LA INMUNOTERAPIA Y

SUS FÁRMACOS

Rosario García Campelo

Servicio de Oncología Médica

Complejo Hospitalario Universitario A Coruña

XXXIX REUNION ANUAL DE LA SOCIEDAD ESPAÑOLA DE ANATOMIA PATOLOGÍA Y

DIVISION ESPAÑOLA DE LA ACADEMIA INTERNACIONAL DE PATOLOGÍA

Should I tell

you

everything?

Tumors Create Chaos

Disordered

•Blood flow and vascular distribution

•Stroma and immune milieu

Immune shaping

•Creates selection pressure so that cancers can evade immune

destruction

•Malignant “evolution”

Jain RK. Adv Drug Deliv Rev. 2001;46:149-168.

Tumors go to great lengths

to evade or subvert the immune response

Therapies in Active Development Likely to Increase Response to Immune Checkpoint Inhibitors

ANTICANCER INMUNOTHERAPY…a whole universe

Galuzzi L, et al. Oncotarget 2014

Therapeutic vaccines

6

Immunotherapy involving cancer vaccines aims to

generate or augment the innate or adaptive antitumour

immune response with the use of a biologically active

whole-cell or specific protein antigen preparation

Anagnostou – Clin Can Res 2015

Sipuleucel-T (PROVENGE): in metastatic prostate cancer

First FDA-approved therapeutic cancer vaccine (Apr. 2010)

Kantoff et al., NEJM 2010

Cheever et al. CCR 2011

Sipuleucel-T is an active cellular

immunotherapy, a type of therapeutic

cancer vaccine, consisting of autologous

peripheral-blood mononuclear cells

(PBMCs), including antigen-presenting

cells (APCs), that have been activated ex

vivo with a recombinant fusion protein

(PA2024)

PA2024 consists of a prostate antigen,

prostatic acid phosphatase, that is fused

to granulocyte–macrophage colony-

stimulating factor, an immune-cell

activator.

Robert H.I. Andtbacka et al. JCO 2015;33:2780-2788

Oct. 2015 : FDA approval for T-VEC (AMGEN)

Talimogene laherparepvec in unresected melanoma (local injections)

NSCLC and therapeutic vaccines

Full protein vaccine (MAGE-A3 vs. placebo); Ph. II (N=182, stage II*)

Peptide (L-BLP25 vaccine vs placebo; Ph III; N=1514, stage III)

Ganglioside vaccine (Racotumomab + BSC vs BSC; Ph III,; N=1082; stage

IIIB/IV*)

Whole tumor cell vaccine (Belagen-pumatucel+BSC vs BSC; Ph III; N=532)

Full protein vaccine (chemo. + TG4010 vaccine vs. chemo); Ph II (N=148;

stage IIIB/IV)

Cuppens K, Vansteenkiste J. Vaccination therapy for non-small-cell lung cancer. Current opinion in oncology. 2014;26(2):165-70.

CTLA-4 = cytotoxic T-lymphocyte-associated protein 4PD-1 = programmed death 1; PD-L1 = programmed death ligand 1Please note that atezolizumab has not received regulatory approval in any country yet

1. Mellman, et al. Nature 20112. Chen & Mellman. Immunity 2013

7

Killing of cancer cells

(immune and cancer cells)

Anti-CTLA-4CTLA-4 is a major negative regulator of T cell activation and

inhibition of CTLA-4 can enhance T cell stimulation, resulting in

more potent anti-tumour responses1

Ipilimumab

Tremelimumab

Anti-PDL1/PD1PD-L1 expression on tumour cells and tumour-infiltrating

immune cells can inhibit T cell activity via its receptor PD-1,

dampening the anti-tumour immune response. Inhibition of

PD-L1 or its receptor PD-1 may restore T cell effector function2

Nivolumab (anti-PD1)

Pembrolizumab (anti-PD1)

Atezolizumab (anti-PDL1)

Durvalumab (anti-PDL1)

Avelumab (anti-PDL1)

CD28

OX40

GITR

CD137

CD27

HVEM

CTLA-4

PD-1

TIM-3

BTLA

VISTA

LAG-3

T cell targets for modulating activity

Activating

Receptors

Inhibitory

Receptors

T cell

stimulation

Agonistic

Antibodies

Blocking

Antibodies

T cell

Inmune Checkpoint antibodies you need to remember…

Today…

April 19, 2015

April 20, 2015

April 19, 2015

June 2, 2013

June 2, 2013

Nov 19, 2014

June 30, 2011

Nov 16, 2014

Aug 19, 2010June 2, 2012

June 28, 2012

May 31 2015

Sept 27, 2015

The challenge…

The challenge…

Unique Biology

• Patient selection

Unique drug development

• Patient selection

Unique Activity Patterns

• Patient management

• Go vs no-go decision

Unique toxicity

• Patient management

Adapted from The Cancer Genome Atlas Project: Govindan & Kondath et al Nature 2013

1 / Mb

10 / Mb

100 / Mb

0.1 / Mb

81 64 38 316 100 17 82 28n=109 119 21 40 20

Hematologic &

Childhood Cancers

Carcinogen-induced Cancers

?

?

Ad

en

oca

Squ

am

ous

Ovarian, Breast,

Prostate Cancers

Mutations

Per Mb DNA

UNIQUE BIOLOGY…Magnitude of Genomic Derangement Is Greatest In Melanoma and Lung

Cancer. This may contribute to increased inmunogenicity

UNIQUE DRUG DEVELOPMENTPembrolizumab Phase I Study as an illustration

• PN-001, Phase I study, began in 2011

• Initially a 32 patient study

• Actually enrolled over 1260 patients

• Became basis for FDA Breakthrough designation in

melanoma + lung cancer

UNIQUE ACTIVITY PATTERNS…

Ascierto AL, Frontiers in Oncol 2015

Tail of the curve best describes benefit

• Landmark or Milestone OS rates are better descriptors than mOS

• “Separation of the Curves” effect represents non-proportional HR

• Plateau typically begins about 18-24 mo and “flattens” by 36-48 mo

• Implications for Trial Design

• Better agents (combinations?) and/or selection of pts using predictive biomarkers may ultimately drive the best trial results

1. Adapted from Ribas A, presented at WCM, 2013

2. Ribas A, et al. Clin Cancer Res 2012;18:336–341

3. Drake CG. Ann Oncol 2012;23(suppl 8):viii41–viii46

CTLA-4 INHIBITORS:

IPILIMUMAB

TREMELIMUMAB

IPILIMUMAB

Immune Checkpoint Blockade: OS Demonstrated in Patients

With Advanced Melanoma

Anti-CTLA-4

T cell

CTLA-4PD-1

Anti-PD-1

aFor illustrative purposes; only select checkpoint molecules, select agents, and select data from 2 clinical trials are shown. OS, overall survival.

1. Hodi FS, et al. N Engl J Med. 2010;363:711-723. 2. Atkinson V et al. Presented at SMR 2015.

Phase 3 data with IPI1

Ipilimumab + gp100 (n=403)

Ipilimumab (n=137)

Gp100 (n=136)

Pa

tie

nts

Ali

ve (

%)

Years

0

20

40

60

80

100

0 1 2 3 4

In pretreated patients

Advanced melanoma: ipilimumab

Schadendorf JCO 2015

3 yr OS rate: 22%

CTLA-4 Immune Checkpoint Inhibition for

Advanced Melanoma

• Ipilimumab is the only approved CTLA-4 checkpoint

inhibitor1

• Data showed durable, long-term survival benefit in patients

with advanced melanoma2,3

• Antitumor activity across patient subgroups and irrespective

of prior therapy or BRAF status4,5

• Associated with immune-mediated adverse reactions that

can be serious, but most are reversible using established

management guidelines5

1. Camacho LH. Cancer Med 2015;4:661-672. 2. Schadendorf D, et al. J Clin Oncol. 2015;33:1889-1894. 3. Maio M, et al. J Clin Oncol. 2015 33:1191-1196. 4. Page DB, et al. Curr Oncol Rep. 2013;15:500-508. 5. Wolchok JD, et al. Ann NY Acad Sci. 2013;1291:1-13.

IPILIMUMAB IN NSCLC

R Phase II CA184-041

Lynch T, J Clin Oncol 2012

Phased ipilimumab regimen improved irPFSand OS in patients with squamous histology: HR: 0.55 (95% CI, 0.27-1.12) also in WHO-PFS

Ipilimumab for NSCLC: Randomized Phase II Study Design

• Primary Endpoint: Immune-related PFS (irPFS)

• Exclusion Criteria – Prior treatment for lung cancer

– Brain metastases

– Autoimmune disease

– P/C: 175 mg/m2 paclitaxel + AUC = 6 carboplatin q 3 weeks x 6 doses

– Concurrent ipilimumab: 10 mg/kg q 3 weeks x 4 doses

– Phased ipilimumab: Placebo q 3 weeks x 2 doses followed by IPI q 3 weeks x 4 doses

Chemotherapy

-naïve stage

IIIB/IV NSCLC

(N = 204)

R A N D O M I Z E

Concurrent ipilimumab

+ P/C (n = 70)

Phased ipilimumab

+ P/C (n = 68)

Placebo + P/C (n = 66)

1:1:1

Ipilimumab q 12 weeks

Ipilimumab q 12 weeks

Placebo q 12 weeks

Lynch TJ, et al. J Clin Oncol. 2012;30(17):2046-2054.

Maintenance

PD-1 AND PD-L1 INHIBITORS:NIVOLUMAB

PEMBROLIZUMAB

ATEZOLIZUMAB

DURVALUMAB

AVELUMAB

NIVOLUMAB

Nivolumab Antitumor Activity

Melanoma

(n = 272)[1]

1. Weber JS, et al. Lancet Oncol. 2015;16:375-384. 2. Rizvi NA, et al. Lancet Oncol. 2015;16:257-265

3. McDermott DF, et al. J Clin Oncol. 2015;[Epub ahead of print]. 4.Ansell SM, et al. N Engl J Med. 2015;372:311-319.

Advanced NSCLC

(N = 117)[2]

Advanced RCC

(N = 34)[3]

Hodgkin’s Lymphoma

(N = 23)[4]

125100

7550250

-25-50-75

-100Ma

x C

ha

ng

e i

n T

arg

et

Le

sio

ns

Fro

m B

L (

%)

Pts

100

75

50

25

0

-25

-50

-75

-100Ma

x C

ha

ng

e i

n T

arg

et

Le

sio

ns

Fro

m B

L (

%)

Pts

Alive

Dead

Confirmed responders

100

50

0

-59

-100Ma

x C

ha

ng

e i

n T

um

or

Bu

rde

n F

rom

BL

(%

) 150

1 mg/kg nivolumab

10 mg/kg nivolumab

Pts

100

-50-60

-40

-70-80-90

-100Ma

x C

ha

ng

e i

n T

um

or

Bu

rde

n F

rom

BL

(%

)-30-20-10

Pts

Stable

DiseasePartial Response

Complete

Response

Immune Checkpoint Blockade: OS Demonstrated in Patients

With Advanced Melanoma

Anti-CTLA-4

T cell

CTLA-4PD-1

Anti-PD-1

aFor illustrative purposes; only select checkpoint molecules, select agents, and select data from 2 clinical trials are shown. OS, overall survival.

1. Hodi FS, et al. N Engl J Med. 2010;363:711-723. 2. Atkinson V et al. Presented at SMR 2015.

2-yr OS=26.7%

Pro

ba

bil

ity

of

Su

rviv

al

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 3 6 9 12 15 18 21 24 27 30

Overall Survival (Months)

2-yr OS=57.7%

NIVO 3 mg/kg Q2W (n=210)

Dacarbazine (n=208)

Phase 3 data with NIVO2

In treatment-naïve patients

RENAL CANCER

Motzer et al. NEJM 2015

NSCLCOS in Nivolumab phase 1 (3yrs FU)

• Pts were heavily pretreated; 54% had 3–5 prior

therapiesGettinger, JCO. 2015.

A phase III study (CheckMate 017) of nivolumab vs docetaxel in previously treated advanced or metastatic squamous (SQ) cell non-small cell lung cancer (NSCLC).

Brahmer J et al. N Engl J Med 2015

Nivoluma

b

(n = 292)

Docetax

el

(n = 290)

mOS, mo 12.2 9.4

HR = 0.73 (96% CI: 0.59, 0.89); P =

0.0015

Phase III, randomized trial (CheckMate 057) of nivolumab(NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC).

Nivolumab

(n = 292)Docetaxel

(n = 290)

mPFS,

mo

2.3 4.2

HR = 0.92 (95% CI: 0.77, 1.11); P = 0.3932

Borghaei H, et al. N Engl J Med 2015

OS by PD-L1 Expression

Nivolumab is FDA approved in unresectable or metastatic

melanoma with disease progression following ipilimumab (and

BRAF inhibitor if BRAF V600+) and in metastatic NSCLC on or after

progression with platinum-based chemotherapy and received

Breakthrough Therapy Designation for Hodgkin’s Lymphoma

ATEZOLIZUMAB

ATEZOLIZUMAB

Vansteenkiste et al. Ann Oncol 2015; 26 (suppl 6): abstr 14LBA

Atezolizumab monotherapy vs docetaxel in 2L/3L non-small cell lung cancer:

Primary analyses for efficacy, safety and predictive biomarkers from a

randomized phase II study (POPLAR)

Vansteenkiste et al. Ann Oncol 2015; 26 (suppl 6): abstr 14LBA

Atezolizumab was associated with significant improvements in OS in the ITT population

Median OS for atezolizumab was 12.6 months compared with 9.7 months for

docetaxel (HR 0.73 [95%CI 0.53, 0.99], p=0.040)

• Patients with higher PD-L1 expression demonstrated improved

OS with atezolizumab

• Tumour cells and tumour-infiltrating immune cells were both

independent predictors of survival improvement with

atezolizumab

Vansteenkiste et al. Ann Oncol 2015; 26 (suppl 6): abstr 14LBA

PEMBROLIZUMAB

Pembrolizumab Antitumor Activity

1. Robert C, et al. Lancet. 2014;384:1109-1117. 2. Garon EB, et al. ESMO 2014. LBA43. 3. Chow LQ, et al. ESMO 2014.

LBA31. 4. O’Donnell P, et al. ASCO GU 2015. Abstract 296. 5. Muro K, et al. ASCO GI 2015. Abstract 03. 6. Nanda R, et al.

SABCS 2014. Abstract S1-09. 7. Moskowitz C, et al. ASH 2014. Abstract 290.

100806040200

-20-40-60-80

-100Ch

an

ge F

rom

Ba

se

lin

e

in S

um

of

La

rge

st

Dia

me

ter

of

Ta

rge

t L

es

ion

s (

%) Melanoma[1] (N = 411)

KEYNOTE-001100806040200

-20-40-60-80

-100

NSCLC[2] (N = 262)

KEYNOTE-001100806040200

-20-40-60-80

-100

HNSCC[3] (N = 61)

KEYNOTE-012

100806040200

-20-40-60-80

-100Ch

an

ge F

rom

Ba

se

lin

e

in S

um

of

La

rge

st

Dia

me

ter

of

Ta

rge

t L

es

ion

s (

%)

Urothelial Cancer[4]

(N = 33)

KEYNOTE-012

100806040200

-20-40-60-80

-100

Gastric Cancer[5]

(N = 39)

KEYNOTE-012

100806040200

-20-40-60-80

-100

TNBC[6] (N = 32)

KEYNOTE-012 100806040200

-20-40-60-80

-100

cHL[7] (N = 29)

KEYNOTE-013

PEMBROLIZUMAB

Estudio Keynote 001

Updated pooled analysis with

665 patients

• PFS: 4.4 meses

• OS: 22.8 meses

Estudio Keynote 001

Treatment-Naïve patients

• PFS: 13,8 meses

• OS: 31,3 meses

Estudio Keynote 006

30% LDH elevada

63% B-RAF WT

80% PD-L1 positivo

35% una línea previa

Estudio Keynote 006. OS (Second Interim Analysis)

1-year estimates of OS:

• 74.1% pembrolizumab 2w (HR 0.63, P<0.0005),

• 68.4% pembrolizumab every 3 weeks (HR 0.69, P = 0.0036)

• 58.2% ipilimumab

Pembrolizumab is FDA approved in unresectable or metastatic

melanoma and in metastatic NSCLC PD-L1 positive on or after

progression with platinum-based chemotherapy

Immune-mediated

adverse reactions

TOXICITY

Immune-mediated adverse reactions

Patient education for early

recognition

Early diagnosis

and appropriate

management essential to

minimise

life-threatening

complications

Systemic high-dose

corticosteroids

may be required for severe

events

Can be severe or

life-threatening; may involve

various organs

Result from increased or

excessive immune activity

Unless an alternate etiology

has been identified,

consider all signs and

symptoms

General health and performance status are important

when considering whether an individual patient

would tolerate one of the higher grade irAEs.

At present there is no test to predict likelihood of

toxicity with immunotherapy.

Let´s see an example

• 61 year old male

• Active smoker 50 packs/year

• May 2014: Stage IV Squamous Cell Lung Cancer

• cT4NxM1b (bilateral adrenal metastasis)

• 1st line: Platinum-Gemcitabine x 6 cycles: PD

• January 2015

• 2nd line Docetaxel: severe acute infusion reaction

• 09/06/2015: 1st dose Nivolumab 3mg/Kg

IN THE NEAR FUTURE...

Several Arguments for Combining

Immunotherapies

MELANOMA COMBO: PFS With the NIVO+IPI Regimen –

ITT Population (CheckMate 067)1,2

NIVO+IPI

(n=314)

NIVO

(n=316)

IPI

(n=315)

Median PFS, months

(95% CI)

11.5

(8.9–16.7)

6.9

(4.3–9.5)

2.9

(2.8–3.4)

HR (99.5% CI)

vs. IPI

0.42

(0.31–0.57)*

0.57

(0.43–0.76)*--

HR (95% CI)

vs. NIVO

0.74

(0.60–0.92)**-- --

*Stratified log-rank P<0.001 vs. IPI

**Exploratory endpoint

No. at Risk

314NIVO+IPI 173 151 65 11 1219 0

316NIVO 147 124 50 9 1177 0

315IPI 77 54 24 4 0137 0

0 6 9 12 15 183 21

NIVO

NIVO+IPI

IPI

Months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pro

po

rtio

n a

liv

e a

nd

pro

gre

ssio

n-f

ree

1. Larkin J, et al. N Engl J Med. 2015;373:23-34. 2. Wolchok JD, et al. Presented at ASCO 2015 abstract LBA1.

SCLCOverall survival: CheckMate 032

mOS = median OS; OS = overall survival; NR = not reached.

Nivolumab

3

n = 80

Nivolumab 1 +

Ipilimumab 3

n = 47

mOS,

months

(95% CI)

3.55

(2.66, 7.46)

7.75

(3.65, NR)

No. of

events

33 19

1-year OS rate = 47.5%

1-year OS rate = 27.1%

100

90

80

70

60

50

40

30

20

10

0

0 3 6 9 12 15 18

Nivolumab 1 + Ipilimumab 3

Nivolumab 3

Patients at risk

Nivolumab 3 mg/kg 80 26 16 14 6 4 0

47 32 13 6 2 1 0Nivolumab 1 mg/kg +

Ipilimumab 3 mg/kg

Time (Months)

OS

(%

)

Calvo E et al. ESMO 2015. Abstract #3098

If we talk about IO, check your enthusiasm

ONE SIZE DOES NOT FIT ALL

PATIENT SELECTION

How to select patients for IO?

• 62 years old male

• Active smoker 45 paq/year

• Routine medical check:

• Thorax X-ray: RUL mass

• CT scan: 5x3 cm RUL mass and a 13 mm traqueobronchial adenopathy

• PET-CT: multiple uptake sites including right parahilar right nodes, 3rd right rib, 7nd

left rib, lumbar, RUL mass and traqueobronchial adenopathy

• Stage IV Squamous Cell Carcinoma

• First line therapy CDDP/Gem

• Lung and costal progression after 3 cycles of platinum-doublet, ECOG 1

Randomized trials In NSCLC

Main activity data in 2nd line setting

Garon GB et al. Lancet. 2014.

Soria JC et al. Lancet Oncol 2015

Bramer J et al. NEJM. 2015.

Vansteenkiste J, et al. ECC 2015.

Herbst R. Lancet Oncol 2015

Docetaxel+Ram

ucirumab

vs Docetaxel

Revel Phase III

Dcoetaxel+Ninte

danib vs

Docetaxel

LumeLung 1

Phase III

Afatinib vs

Erlotinib

Lux-LUNG 8

Phase III

Nivolumab vs

Docetaxel

CheckMate

017 Phase III

Nivolumab vs

Docetaxel

CheckMate 057

Phase III

Pembrolizumb

vs Docetaxel

KeyNote 010

Phase III

Atezolizumab

vs Docetaxel

Poplar

Phase II

ORR 23 vs 14% 4.7% vs 3.6% 5.5% vs 2.8% 20% vs 9% 19% vs 12% 18% vs 18% 15% vs 15%

PFS m 4.5 vs 3 4 vs 2.8 2.6 vs 1.9 3.5 vs 2.8 2.3 vs 4.2 3.9 vs 4 vs 4 2.7 vs 3

OS m10.4 vs 9.1

9.5 vs 8.2 (SCC)

12.6 vs 10.3

(Adenocarcinoma)7.9 vs 6.8 9.2 vs 6 12.2 vs 9.4m

10.4-12.7 vs 8.5 12.7 vs 9.7

10.1 vs 8.6

(SCC)

HR OS

HR PDL1-

HR PDL1+

0-86

0.883 (SCC)

NA

NA

0.83

NA

NA

0.81

NA

NA

0.59

0.70

0.50

0.73

0.87

0.40

0.71-0.61

NA

0.54-0.50

0.73

1.09

0.49

Toxicity…It can make a difference

Docetaxel+

Ramucirumab

vs Docetaxel

Revel

Afatinib vs

Erlotinib

Lux-Lung 8

Nivolumab vs

Docetaxel

CheckMate 017

Atezolizumab

vs Docetaxel

Poplar

Pembrolizumab

vs Docetaxel

KeyNote 010

Any 98% vs 95% 99.5% vs

97.5%

58% vs 86% 67% vs 88% 63% vs 81%

Gr 3-4 79% vs 71% 57.1% vs

57.4%

7% vs 55% 11% vs 39% 13% vs 35%

Gr 5 5% vs 6% 1.5% vs 1.3% 0 vs 2.1% 1 vs 2% -

Any AEs leading

to discontinuation

15% vs 8,8% 20.2% vs 17% 4% vs 10% 8% vs 22 % 4% vs 10%

Garon GB et al. Lancet. 2014.

Soria JC et al. Lancet Oncol 2015

Bramer J et al. NEJM. 2015.

Vansteenkiste J, et al. ECC 2015

Herbst R et al. Lancet Oncol 2015

Histology is not Predictive

RR

SQUAMOUS

CARCINOMA

NON-

SQUAMOUS

NIVOLUMAB 20% 19%

ATEZOLIZUMAB 27% 21%

PEMBROLIZUMAB 23.5% 18.7%

Bramer J et al. NEJM. 2015.

Borghaei H et al. NEJM. 2015.

Soria JC et al. ESMO 2014.

Garón et al. NEJM. 2015.

1L line, 2L line or beyond?

Besse B, et al. ECC 2015

66

SMOKING HISTORY

Rizvi N, et al. Science 2015.

Genomic landscape of lung cancers shape response to

anti-PD-1 therapy

Mutational landscape determines sensitivity

to PD-1 blockade in non-small cell lung cancer

• Whole-exome sequencing of NSCLC treated with Pembrolizumab

• In two independent cohorts, higher nonsynonymous mutation burden

in tumors associated with improved ORR, durable clinical benefit,

and PFS

• Efficacy also correlated with the molecular smoking signature, higher

neoantigen burden, and DNA repair pathway mutations

Oncogene addicted NSCLC

Broghaei et a. NEJM. 2015

Horn et al. WCLC 2013Hellmann et al. WCLC 2015

Human microbiome: gut – influence on

immunotherapeutic efficacy

Sivan. Science. 2015; Vetizou. Science. 2015.

Almost CR after 2 cycles of MPDL3280Acommon pattern of response

Some take home messages

IO, THE CHALLENGE

• IO WORKS…AND IT WORKS REALLY WELL

• Patient selection for therapy: IT´S AN URGENT ISSUE

• Toxicity management:

• Physician education

• Patient education

• Early recognition and consideration: reinforce to patients the

importance of reporting any new or worsening symptoms

Conclusions:

Presented By Leonard Saltz at 2015 ASCO Annual Meeting