Immunoterapia e carcinoma della mammella

(1)

“Immunoterapia e carcinoma della mammella”

Maria Vittoria Dieci

Università di Padova

IOV - IRCCS

(2)

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)

(3)

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

(4)

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 chemotherapy

Sherene 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.

(5)

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

(6)

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

(7)

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 1

PD 55 40 30 28 11 3

3y OS: 100%

1-y OS: 33%

1-y OS: 51%

2y OS: 100%

1y OS: 100%

Overall Survival

Time (months)

Response

■ CR/PR

■ SD

■ PD

Atezolizumab single agent in

mTNBC ≥1L, PDL1+/-

Schmid P, et al. AACR 2017

OS according to response

(8)

- Optimize patients selection - Combinations

- Chemotherapy - PARP inhibitors

- Move to the early setting

How to move forward in TNBC

(9)

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

17%

8%

PDL1- PDL1+

Objective Response Rate (%)

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

(10)

Loi S, ESMO 2017

KEYNOTE-086: TILs and ORR

(11)

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

(12)

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

Chemotherapy as a trigger for immune activation

(13)

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%

(14)

Results expected at ESMO 2018

(15)

Kok M, ASCO 2018

TONIC phase II study

Induction → Nivolumab (n=66 mTNBC)

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

Max 3

ORR%

lines MBC

(16)

Rationale for Parp + Checkpoint Inhibitors

Jiao et al, Clin Cancer Res 2017

Rationale for combining PARP inhibitors

+ immune checkpoint inhibitors

(17)

MEDIOLA, phase II basket study of olaparib and durvalumab:

gBRCAmut HER2- MBC (n=25)

Domcheck et al, SABCS 2017

(18)

TOPACIO: Niraparib + Pembrolizumab (n=46)

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

(19)

(20)

Stratum A: Adjuvant

High-risk TNBC pts (>4 metastatic axillary lymph nodes) who received curative intent surgery and completed

adjuvant chemotherapy

Stratum B: Post-neoadjuvant

TNBC 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+ patients Secondary endpoints: OS, Safety, Biomarkers

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

Randomization 1:1 (after RT, if indicated) balanced for adjuvant and post-neoadjuvant patients.

Sponsor: DiSCOG - UNIPD PI: P. Conte

Amendment 2, v3.0:

post-neoadjuvant CT for

up to 6 months allowed

prior to randomization

(21)

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 pCR

and long term outcome in early HER2+ BC patients

(22)

PANACEA study: Pembrolizumab + Trastuzumab in trastuzumab-resistant HER2+ ABC

Patients

Loi S et al, SABCS 2017

(23)

PANACEA study: patients characteristics

(24)

PANACEA study: results overall and by PD-L1

Primary endpoint: ORR

PD-L1+ cohort: disease control

Median duration of disease control: 11.1 months

(25)

PD-L1+ cohort

PANACEA study: results overall and by PD-L1 and TILs

(26)

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

Heterogeneity of immune microenvironment in HER2+ BC

CD8+ T cells

(27)

2016

(28)

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

(29)

STUDY DESIGN

E

NGAGING THE IMMUNE SYSTEM TO IMPROVE THE EFFICACY OF

NEOADJUVANT CHEMO

-

ENDOCRINE THERAPY FOR PREMENOPAUSAL LUMINAL B BREAST CANCER PATIENTS

.

Frozen tumor FFPE tumor

Plasma

FFPE (biopsy) Plasma

FFPE (surgery) Plasma

Sponsor: University of Padova PI: P.Conte Financial Support: BMS

Population: n=48 Primary endpoint: pCR

Secondary endpoints: OR, molecular response (Ki67), PEPI score, conservative surgery rate, safety, biomarkers

Luminal B (HR+/HER2-, G3 or Ki67 >20%)

premenopausal

stage II-IIIA BC patients

(30)

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?

(31)

• 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