIncreased AST, rash, and pneumonitis (n = 1 each); bAutoimmune hepatitis (n=2), increased ALT, and increased AST (n = 1 each); cColitis (n = 1); dIncreased transaminase, encephalopathy, facial nerve disorder, rash, and pneumonitis (n = 1 each); eMedian number of ipilimumab doses was not calculated as patients received a maximum of 4 doses

Nivo 1 + Ipi 1 Q3W

(n = 31)

Nivo 1 Q2W + Ipi 1 Q6W

(n = 40)


(n = 38)


(n = 39)

Confirmed ORR, % (95% CI) 13(4, 30)

25(13, 41)

39(24, 57)

31(17, 48)

Confirmed DCR, % (95% CI) 55 (36, 73) 58 (41, 73) 74 (57, 87) 51 (35, 68)

Best overall response, %

Complete response Partial responseUnconfirmed partial response

0133

0253

0395

0318

Stable diseaseProgressive diseaseUnable to determine

42356

333010

34138

212615

PFS rate at 24 wks, % (95% CI) 55 (36, 71) NC 63 (44, 76) NC

Median PFS, mos (95% CI) 10.6 (2.1, 16.3) 4.9 (2.8, ) 8.0 (4.2, ) 8.3 (2.6, )

Median OS, mos (95% CI) NR (11.5, ) NR (8.9, ) NR NR (8.7, )

Median length of follow-up, mos (range)

16.6(1.8–24.5)

6.2(0.4–13.1)

8.4(0.9–12.3)

7.7(1.1–12.2)

Summary of Efficacy

26NR: the time point at which the percent of survivors drops below 50% has not been reached due to insufficient number of events and/or follow up.

• Median DOR was not reached in any arm• Unconventional immune-related responses were observed in arms Nivo 3 Q2W + Ipi 1 Q12W (n = 2), Nivo 3 Q2W + Ipi 1 Q6W (n = 1) and

Nivo 3 Q2W (n = 3)

Efficacy by Tumor PD-L1 Expression

27

≥1% PD-L1 expression <1% PD-L1 expression

Nivo 1+ Ipi 1 Q3W

(n = 12)

Nivo 1 Q2W

+ Ipi 1 Q6W

(n = 21)


(n = 21)

Nivo 3 Q2W

+ Ipi 1 Q6W

(n = 23)

Nivo 1+ Ipi 1 Q3W

(n = 13)

Nivo 1 Q2W

+ Ipi 1 Q6W

(n = 7)

Nivo 3 Q2W+ Ipi 1 Q12W(n = 9)

Nivo 3 Q2W

+ Ipi 1 Q6W

(n = 7)

ORR, % 8 24 48 48 15 14 22 0

mPFS, wks(95% CI)

11.5(7.1, )

21.1(11.4, )

34.6(15.9, 35.3)

NR(15.4, )

34.0(8.9, )

NR(10.1, )

23.1(4.0, )

10.3(7.4, 12.7)

PFS rate at 24 wks, % (95% CI)

42(15, 67)

40(18, 61)

74(48, 88)

65(42, 81)

57(25, 80)

NC 39(9, 69)

0

NR: the time point at which the percent of survivors drops below 50% has not been reached due to insufficient number of events and/or follow up

• PD-L1 expression was measured using the Dako/BMS automated IHC assay1,16

– Fully validated with analytical performance having met all predetermined acceptance criteria for sensitivity, specificity,precision, and robustness

• All patients had available pretreatment tumor samples; 76% (113/148) had samples evaluable for PD-L1 expression

• Median DOR was not reached in any arm, regardless of PD-L1 expression

Efficacy by Tumor PD-L1 Expression

28NR: the time point at which the percent of survivors drops below 50% has not been reached due to insufficient number of events and/or follow up

• PD-L1 expression was measured using the Dako/BMS automated IHC assay1,16

– Fully validated with analytical performance having met all predetermined acceptance criteria for sensitivity, specificity,precision, and robustness

• All patients had available pretreatment tumor samples; 76% (113/148) had samples evaluable for PD-L1 expression• Median DOR was not reached in any arm, regardless of PD-L1 expression

≥1% PD-L1 expression

Nivo 1+ Ipi 1 Q3W

(n = 12)


(n = 21)


(n = 21)


(n = 23)

ORR, % 8 24 48 48

mPFS, wks(95% CI)

11.5(7.1, )

21.1(11.4, )

34.6(15.9, 35.3)

NR(15.4, )

PFS rate at 24 wks, % (95% CI)

42(15, 67)

40(18, 61)

74(48, 88)

65(42, 81)

Summary• First-line therapy with nivolumab plus ipilimumab demonstrates a high level of clinical

activity characterized by deep and durable responses in advanced NSCLC– Confirmed ORR:13–39% – Encouraging mPFS: 4.9–10.6 mos

• Nivolumab plus ipilimumab is associated with a favorable safety profile – Low frequency of treatment-related grade 3–4 AEs leading to discontinuation: 3–10%– No treatment-related deaths

• Clinical activity was observed regardless of tumor PD-L1 expression– Preliminary evidence of greater activity in ≥1% PD-L1 expressing tumors

• A phase 3 trial comparing nivolumab or nivolumab plus ipilimumab vs PT-DC in patients with chemotherapy-naïve stage IV or recurrent NSCLC is ongoing(CheckMate 227; NCT02477826)

29



•Practical approach and…

31

Are we ready to select REAL patients for anti-PD1 treatment?

Hussein M, et al. Safety and efficay of nivo…population

MINI03.05: Efficacy of Pembrolizumab in Key Subgroups of Patients with Advanced NSCLC – Hellmann MD et al

• Key results

– Within all subgroups, higher TPS (≥50% vs. 1–49% and <1%) was associated with improved outcome (i.e., ORR, PFS and OS)

– EGFR wild-type was associated with higher ORR vs. EGFR mutant for TPS ≥50% (39.8% vs. 20.0%), TPS 1–49% (12.2% vs. 8.7%) and TPS <1% (12.7% vs. 0%)

– KRAS mutation had no significant effect on ORR • Conclusions

– The interdependency between PD-L1 status, mutational status and smoking history will be further explored in ongoing randomised trials, including KEYNOTE-010

Hellmann et al. J Thorac Oncol 2015; 10 (suppl 2): MINI03.05

Odds Ratio (95%CI) p-value Interaction p-valueHistology Squamous —

0.63 0.81Nonsquamous 1.16 (0.62, 2.08)

Smoking history Never —0.009 0.27

Current or former 2.50 (1.27, 4.89)PD-L1 TPS <50% —

<0.0001 —≥50% 4.45 (2.27, 7.13)

ORAL31.02: Pembrolizumab for NSCLC: Immune-Mediated Adverse Events and Corticosteroid Use – Leighl N et al

• Study objective– To examine the incidence of immune-mediated AEs and use of corticosteroids in the

management of patients with NSCLC (n=550) in the KEYNOTE-001 trial• Study design

– Patients received pembrolizumab at 2 mg/kg q3w (n=61), 10 mg/kg q3w (n=287) or 10 mg/kg q2w (n=202)

• Key results– The most common immune-mediated AEs were: hypothyroidism (7.6%), pneumonitis

(3.8%) and infusion reactions (3.5%) and mainly occurred with the first 2–4 months

• Conclusions– This limited data suggests that there is no clear relationship between continued pembrolizumab

efficacy and steroid use

Leighl et al. J Thorac Oncol 2015; 10 (suppl 2): ORAL31.02

Steroid use No steroid use

ORR, % (95%CI) 32.1 (15.9, 52.4) 19.5 (16.2, 23.2)

DCR, % (95%CI) 64.3 (44.1, 81.4) 49.6 (45.2, 54.0)

PFS, months (95%CI) 4.6 (2.1, 6.2) 3.4 (2.6, 4.1)

OS, months (95%CI) 11.4 (5.0, NR) 13.5 (10.6, 15.5)

Duration of corticosteroid use Event sample is too small No apparent harm

34Chaft J, et al- Atezolizumab.

ORAL02.01 - Phase 3, Randomized Trial (CheckMate 017) of Nivolumab (NIVO) vs Docetaxel in Advanced Squamous (SQ) Cell Non-Small Cell Lung Cancer (NSCLC)K. Reckamp, D.R. Spigel, N.A. Rizvi, E. Poddubskaya, H. West, W.E.E. Eberhardt, P. Baas, S.J. Antonia, A. Pluzanski, E. Vokes, E. Holgado, D. Waterhouse, N. Ready, J.F. Gainor, O. Arén Frontera, L. Horn, L. Paz-Ares, A. Li, M. Lynch, J.R. Brahmer

ORAL02.02 - Safety and Efficacy of Nivolumab in an Ongoing Trial of a PD-L1+/- Patient Population with Metastatic Non-Small Cell Lung Cancer (M. Hussein, M. McCleod, J. Chandler, G. Blumenschein, Jr., L. Schwartzberg, H. Burris, D. Waterhouse, R. Jotte, T. Bauer, D. Thompson, X. Li, C.H. Reynolds

ORAL02.03 - Longer-Term Follow-Up of a Phase 2 Study (CheckMate 063) of Nivolumab in Patients with Advanced, Refractory Squamous Non-Small Cell Lung Cancer L. Horn, N.A. Rizvi, J. Mazières, D. Planchard, T.E. Stinchcombe, G.K. Dy, S.J. Antonia, H. Léna, E. Minenza, B. Mennecier, G.A. Otterson, L.T. Campos, D.R. Gandara, B.P. Levy, S.G. Nair, G. Zalcman, J. Wolf, P. Paik, A. Li, D. Xu, J. Neely, Z. Qi, C. Harbison, M. Lynch, S.S. Ramalingam

ORAL02.05 - Safety and Efficacy of First-Line Nivolumab (NIVO; Anti-Programmed Death-1 [PD-1]) and Ipilimumab in Non-Small Cell Lung Cancer (NSCLC) N.A. Rizvi, S.N. Gettinger, J.W. Goldman, M.D. Hellmann, L.Q. Chow, R. Juergens, H. Borghaei, J.R. Brahmer, Y. Shen, C. Harbison, F. Nathan, N. Ready, S.J. Antonia

ORAL02.06 - Evaluation of PD-L1 Expression in Metachronous Tumor Samples and FDG-PET as a Predictive Biomarker in Ph2 Study (FIR) of Atezolizumab (MPDL3280A) J.E. Chaft, B. Chao, W.L. Akerley, M. Gordon, S.J. Antonia, J. Callahan, A. Sandler, R. Funke, Z. Li, J. Fredrickson, M. Kowanetz, S.N. Gettinger

ORAL02.07 - Atezolizumab (MPDL3280A) Combined with Platinum-Based Chemotherapy in Non-Small Cell Lung Cancer (NSCLC): A Phase Ib Safety and Efficacy Update .R. Camidge, S.V. Liu, J. Powderly, N. Ready, S. Hodi, S.N. Gettinger, G. Giaccone, B. Liu, J. Wallin, R. Funke, D. Waterkamp, R. Heist

MINI03.05 - Efficacy of Pembrolizumab in Key Subgroups of Patients with Advanced NSCLC M.D. Hellmann, E.B. Garon, L. Gandhi, R. Hui, J. Zhang, R. Rangwala, G. Lubiniecki, N.A. Rizvi

MINI03.06 - Phase II Studies of Nivolumab in Patients with Advanced Squamous (SQ) or Non-Squamous (NSQ) Non-Small-Cell Lung Cancer (NSCLC) K. Nakagawa, M. Nishio, T. Hida, H. Sakai, N. Nogami, S. Atagi, T. Takahashi, H. Nokihara, H. Saka, M. Takenoyama, S. Fujita, H. Tanaka, K. Takeda, M. Satouchi, H. Isobe, M. Maemondo, K. Goto, T. Hirashima, K. Minato, T. Tamura

MINI03.07 - Clinical Attributes of Lung Cancer in US Community Oncology Practice: Implications for Immunotherapy P. Reddy, D. Richards, B. Ulrich, V. Gunuganti, R. Jotte, S. Wilks, D. Waterhouse, M. Mohamed, J. Chandler, L. Schwartzberg, D. Khan, M. Hancock, C. Bromley, K. Kulig, M. Hussein

MINI03.03 - Pembrolizumab 2 mg/kg Q3W for Previously Treated, PD-L1-Positive Advanced NSCLC O. Flotten, E.B. Garon, H. Arkenau, R. Hui, L. Gandhi, E. Felip, H. Lena, F. Cappuzzo, L. Horn, M. Gubens, J. Zhang, G. Lubiniecki, E. Im, M. Hellmann

ORAL04.01 - Final Results of Phase III Trial of Adjuvant Chemo-Immunotherapy in Lung CancerH. Kimura, Y. Matsui, A. Ishikawa, T. Iizasa, M. Shingyoji, M. Nakajima, I. Yoshino

ORAL18.01 - TG4010 Immunotherapy plus Chemotherapy as First Line Treatment of Advanced NSCLC: Phase 2b Results E. Quoix, F. Forget, C. Chouaid, Z. Papai, G. Losonczy, E. Felip, M. Cobo, C. Ottensmeier, J.T. Beck, B. Bastien, A. Tavernaro, G. Lacoste, J. Limacher, H. Léna

Hellmann et al. J Thorac Oncol 2015; 10 (suppl 2): MINI03.05

ORAL18.02: MUC1-Targeted Dendritic Cell-Based Vaccine Immunotherapy inPatients with Standard Treatments-Refractory Non-Small-Cell Lung Cancer

– Teramoto K et al

• Study objective– To evaluate the efficacy of MUC1-targeted dendritic cell-based vaccine immunotherapy in

patients with advanced NSCLC who are refractory to standard treatments• Study design

– Patients (n=41) with histologically- or cytologically-confirmed NSCLC, ECOG PS 0–2 were administered subcutaneous MUC1-targeted dendritic cell-based vaccine immunotherapy q2w

– Tumour responses were assessed in 29 patients• Key results

– Median number of vaccinations was 6 (range 1–42)– Across all patients the median OS from first vaccination was 7.4 months (95%CI 4.5, 10.3);

1-year survival rate was 29.3% (95%CI 15.3, 41.2)– In patients who received >6 vaccinations (n=29), median OS was 10.1 months (95%CI 8.3,

11.9) from the first vaccination and 1-year survival rate was 41.4% (95%CI 23.5, 59.3)– Patients with immune-related AEs or peripheral white blood cells >20% had the best prognosis

• Conclusion– MUC1-targeted dendritic cell-based vaccine immunotherapy demonstrated interesting early

activity in patients with NSCLC refractory to standard treatmentsTeramoto et al. J Thorac Oncol 2015; 10 (suppl 2): ORAL18.02

mariano provencio hospital universitario puerta de hierro- … · 2019. 7. 16. · título de...

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