Evolving Strategies for Enhancing the Impact of Immunotherapy in Breast Cancer

Hope S. Rugo, MD, FASCO

Professor of Medicine

Director, Breast Oncology and Clinical Trials Education

University of California San Francisco Comprehensive Cancer Center

TILS in Breast Cancer

• High TILS are more frequent in TNBC (30%)>HER2 (19%)>luminal tumors (13%)

• Correlate with grade but not other CP factors

• High TILS predictive of:

• DFS and OS in TN early stage breast cancer

• pCR in TN and HER2+ breast cancer

• Improved DFS and OS in untreated largely node negative TNBC (>30%)

• International consensus scoring recommendations see www.tilsinbreastcancer.org

Salgado, Denkert et al, 2014 Ann Oncol

Denkert et al 2016 Modern Path

Loi et al, JCO 2019; TILs images from www.tilsinbreastcancer.org

Park et al, Ann Oncol 2019

0% TILS 30% TILS

80% TILS

Checkpoint Inhibitor Monotherapy: Line of Therapy MattersAgent Subtype N ORR ORR (PD-L1+)*

Pembrolizumab• Single agent (Keynote-012)• Single agent (Keynote-028)• Single agent (Keynote-086-A)• Single agent (Keynote-086-B)• Plus trastuzumab (PANACEA)

TNBCER+

TNBCTNBCHER2+

3225

1708458

18.5%12.0%

5.7% (PD-L1+)21.4%

18.5%12.0%5.7%

21.4%15.0%

Atezolizumab• Single agent• Single agent (expanded)

TNBCTNBC

21115

19.0%10.0%

IL (n=21): 26%; >2L (n=91): 6%

19.0%13.0%

Avelumab• Single agent (Javelin) All

ER+/HER2-HER2+TNBC

168723858

4.8%2.8%3.8%8.6%

33.3%NRNR

44.4%

*Studies used different antibodies and cutoffs for PD-L1 positivity

Nanda et al, JCO 2016; Rugo et al, CCR 2018; Dirix et al, BCRT 2017; Loi et al, SABCS 2017; Emens et al, JAMA Onc 2019; Adams et al, Ann Onc 2019

Immunologic Differences Between Primary and

Metastatic Tumor Samples

Percent TIL counts in full

sections and TMAs.

PD-L1 + rates (≥1%

stromal or tumor cells)Change in PD-L1 status

between the primary and

metastatic cohorts.

Szekely, et al (Pusztai), Ann Oncol 2018

Monotherapy: Overall Survival by RECIST in First-Line Setting Atezolizumab Pembrolizumab

Adams et al, Ann Onc 2019; Emens et al, Jama Onc 2019

N=84Median OS: 18 mo

N=116Median OS: 17.6mo

Augmenting the Cancer

Immunity Cycle

Chen DS and Mellman I. Immunity 2013;39:1-9

◆ Co-primary endpoints were PFS and OS in the ITT and PD-L1+ populationsd

– Key secondary efficacy endpoints (ORR and DOR) and safety were also evaluated

IMpassion130 study design

Schmid P, et al. NEJM 2018, ASCO 2019

IC, tumour-infiltrating immune cell; TFI, treatment-free interval. a ClinicalTrials.gov: NCT02425891. b Locally evaluated per ASCO–College of American Pathologists (CAP)

guidelines. c Centrally evaluated per VENTANA SP142 IHC assay (double blinded for PD-L1 status). d Radiological endpoints were investigator assessed

(per RECIST v1.1).

Key IMpassion130 eligibility criteriaa:

• Metastatic or inoperable locally advanced TNBC

‒ Histologically documentedb

• No prior therapy for advanced TNBC

‒ Prior chemo in the curative setting, including

taxanes, allowed if TFI ≥ 12 mo

• ECOG PS 0-1

Stratification factors:

• Prior taxane use (yes vs no)

• Liver metastases (yes vs no)

• PD-L1 status on IC (positive [≥ 1%] vs negative [< 1%])c

Atezo + nab-P arm:

Atezolizumab 840 mg IV

‒ On days 1 and 15 of 28-day cycle

+ nab-paclitaxel 100 mg/m2 IV

‒ On days 1, 8 and 15 of 28-day cycle

Plac + nab-P arm:

Placebo IV

‒ On days 1 and 15 of 28-day cycle

+ nab-paclitaxel 100 mg/m2 IV

‒ On days 1, 8 and 15 of 28-day cycle

Double blind; no crossover permittedRECIST v1.1

PD or toxicityR1:1

Rugo et al. Abstract 6571

IMpassion130 PD-L1 IHC

https://bit.ly/30OmOqz

PD-L1 IC status by SP142 predicts PFS and OS

benefit with atezolizumab + nab-paclitaxel1,2

(41% positive by SP142)

A + nP, atezolizumab + nab-paclitaxel; HR, hazard ratio; ITT, intention to treat; OS, overall survival; P + nP, placebo + nab-paclitaxel; PFS, progression-free survival.

PD-L1 IC+: PD-L1 in ≥ 1% of IC as percentage of tumour area assessed with the VENTANA SP142 assay.

NCT02425891. Stratification factors: prior taxane use, liver metastases and PD-L1 IC status. Co-primary endpoints in ITT and PD-L1 IC+: PFS and OS.

Clinical cutoff date: 2 January 2019.

1. Schmid, ASCO 2019. 2. Schmid et al., submitted.

PopulationMedian OS HR

(95% CI)A + nP P + nP

PD-L1 IC+ 25.0 mo 18.0 mo0.71

(0.54, 0.93)

PD-L1 IC- 19.7 mo 19.6 mo0.97

(0.78, 1.20)

PopulationMedian PFS HR

(95% CI)A + nP P + nP

PD-L1 IC+ (41%) 7.5 mo 5.3 mo0.63

(0.50, 0.80)

PD-L1 IC- (59%) 5.6 mo 5.6 mo0.93

(0.77, 1.11)

A + nP (IC+, n = 185)

P + nP (IC+, n = 184)

A + nP (IC-, n = 266)

P + nP (IC-, n = 267)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 420 3 6 9 12 15 18 21 24 27 30 33 36 39 42

100

90

80

70

60

50

40

30

20

10

0

100

90

80

70

60

50

40

30

20

10

0

Overa

ll S

urv

ival (%

)

Pro

gre

ssio

n-F

ree S

urv

ival (%

)

MonthsMonths

Immune-Related Adverse Events

Schneeweiss, Rugo et al, ASCO 2019

AESI = adverse event of special interest

Immune-Mediated AESI Requiring Systemic Corticosteroids

Most Clinically Relevant AESI by Grade

Rugo et al. Abstract 6571

IMpassion130 PD-L1 IHC

https://bit.ly/30OmOqz

Efficacy in PD-L1 IC+

PFS OS

Pri

mary

Meta

sta

tic

PD-L1 status in primary vs metastatic tissues

a Evaluable population (n = 901). PD-L1 IC+: PD-L1 in ≥ 1% of IC as percentage of tumour area assessed with the VENTANA SP142 assay.

HRs adjusted for prior taxanes, presence of liver metastases, age and ECOG PS. No major differences were observed for clinical benefit in samples collected within 61 days of randomization or

beyond that period (Emens, et al, manuscript in preparation).

Atezolizumab + nab-paclitaxel

Placebo + nab-paclitaxel

HR, 0.61 (95% CI: 0.47, 0.81)

HR, 0.55 (95% CI: 0.32, 0.93)

HR, 0.79 (95% CI: 0.57, 1.09)

HR, 0.69 (95% CI: 0.46, 1.03)S

urv

ival (%

)

Surv

ival (%

)S

urv

ival (%

)

Surv

ival (%

)

Months

MonthsMonths

Months

44%

36%

0% 20% 40% 60%

Primary tissue (62%)

Metastatic tissue (38%)

P = 0.014

43%

51%

43%

13%

30%

48%

36%

0% 20% 40% 60%

Breast (64%)

Lymph node (12%)

Lung (6%)

Liver (5%)

Soft tissue (4%)

Skin (2%)

Other (6%)

PD-L1 IC+

PD-L1 status by

primary vs metastatic tissuea

PD-L1 status by anatomical locationa

PD-L1 IC+▪ Median time of sample collection to randomization: 61 days

Rugo et al. Abstract 6571

IMpassion130 PD-L1 IHC

https://bit.ly/30OmOqz

▪ Intensity of PD-L1 staining did not impact clinical outcome (1 – 3+) (Emens et al, SABCS2018)

▪ Central testing of VENTANA PD-L1 SP142, DAKO 22C3 and VENTANA PD-L1 SP263

IHC assays performed according to the respective package insertsa

▪ PD-L1 IC algorithm (SP142 and SP263)

− Presence of discernible PD-L1 staining of any intensity in IC covering ≥ 1% of tumour area occupied by

TC, associated intratumoural and continuous peritumoural stroma

▪ PD-L1 CPS algorithm (22C3)

− Number of PD-L1–stained cells (TC, lymphocytes and macrophages) divided by the total number of viable

TC, multiplied by 100

▪ BEP population: 614 patients (68% of ITT) with samples tested with the 3 PD-L1 assays

− Prevalence of PD-L1 IC+ status according to SP142 was higher in the BEP (46%) than the ITT (41%).

All other evaluated baseline characteristics were balanced between BEP and ITT

− PFS outcome with A + nP in the BEP slightly overperformed compared with PFS outcome in the ITT

Comparison of PD-L1 Assays:

Exploratory post hoc IMpassion130 substudy

CPS, combined positive score; TC, tumour cells. a Using respective platforms. b SP142: 5 pathologists trained for TNBC; 22C3: 2 pathologists trained for non-TNBC; SP263: 3 pathologists trained for non-TNBC.

Rugo et al. Abstract 6571

IMpassion130 PD-L1 IHC

https://bit.ly/30OmOqz

SP142 (IC 1%)

and SP263 (IC 1%)

OPAc 69%

PPA 98%

NPA 45%

SP142 (IC 1%)

and 22C3 (CPS 1)

OPAc 64%

PPA 98%

NPA 34%

PD-L1 IHC assays: prevalence and

analytical concordance

NPA, negative percentage agreement; OPA, overall percentage agreement; PPA, positive percentage agreement.a > 97% of SP142+ samples included in 22C3+ or SP263+ samples. b Compared with 41% in ITT (Schmid, New Engl J Med 2018).c ≥ 90% OPA, PPA and NPA required for analytical concordance.

SP142-

22C3-

(18%)

SP142+

22C3+

(45%)a

SP142-

22C3+

(36%)

SP142+

22C3-

(1%)

SP142-

SP263+

(30%) SP142-

SP263-

(24%)

SP142+

SP263+

(45%)a

PD

-L1+

Cases

PD-L1+

prevalence

SP142+

SP263-

(1%)

46%

81%

75%

0%

20%

40%

60%

80%

100%

SP142 (IC ≥ 1%)

22C3 (CPS ≥ 1)

SP263 (IC ≥ 1%)

b

Rugo et al. Abstract 6571

IMpassion130 PD-L1 IHC

https://bit.ly/30OmOqz

Population PFS OS

SP142+

22C3+(45%; 279/614)

SP142-

22C3+(36%; 218/614)

SP142-

22C3-(18%, 111/614)

Median OS, mo HR

(95% CI)A + nP P + nP ∆

27.3 18.0 9.3 0.71 (0.52, 0.98)

Median PFS, mo HR

(95% CI)A + nP P + nP ∆

8.3 3.9 4.4 0.60 (0.46, 0.78)

Clinical outcomes in BEP subpopulations

defined by SP142 (IC 1%) and 22C3 (CPS 1)13

Double positive: SP142 IC ≥ 1%, 22C3 CPS ≥ 1; single positive: SP142 IC < 1%, 22C3 CPS ≥ 1; double negative: SP142 IC < 1%, 22C3 CPS < 1.

HR adjusted for prior taxanes, presence of liver metastases, age and ECOG PS.

7.3 5.6 1.7 0.81 (0.61, 1.09) 21.3 21.8 −0.5 0.92 (0.64, 1.31)

5.5 5.6 −0.1 1.00 (0.66, 1.51) 14.7 19.6 −4.9 1.08 (0.67, 1.76)

Double

positives

Single

positives

Double

negatives

Surv

ival (%

)

Surv

ival (%

)

Months

Months

Months

Months

Surv

ival (%

)

Surv

ival (%

)

Surv

ival (%

)

Surv

ival (%

)

Months Months

Rugo et al. Abstract 6571

IMpassion130 PD-L1 IHC

https://bit.ly/30OmOqz

In this post hoc exploratory biomarker sub-study of the IMpassion130 trial

▪ Clinical activity was observed in the SP142 PD-L1 IC+ subgroup, regardless of whether

the sample was from the primary tumour or metastatic tissue

▪ With overall percentage agreements of 64% (22C3) and 69% (SP263), the analytical

concordance was subpar (< 90%) and the assays are not equivalent

− 22C3 (CPS ≥ 1) and SP263 (IC ≥ 1%) PD-L1 assays identified a larger patient population

of which SP142+ (IC ≥ 1%) is a subgroup

▪ The clinical benefit in 22C3+ and SP263+ subgroups was driven by the SP142+ subgroup

− The SP142 assay identified patients with the smallest HR point estimates and

longest median PFS and OS from atezolizumab + nab-paclitaxel

▪ At the present time, the SP142 assay at IC >1% cutoff is the approved diagnostic test used

to identify patients with mTNBC most likely to benefit from the addition of atezolizumab to

nab-paclitaxel

Conclusions

0 5 10 15 20 25 30 35 40

0

10

20

30

40

50

60

70

80

90

100

Time, monthsNo. at risk

312 224 154 112 76 57 031 6

310 233 163 108 75 48 021 6

Pembro

Chemo

OS

, %

0 5 10 15 20 25 30 35 40

0

10

20

30

40

50

60

70

80

90

100

Time, months

OS

, %

No. at risk

203 151 109 76 51 40 020 3

202 152 102 66 42 27 012 3

Pembro

Chemo

0 5 10 15 20 25 30 35 40

0

10

20

30

40

50

60

70

80

90

100

Time, months

OS

, %

No. at risk

96 79 57 41 26 23 011 1

98 80 54 36 23 12 04 1

Pembro

Chemo

0 5 10 15 20 25 30 35 40

0

10

20

30

40

50

60

70

80

90

100

Time, months

OS

, %

No. at risk

57 50 39 28 21 18 08 1

52 41 29 20 13 6 02 0

Pembro

Chemo

Events

HR

(95% CI) P

77.1% 0.78

(0.57-1.06)

0.057

88.8%

Events

HR

(95% CI) P

84.2% 0.86

(0.69-

1.06)

0.073

90.6%

Events HR (95% CI)

85.3% 0.97(0.82-1.15)

88.1%

Events HR (95% CI)

70.2% 0.58 (0.38-0.88)

92.3%

OS in the ITT, CPS ≥1 and CPS ≥10 populations were primary endpoints; OS in the CPS ≥20 population was an exploratory endpoin t. Data cutoff date: April 11, 2019

KEYNOTE 119: Phase III Pembrolizumab vs. Chemo in 2L/3L TNBC: OS by PD-L1 CPS

ITT

N=622

CPS ≥1

CPS ≥10 CPS ≥20

Median (95% CI)

12.7 mo (9.9-16.3)

11.6 mo (8.3-13.7)

Median (95% CI)10.7 mo (9.3-12.5)

10.2 mo (7.9-12.6)

Median (95% CI)

14.9 mo (10.7-19.8)

12.5 mo (7.3-15.4)

Median (95% CI)

9.9 mo (8.3-11.4)

10.8 mo (9.1-12.6)

Cortes et al, ESMO 2019

65%

31% 18.5%

0 10 20 30 400

10

20

30

40

50

60

70

80

90

100

Time, monthsNo. at risk

312 154 76 31 0

203 109 51 20 0

All

CPS 1

OS

, %

CPS 10

CPS 20

96 57 26 11 0

57 39 21 8 0

0 10 20 30 400

10

20

30

40

50

60

70

80

90

100

Time, monthsNo. at risk

310 163 75 21 0

202 102 42 12 0

All

CPS 1

OS

, %

CPS 10

CPS 20

98 54 23 4 0

52 29 13 2 0

OS by PD-L1 CPS: Role of high score?

Data cutoff date: April 11, 2019.

ChemoPembro

Cortes et al, ESMO 2019

I-SPY ™ | The right drug. The right patient. The right time.™

pCR is a highly significant predictor of EFS and DRFS

17

I-SPY2 TRIAL

EFS DRFSOVERALL

Yee et al SABCS 2018

Event Free Survival by pCR & non-pCR by SubtypeI-SPY2 TRIAL

Yee et al., SABCS 2018

pCR is a Great Early Endpoint

I-SPY2: Pembrolizumab Graduated for Efficacy in HER2-Negative Cohorts

Current I-SPY2 Immunotherapy Arms:• Pembolizumab x 8, extended through AC• Olaparib/Durvalumab/Pac -> AC• SD101/paclitaxel/pembrolizumab -> AC

Nanda et al, ASCO 2017

SD-101:TLR9 agonist (30 nucleotide

phosphorothioate oligodeoxynucleotide with

juxtaposed CpG motifs)

aMust consist of at least 2 separate tumor cores from the primary tumor. bCarboplatin dose was AUC 5 Q3W or AUC 1.5 QW.cPaclitaxel dose was 80 mg/m2 QW.

dDoxorubicin dose was 60 mg/m2 Q3W.eEpirubicin dose was 90 mg/m2 Q3W.fCyclophosphamide dose was 600 mg/m2 Q3W.

KEYNOTE-522 Study Design (NCT03036488)

Stratification Factors:• Nodal status (+ vs -)• Tumor size (T1/T2 vs T3/T4)• Carboplatin schedule (QW vs Q3W)

Key Eligibility Criteria

• Age ≥18 years

• Newly diagnosed TNBC of

either T1c N1-2 or T2-4 N0-2

• ECOG PS 0-1

• Tissue sample for PD-L1

assessmenta

Neoadjuvant Treatment 1

(cycles 1-4; 12 weeks)

Neoadjuvant Treatment 2

(cycles 5-8; 12 weeks)

Adjuvant Treatment

(cycles 1-9; 27 weeks)

Carboplatinb +

Paclitaxelc

Doxod/Epirubicine+

Cyclophosphamidef

Pembrolizumab 200 mg Q3W

84% PD-L1+

Pembrolizumab 200 mg Q3W

Placebo

81% PD-L1+

Placebo

R

2:1

Neoadjuvant Phase Adjuvant Phase

Carboplatinb +

Paclitaxelc

Doxod/Epirubicine +

Cyclophosphamidef

S

U

R

G

E

R

Y

Neoadjuvant phase: starts from the first neoadjuvant treatment and ends after definitive surgery (post treatment included)

Adjuvant phase: starts from the first adjuvant treatment and includes radiation therapy as indicated (post treatment included)

PD-L1 + defined by CPS >1

Schmid et al, ESMO 2019

Pathological Complete Response at IA1Total N=1174; pCR in 1st 602 pts, P value boundary for significance 0.003

aEstimated treatment difference based on Miettinen & Nurminen method stratified by randomization stratification factors. bPD-L1 assessed at a central laboratory using the PD-L1 IHC

22C3 pharmDx assay and measured using the combined positive score (CPS; number of PD-L1–positive tumor cells, lymphocytes, and macrophages divided by total number of tumor

cells x 100); PD-L1–positive = CPS ≥1. Data cutoff date: September 24, 2018 – after last patient enrolled

0

10

20

30

40

50

60

70

80

90

100

ypT0/Tis ypN0

pC

R,

% (

95

% C

I)

Primary Endpoint: ypT0/Tis ypN0

64.8%

51.2%

Δ 13.6 (5.4–21.8)a

P=0.00055

0

10

20

30

40

50

60

70

80

90

100

PD-L1–Positive PD-L1–Negative

pC

R,

% (

95

% C

I)

By PD-L1 Statusb: ypT0/Tis ypN0

68.9%

54.9%

Δ 14.2 (5.3–23.1)a

45.3%

30.3%

Δ 18.3 (–3.3–36.8)a

260/401 103/201 230/334 90/164 29/64 10/33

Pembro + Chemo

Placebo + Chemo

Event-Free Survival at IA2: 1st Interim AnalysisP value boundary for significance 0.000051 (HR<0.4)

aPrespecified P value boundary of 0.000051 not reached at this analysis (the first interim analysis of EFS). IA2: If pCR hypothesis successful at IA1, pCR will not be formally tested at IA2

HR (CI) analyzed based on a Cox regression model with treatment as a covariate stratified by randomization stratification fac tors. Data cutoff April 24, 2019; 24 mo after last pt enrolled

0 3 6 9 12 15 18 21 24 270

10

20

30

40

50

60

70

80

90

100

Months

EF

S, %

No. at Risk784 780 666 519 242376 073 2765390 386 337 264 116186 035 1380

91.3%

85.3%

EventsHR

(95% CI)

Pembro + Chemo/Pembro 7.4% 0.63a

(0.43-0.93)Placebo + Chemo/Placebo 11.8%

Immune related Aes:

• 14.1 vs 2.1% grade 3-5

Discontinuation of any drug:

• 9.5 vs 2.6% 9% events with median FU 15.5 months

Immune-Mediated AEs and Infusion Reactions in Combined Phases: IA2

0

10

20

30

40

50

60

70

80

90

100

Inc

ide

nc

e, %

a1 patient from pneumonitis.

Considered regardless of attribution to treatment or immune relatedness by the investigator. Related terms included in additi on to preferred terms listed. Data cutoff date: April 24, 2019.

Immune-Mediated AEs and Infusion Reactions With Incidence ≥10 Patients

1-2

Grade

3-5

Pembro Arm

Placebo Arm

Pembro Arm(N = 781)

Placebo Arm(N = 389)

Any grade 42.3% 21.3%

Grade 3-5 14.1% 2.1%

Led to death 0.1%a 0

Led to discontinuation of any drug

9.5% 2.6%

17.7

11.614.9

5.7 5.5

1.05.1

1.8 2.70

1.9 1.5 1.8 0.8 1.8 0.3 1.7 1.0 1.4 0.5

*Tissue: FFPE, fresh frozen;

Liquid biopsies: full blood; plasma, serum;

GeparNUEVO Study Design

12 weeks*

Su

rge

ry

Nab-Pac

+DurvalumabN=174

TNBC

Stratum:TILs

(low/med/high)C

linic

al re

sp

on

se

R

Durvalumab

Placebo

2 weeks

Co

re b

iop

sy Nab-Pac

+PlaceboECx4

+Placebo

ECx4

+Durvaluma

b

8 weeks

Window of opportunity

until amendment

Durvalumab

(0.75g) 1.5g d1q28 nab-Paclitaxel 125mg/m²

weekly

Epirubicin 90mg/m²;

Cyclophosphamide 600mg/m² d1q14

Loibl et al, Ann Oncol 2019

Subgroup Analysis of the Window Cohort(Overall pCR 52.4% vs 44.2%; Adjusted OR 1.53, p 0.182)

61.0%

41.4%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Durvalumab Placebo

P=0.052

37.9%

50.0%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Durvalumab Placebo

P=0.515

Window (N=117) No window

(N=57)

N=59 N=58 N=29 N=28

pCR +carbo/pac pCR + pac pCR + IO carbo/pac delta

Meta-analysis Poggio et al 2018

52.1%

KN522

N=1174

51.2% ITT 64.8% (pembro) 13.6%

ISPY2 20% 60%(pembro/no carbo) NA

GeparNeuvo

ITT

N=174

44.2% 53.4%(durva/no

carbo/nab-pac)

9.2%

GeparNeuvo

window

N=117

ITT 41.4% ITT 61% 19.6%

KN173 N=80

window

Single arm ITT 60% (pembro) NA

pCR Rates Across IO Studies

Courtesy of Sherene Loi; adapted

Stage I/II high TIL/PD-L1 patients do very well

Should we personalize treatment based on TILS?

50-67% 56-71%

Do All Patients with Early Stage TNBC Need Immunotherapy?

81-89% 86-93%

91-97% 95-99%

N=2210 early stage TNBC patients treated with AC-T;

Loi et al, JCO 2019

Ongoing Phase III Trials with IO in TNBC

Neoadjuvant/adjuvant

• Atezolizumab

• Impassion 31 (n=204)

• Nab-pac AC or EC

• NeoTRIPaPDL1 (n=272)

• Nab-pac/Carbo (no post-op IO)

• NSABP B59/GeparDouze (n=1520)

• Pac/carbo AC/EC

• Pembrolizumab

• EFS Keynote 522

Adjuvant

• Atezolizumab• Impassion 30 (n=2300)

• Pac AC/EC

• Avelumab• A-Brave (n=335)

• Adjuvant and post NAC high risk: avelumab alone

• Pembrolizumab• SWOG S1418/NRG BR006 (n=1000)

• Post NAC: Pembro vs Obs x 1 yr

Metastatic:• Keynote 355: Pembro + gem/carbo or paclitaxel/nab-P• Impassion 131: Atezo + paclitaxel • Impassion 132: Atezo + gem or carbo or capecitabine

Improving the response to immunotherapy

Turning cold tumors hot

TONIC Trial

Radiotherapy 3x 8 Gy

Doxorubicin2x 15 mg IV

Cyclophosphamide2 weeks 50 mg daily

Cisplatin2x 40 mg/kg IV

ControlNo induction

Randomization

anti-PD1

2 weeks

anti-PD1

anti-PD1

anti-PD1

anti-PD1

biopsy + blood biopsy + blood biopsy + blood

8 weeks

Voorwerk et al, Nat Medicine 2019

Anti-PD1: Nivolumab

7 patients who died within 6 weeks of nivolumab are not included

Biomarkers in the TONIC Trial

TONIC stage II: randomized to doxorubicin lead-in or no lead-in

InCITe: Innovative Combination Immunotherapy for Metastatic Triple Negative BC

TBCRC 047

A multicenter, multi-arm TBCRCstudy funded by the Breast Cancer Research Foundation

PI: Hope S. Rugo; Co-PI: Ingrid Mayer

Metastatic TNBC• Measurable disease

• No more than 3 prior metastatic lines of chemotherapy• Known PD-L1 status

• Prior IO allowed

Tumor biopsy

Blood collection

Utomilumab

Binimetinib

PF04518600

Binimetinib + Avelumab

Utomilumab + Avelumab

PF04518600 + Avelumab

Tumor biopsy

Blood collection

15 day lead-in1 Cycle=4 weeksTumor assessments & PRO q 8 wks

Blood collection (at

8 weeks and at PD)

Novel agent 1: Binimetinib, a MEK inhibitor

Novel agent 2: Utomilumab, a 4-1BB agonist

Novel agent 3: PF04518600, an OX40 agonist

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PARP Inhibition May Enhance Immune Surveillance Through Multiple Mechanisms

Topacio and Mediola trials indicate safety combining PARPi with IO: subset analysis unclear (Domchek, Vinayak, SABCS 2018)

MEDIOLA:SchemaforThirdStage

PI:Domchek,OT3-5-03,SABCS2018

Enhancing Efficacy of Immunotherapy:Paclitaxel/Atezolizumab plus Ipatasertib

The combination of (nab-)paclitaxel, ipatasertib and atezolizumab not approved for triple-negative breast cancer, investigational use. AKT, protein kinase B; CI, confidence interval; IV, intravenous; ORR, objective response rate; PD, progressive disease; PD-L1, programmed death-ligand 1; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha;PR, partial response; SD, stable disease; SLD, sum of longest diameters; TNBC, triple-negative breast cancer. Schmid P, et al. AACR 2019 (Abstract CT049).

ORR 73% (95% CI = 53, 88)

- PD-L1+: 82%

- PD-L1–: 75%

- PIK3CA/AKT+: 71%

- PIK3CA/AKT–: 82%

A phase III trial is planned

Enhancing the Efficacy of Immunotherapy

• Most studies in breast are studying CPI; a small number of trials are evaluating vaccines and adoptive T-cell therapy

Adams et al, JAMA Onc 2019

Immune-Related AEs

Postow et al: NEJM. 2018Cancer Treatment Reviews 45 (2016) 7–18

Awareness, provider and patient education, early intervention is critical

Case History

• 40 year old woman

• Stage II TNBC treated with AC/T and radiation

• No germline mutation

• 1.5 years later routine CXR picks up nodular density

• CT: multiple pulmonary nodules

• FNA+ TNBC

• Treatment

• Capecitabine: stabilitization then increase in one nodule at 10 weeks

• Pembrolizumab on single agent >2nd line trial

Outcome• CT scans: reduction in lung nodules

• After a trip to Mexico 3 months after starting pembrolizumab, developed diarrhea that improved then worsened after a brief antibiotic course

• Colonoscopy with blind biopsy revealed inflammatory changes consistent with immune colitis

• With loperamide, up to 3 loose stools/day

• Treated with oral budesonide with complete resolution of symptoms

• CT scan at 8 months: one residual 1 cm nodule RUL, no FDG avidity

• SBRT to single nodule

• 4.5 years after starting pembrolizumab, remains NED on occasional budesonide

• Immunotherapy comes of age in breast cancer!

• Checkpoint blockade + chemotherapy

• IMpassion130: Defining a subset of patients with mTNBC who benefit!

• Regulatory approval for atezolizumab + nab-paclitaxel as first line therapy for PD-L1+

(IC) mTNBC

• Survival benefit > PFS benefit suggests change in tumor microenvironment and host

response

• Keynote 522: success in treating earlier line independent of PD-L1 positivity?

• Await EFS results next year

• Novel combination strategies offer great promise

• Role in HER2+ and ER+ disease also being actively explored

Conclusions

The Dawn of Immunotherapy for Breast Cancer!

Thank you!