“Immunoterapia e carcinoma della mammella”Maria Vittoria Dieci

Università di Padova

IOV - IRCCS

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

OS

HR 0.84 0.77-0.92

Loi S, SABCS 2015

Pooled individual patient data analysis of tumor infiltrating lymphocytes (TILs) in primary triple negative breast cancer (TNBC) treated with

anthracycline-based chemotherapySherene Loi, Damien Drubay, Sylvia Adams, Prudence A Francis, Heikki Joensuu, Maria Vittoria Dieci, Sunil Badve, Sandra Demaria, Robert Gray, Martine J Piccart, Pirkko-Liisa Kellokumpu-Lehtinen, Fabrice Andre, Carsten Denkert, Roberto Salgado, Stefan Michiels.

Adams S, ASCO 2017; Schmid P, AACR 2017; Dirix L, BCRT 2018

Pembrolizumab Atezolizumab Avelumab

Phase II I I

N 222 115 58

ORR

ORR 1L

ORR 2L+

---

23.1%*

4.7%

10%

26%

11%

5.2%**

---

---

Immune checkpoint inhibitors in

metastatic TNBC PDL1+/-

*All PD-L1+

**50% received > 2 previous lines of anticancer treatment

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

Median OS follow-up (range) was 15.2 mo (0.4+ to 36.7) in all patients, 17.0 mo (0.43+ to 36.7) in IC2/3 patients and 12.8 mo (0.8+ to 16.9) in IC0/1 patients.

No. At Risk: CR/PR 15 15 14 14 12 10 6 6 6 4 3 2 1

SD 19 18 17 10 6 5 1PD 55 40 30 28 11 3

3y OS: 100%

1-y OS: 33%

1-y OS: 51%

2y OS: 100%1y OS: 100%

Ove

rall S

urv

iva

l

Time (months)

Response

■ CR/PR■ SD ■ PD

Atezolizumab

single agent in

mTNBC ≥1L,

PDL1+/-

Schmid P, et al. AACR 2017

OS according to response

- Optimize patients selection

- Combinations

- Chemotherapy

- PARP inhibitors

- Move to the early setting

How to move forward in TNBC

Schmid P, et al. AACR 2017; Adams S, et al ASCO 2017; Loi, ESMO 2017

17%

8%

PDL1-PDL1+

Ob

ject

ive

Res

po

nse

Rat

e (%

)

10%

20%

30%

0%

4.8% 4.7%

Pembrolizumab(Cohort A)

Atezolizumab

Anti-PD-L1/PD-1 single agent in mTNBC ≥1L, PDL1+/-

PDL1-PDL1+

PD-L1 expression and response to single agent immune

checkpoint inhibitor

Loi S, ESMO 2017

KEYNOTE-086: TILs and ORR

Schmid P, et al. AACR 2017 Phase Ia

Atezolizumab in TNBC

11

≤ 10% TILs (n = 53)

> 10% TILs(n = 56)

mOS(95% CI)

6.6 mo (4.9, 10.2)

12.6 mo (10.5, NA)

OS by TILs - atezolizumab

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

Chemotherapy as a trigger for immune activation

1L

n=13

2L+

n=20

IC1/2/3

n=12

IC0

n=12

Unknown

n=9

Confirmed ORR

(95% CI)

54%

(25-81)

30%

(12–54)

42%

(15-72)

33%

(10-65)

44%

(14-79)

CR 1 (8%) 0 1 (8%) 0 0

PR 6 (46%) 6 (30%) 4 (33%) 4 (33%) 4 (44%)

SD 4 (31%) 9 (45%) 6 (50%) 5 (42%) 2 (22%)

PD 2 (15%) 4 (20%) 1 (8%) 3 (25%) 1 (11%)

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

Pohlmann PR, AACR 2018

ORR 39%, mPFS 5.5 months, mOS 14.7 months

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%

Results expected at ESMO 2018

Kok M, ASCO 2018

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.

ORR%Max 3

lines

MBC

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=25)

Domcheck et al, SABCS 2017

TOPACIO: Niraparib + Pembrolizumab (n=46)

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

Stratum A: AdjuvantHigh-risk TNBC pts (>4 metastatic axillary lymph nodes)

who received curative intent surgery and completed adjuvant chemotherapy

Stratum B: Post-neoadjuvantTNBC pts treated with neoadjuvant chemotherapy and

with residual invasive breast cancer in the breast and/or in the axilla at surgery (except from ypT1micN0,

ypT1micN0i+, ypT0N0i+)

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 (after RT, if indicated) balanced for adjuvant and post-neoadjuvant patients.

Sponsor: DiSCOG - UNIPDPI: P. Conte

Amendment 2, v3.0: post-neoadjuvant CT for up to 6 months allowedprior to randomization

Dieci MV, Ann Oncol 2016

Immune markers and pCR (CherLOB)TILs and DFS in N9831 (n=1581)

Kim RS, ASCO 2018

Immune-related markers are associated with pCRand long term outcome in early HER2+ BC patients

PANACEA study: Pembrolizumab + Trastuzumab in

trastuzumab-resistant HER2+ ABC

Patients

Loi S et al, SABCS 2017

PANACEA study: patients characteristics

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

PD-L1+ cohort

PANACEA study: results overall and by PD-L1

and TILs

Loi S et al, SABCS 2017

Luen S, Lancet Oncol 2017 Dieci MV, Breast Cancer Res 2018

Heterogeneity of immune microenvironment in

HER2+ BC

CD8+ T cells

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

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, molecular response (Ki67), PEPI score, conservative surgery rate, safety, biomarkers

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

Conclusions• TNBC:

• promising results from immune check point inhibitors + CT, especially for 1° line mTNBC (pending IMPASSION130 data)

• Combination with PARPi deserves further evaluation in BRCAmut HER2-

• Ongoing phase III neoadjuvant and adjuvant studies

• HER2+ BC:

• complex biologic interactions

• crowded landscape

• role of CT? T-DM1?

• earlier lines in advanced disease?

• HR+ BC:• crowded landscape• more results needed• combination with CDK4/6 inhibitors?

• Biomarkers:• TILs++• PD-L1+• TMB?• Host-related?→which role in CT+immunotherapy combos? →Need to develop non-invasive dynamic markers

• Other drugs/combinations on the horizon:• New compounds (new immune checkpoint inhibitors, new anti-HER2 moAbs, i.e. margetuximab)• Immune attractants/agonists• Combination with radiotherapy

Conclusions