LETTURA:

IMMUNO ONCOLOGY IN BREAST CANCER:

OPPORTUNITIES AND CHALLENGES

Pierfranco ConteDiSCOG - Università di Padova

Oncologia Medica 2 - Istituto Oncologico Veneto IRCCS

PierFranco Conte Disclosure of potential conflicts of interests

• Consultant:Novartis, EliLilly, Astra Zeneca, Tesaro

• Honoraria:BMS,Roche, EliLilly, Novartis, AstraZeneca

• Research Funding from profit organizations:Novartis, Roche, EliLilly, BMS, Merck-KGa

• Funding from non profit organizations:National Research Council, Ministry of Education and Research, Italian Association for Cancer Research, Italian Drug Agency (AIFA), EmiliaRomagna Secretary of Health, Veneto Secretary of Health, University of Padova, Ministry of Health

Immuno-oncology in Breast Cancer: Opportunities

Alexandrov, Nature 2013

Mutational load across tumor types

Luen S et al, Breast 2016

QUALITY and not (only) QUANTITY of neoantigens is important for response to immunotherapy(reviewed by McArthur HL, ASCO 2018)

Median %

N None/absent Intermediate/present High

All 4161 16 89 11

TN 1640 15 80 20

HER2+ 929 9 84 16

HR+ 2410 20 94 6

2016

High TILs are associated with increased pCR rates

Denkert C, Lancet Oncol 2018

TILs: established prognostic factor for TNBC

OS

Loi S, J Clin Oncol 2019

Activity of immunotherapy after Pseudo-progression

Adams S, ASCO 2017

Pembrolizumab single agent in

TNBC PD-L1+, untreated for MBC

Pembrolizumab single agent in TNBC

PD-L1+/-, >2L

KEYNOTE-086

Cohort A

KEYNOTE-086

Cohort B

Immune checkpoint inhibitors in metastatic TNBC:

durable responses

Adams S, ASCO 2017

Adams S, ASCO 2017; Emens L, JAMA Oncol 2018; Dirix L, BCRT 2018

Immune checkpoint inhibitor in mTNBC:

key results from phase I/II monotherapy studies

• Modest overall response rates, higher in 1st line (up to 24%)

• Responses in both PD-L1+ and PD-L1- patients

• Some durable responses

Dieci MV, et al. Ann Oncol. 2014 Bracci L, et al. Cell Death Differ 2014

Chemotherapy as a trigger for immune activation

Kok M, Nat Med 2019

TONIC phase II studyInduction→ Nivolumab (n=66 mTNBC)

The doxorubicin cohort as an «immune induction» will be expanded in the stage II of the trial.

Max 3

lines

MBC

ORR%

CT + immune checkpoint inhibitor for mTNBC PD-L1+/-

ORR 26%, mPFS 4.2 months, mOS 17.7 months

Atezolizumab + nab-paclitaxel, n=33 Pembrolizumab + eribulin, n=107

Tolaney S, SABCS 2017

PD-L1+

PD-L1-

PD-L1 NA

PD-L1+

PD-L1-

PD-L1 NA

1st line: ORR 29.2%

2nd-3rd line: ORR 22%All

N=33

1° line

N=13

2° line

N=20

PD-L1+

N=12

PD-L1-

N=12

Confirmed ORR 13 (39) 7 (54) 6 (30) 5 (42) 4 (33)

Median DoR, m 9.1 7.8 10.9 9.1 10.2

Median PFS 5.5 8.6 5.1 6.9 5.1

Median OS 14.7 24.2 12.4 21.9 11.4

Adams S, JAMA Oncol 2018

Schmid P, ESMO 2018, NEJM 2018

Primary analysis: PFS

Schmid P, NEJM 2018

PFS ITT

Events/pts mPFS, months (95%CI) 1yr PFS% (95%CI)

Atezo+Nab 358/451 7.2 (5.6-7.5) 23.7 (19.6-27.9)

Plac+Nab 378/451 5.5 (5.3-5.6) 17.7 (14.0-21.4)

HR 0.80 (95%CI 0.69-0.92)

P=0.0025

PD-L1+ mPFS, months (95%CI) 1yr PFS% (95%CI)

Atezo+Nab 7.5 (6.7-9.2) 29.1 (22.2-36.1)

Plac+Nab 5.0 (3.8-5.6) 16.4 (10.8-22.0)

PFS by PD-L1

41% PD-L1+

SP142, 1% of positively stained IC over the total tumor area

IMpassion130: OS

2° interim (59% deaths in ITT population)

ITT By PD-L1

Schmid P, ASCO 2019

Formal testing not performed for hierarchical study design

GeparNUEVO Study Design

Loibl S, ASCO 2018, Ann Oncol 2019

Loibl S, ASCO 2018, Ann Oncol 2019

GeparNuevo: study results

KEYNOTE – 522 study design

N=1174

KEYTRUDA is the First Anti-PD-1 Therapy to Demonstrate a Statistically Significant Improvement in pCR Rates as

Neoadjuvant Therapy for TNBC Regardless of PD-L1 Status

Setting Trial Phase Regimen Patients StatusEstimated

End

Neoadjuvant

NCT03639948 (NeoPACT)

II Carboplatin + docetaxel + pembrolizumab 100 R November 2024

NCT03289819 II Pembrolizumab + Nab-paclitaxel➔ pembrolizumab + epirubicin and cyclophosphamide 50 R December 2019

NCT03356860(B-IMMUNE)

II Paclitaxel + epirubicin + cyclophosphamide ± durvalumab 57 R April 2021

Neoadjuvant/

Adjuvant

NCT03036488 (KEYNOTE-522)

III Carboplatin + paclitaxel + (anthracycline)+ cyclophosphamide ± pembrolizumab➔ pembrolizumab 1174 ANR September 2025

NCT03281954 III Doxorubicin + cyclophosphamide + paclitaxel + carboplatin ± atezolizumab➔ atezolizumab 1520 R June 2024

NCT03197935 (IMpassion031)

III Doxorubicin + cyclophosphamide + nab-paclitaxel ± atezolizumab➔ atezolizumab 204 ANR January 2023

Adjuvant only for

patients with

residual disease

after neoadjuvant

chemotherapy

NCT02954874 III Pembrolizumab vs. observation 1000 R May 2026

NCT03756298 II Capecitabine ± atezolizumab 284 R January 2027

Adjuvant

NCT03498716 (IMpassion030)

III Paclitaxel➔ dose-dense doxorubicin/epirubicin + cyclophosphamide ± atezolizumab 2300 R December 2024

NCT02926196(A-Brave)

III Avelumab vs. observation 335 R November 2024

R recruiting, ANR active, not recruiting

Estimated End of ongoing Immunotherapy Trials in early TNBC

Immuno-oncology in Breast Cancer: Opportunities

• TILs are prognostic & predictive across breast cancer subtypes(more solid data for TN disease)

• ICIs have a modest activity as single agents in advanced TNBC

• Chemotherapy can trigger immunity and is synergistic with ICIs

• Impassion 130 trial demonstrates the efficacy of ICIs + chemo foradvanced TNBC

• PD-L1 may enrich the population of patients benefiting from ICIs

• KEYNOTE 522 data coming soon

Immuno-oncology in Breast Cancer: Challenges

PD-L1 +

«FDA-approved test»

PD-L1+

So far, EMA has not approved any PD-L1 test

IMPASSION 130 KEYNOTE - 522

IMP Atezolizumab Pembrolizumab

Patients 902 1174

EndpointPFS, OS

(ITT population, PD-L1 +)

pCR, EFS

(ITT population, PD-L1+)

Antibody SP142 (Ventana) 22C3 (Dako)

PD-L1 positivity cutoff PD-L1 on IC (percentage of tumor area): ≥1% CPS: ≥ 1%

Results Approved for PD-L1+ only Positive regardless of PD-L1

ICIs for TNBC - Studies comparison

“The Clone Wars”

5 drugs, each with its own PD-L1 IHC assay

Comparison of PD-L1 IHC antibodies in TNBC

Scott M, ESMO Breast 2019

Loi S, ESMO 2017

KEYNOTE-086: TILs and ORR

ASSOCIATED WITH ORR IN MULTIVARIABLE ANALYSIS

TIL-/PD-L1+ tumors benefit from immunotherapy + CT

• Which effector cells drive the benefit from immunotherapy?

• Role of CT?

TIL+/PD-L1- tumors do not benefit from immunotherapy + CT

• No need for immunotherapy?

• Other suppressors involved?

Methods:

• Multiple studies showed at least moderate correlation between PD-L1 and TILs : are the cut-offs

reliable?

• No analyses with continuous variables were presented or interaction with TILs

• Concordance for PD-L1 evaluation 1% cut-off is low (Solinas C, AACR 2018)

• 2/3 of samples from primary tumors: does this reflect the immune landscape of metastatic disease?

IMpassion130: consideration on biomarker data

Post NeoAdjuvant trials to de-escalate treatment

PST

Chemotherapy

Chemo + antiPD1/PDL1

After PST< pCR

No further therapy

AntiPDL1

HR 0.60 = NNT 18

HR 0.60 = NNT 5

HIGH RISK PRIMARY TNBC PTS WHO COMPLETED TREATMENT

WITH CURATIVE INTENT INCLUDING SURGERY, CHEMOTHERAPY AND

RADIOTHERAPY (if indicated)

Stratum A: AdjuvantStratum B: Post-neoadjuvant

R

Avelumab for 1 year

Observation

Co-primary endpoints: 1. DFS in all-comers; 2. DFS in PD-L1+ patientsSecondary endpoints: OS, Safety, Biomarkers

n=335 (for the 1st co-primary endpoint)

Randomization 1:1 balanced for adjuvant and post-neoadjuvant patients. Amendment 2, v3.0: post-neoadjuvant CT for up to 6 months allowedprior to randomization

Preplanned Correlative Studies

Tumor Tissue biomarkers- PD-L1

- Necessary for second co-primary endpoint evaluation

- TILs- HES slides (Salgado R., Ann oncol 2014)- TILs characterization (CD8, foxp3, CD56) and other immune biomarkers by IHC

- Panel of DNA mutations

- Gene expression

Circulating biomarkers- Cytokine/chemokine multiplex panel- ctDNA

Fecal microbiome

TUMOR TISSUE STRATUM A(ADJUVANT)

STRATUM B (NEOADJUVANT)

Diagnostic core biopsy X

Surgical specimen X X

PLASMA SAMPLES ALL PATIENTSScreening (-30 days) X

4 months from randomization X

12 months from randomization X

At progression (if applicable) X

FECAL SAMPLES ALL PATIENTSScreening (-30 days) X

Biological samples/biomarkers

Rationale for Parp + Checkpoint Inhibitors

Jiao et al, Clin Cancer Res 2017

Rationale for combining PARP inhibitors + immune checkpoint inhibitors

MEDIOLA, phase II basket studyof olaparib and durvalumab: gBRCAmut HER2- MBC (n=30)

Domchek et al, SABCS 2018

30% first line, 33% 2+ lines

43% prior platinum

43% HR+, 57% TN

50% BRCA1

ORR 63%

TOPACIO: Niraparib + Pembrolizumab (n=46)

ORR: 28% all; 60% tBRCAmut, 36% PD-L1+

TILs are prognostic for HER2+ BC pts treated with adjuvant CT + anti-HER2

Dieci MV, Ann Oncol 2019

ShortHER

Krop I, ASCO 2019

Aphinity

FCγ receptor polymorphisms mayinfluence immune responses.F allele: low affinityV allele: high affinity

Gavin P, JAMA Oncol 2017

FCGR3A receptor polymorphism is predictive of trastuzumab

efficacy in NSABP-B31

PANACEA study: Pembrolizumab + Trastuzumab in

trastuzumab-resistant HER2+ ABC

Patients

Loi S et al, SABCS 2017

PANACEA study: results overall and by PD-L1

Primary endpoint: ORR

PD-L1+ cohort: disease controlMedian duration of disease control: 11.1 months

Loi S et al, SABCS 2017

N=58, all trastuzumab pre-treated, 88% received additional anti-HER2

Margetuximab: Fc-engineered to Activate Immune Responses

Study CP-MGAH22-04 (SOPHIA) Design1,2

Safety: infusion related-reactions any grade 13% (Margetuximab) vs 4% (Trastuzumab);

grade 3/4 4% (Margetuximab) vs 0% (Trastuzumab)

Rugo H, ASCO 2019

SOPHIA TRIAL: PFS results

2016

Rugo H, Clin Cancer Res 2018

Pembrolizumab HR+/HER2-% PD-L1+/screened 19%

PD-L1 cut-off >1% tumor cells or any stromal staining

Evaluable pts 25 (PD-L1+)

ORR 3 (12%)

CR 0

PR 3 (12%)

SD 4 (16%)

PD 15 (60%)

Median duration of response 12 months

Median time to response 8 w

No assessment/Unavailable data 3 (12%)

Available data on immune checkpoint inhibitor for

HR+/HER2- mBC

Results: Progression Free Survival (ITT)

Tolaney S, ASCO 2019

STUDY DESIGN

ENGAGING THE IMMUNE SYSTEM TO IMPROVE THE EFFICACY OF

NEOADJUVANT CHEMO-ENDOCRINE THERAPY FOR PREMENOPAUSAL LUMINAL B BREAST CANCER PATIENTS.

Frozen tumorFFPE tumor

Plasma

FFPE (biopsy) Plasma

FFPE (surgery) Plasma

Sponsor: University of PadovaPI: P.Conte

Financial Support: BMS

Population: n=48 Primary endpoint: pCRSecondary endpoints: OR, molecularresponse (Ki67), PEPI score, conservativesurgery rate, safety, biomarkers

Luminal B (HR+/HER2-, G3 or Ki67 >20%) premenopausalstage II-IIIA BC patients

FIRST SIMON’S STEP ACCOMPLISHED (AT LEAST 3 pCR IN FIRST 18 ENROLLED PTS)

Immuno-oncology in Breast Cancer: Challenges

• PD-L1 testing: platform?, antibody?, primary or metastatic tumor?, score?

• Other Immune Biomarkers:TILs?, Microbioma?

• Settings (beyond TN ABC):neoadjuvant?, post-neoadjuvant?, high-risk adjuvant?

• Combos other than chemo:PARPi + ICI (all TN?, BRCAm TN?)

• HER2+ BC:selection of patients & setting

combo with antiHER2 agents

• HR+ BC:mostly «cold» tumors (possible exception Luminal B)

integration of ICIs with ET+ CDK4/6i and Chemotherapy