Immunotherapy Combinations in

Triple Negative Breast Cancer

Mafalda Oliveira, MD PhD

Vall d’Hebron University Hospital | Vall d’Hebron Institute of Oncology |

SOLTI Breast cancer Group
DECLARATION OF INTERESTS
Grant/Research Support (to the Institution): AstraZeneca, Philips Healthcare, Genentech, Roche, Novartis,
Immunomedics, Seattle Genetics, GSK, Boehringer-Ingelheim, PUMA Biotechnology, Zenith Epigenetics
Consultant: Roche/Genentech, GSK, PUMA Biotechnology, AstraZeneca
Honoraria: Roche, Seattle Genetics, Novartis
Travel Grants from Roche, Pierre-Fabre, Novartis, Eisai

Non-financial disclosure: member of the SOLTI Breast Cancer Research Executive Board
Immunotherapy in Triple negative breast cancer

• Metastatic TNBC is an area of high clinical need

• TNBC is most likely to respond to immunotherapy
• Higher proportion of TILs
• Higher expression of PD-1 and other inhibitory checkpoint molecules
• Higher levels of overexpression of immune-related signatures
• Higher rate of genomic complexity giving rise to tumor-specific neoantigens

Keenan TE & Tolaney SM. J Natl Compr Canc Netw 2020 Apr;18(4):479-489 | Blackley EF & Loi S. Breast 2019 Nov;48 Suppl 1:S44-S48
 Complete response
Partial response

ORR for single-agent anti-PD-(L)1 Complete response

Partial response

Pembrolizumab Pembrolizumab
Atezolizumab
Keynote-086 Keynote-119
(N=115)
Objective Response Rate (%)

30%
(N=222) (N=312)
24% 26%
23%

20% 18%

12%
10% 6%
4.7%

0%
1L 2L+ 1L 2L+
PD-L1+ All CPS>20 CPS>10 CPS>1
N=57 N=96 N=203

Adams S et al. Ann Oncol 2019;30:405-411 | Adams S et al. Ann Oncol 2019;30(3):397-404 |
Emens L et al. JAMA Oncol. 2019;5(1):74-82 | Winer E et al. Lancet Oncol 2021; 22: 499–511
Rationale for Combination Regimens in TNBC
Significant proportion of TNBC

• Do not respond to single agent ICI

• “Cold” tumors
• Scarce infiltration by effector T-cells
• Expression of immune-inhibitory targets, both at immune cells and in TME (TIGIT,
LAG3, IDO, adenosine, …)
• Express genes that could be targeted for combination therapy (TLRs, TNF, ICOS)

Objective: turn a “cold” tumor “hot”

Chemotherapy Dual ICI / TME modulators Targeted therapy Intratumoral therapies Adoptive cell therapy

Enhancing immunotherapy efficacy

Meric-Bernstam F, Larkin J, Tabernero J & Bonini C. Lancet 2021;397:1010-22

Chemotherapy Dual ICI / TME modulators Targeted therapy Intratumoral therapies Adoptive cell therapy

Chemotherapy
Mechanisms of synergy of Chemotherapy and ICI

Salas-Benito D et al. Cancer Discov 2021 Mar 12

 Chemotherapy Dual ICI / TME modulators Targeted therapy Intratumoral therapies Adoptive cell therapy

First-line ICI trials in patients with metastatic TNBC

IMpassion130 IMpassion131 Keynote 355
(n=902) (n=943) (n=847)
Atezolizumab / Placebo Atezolizumab / Placebo Pembrolizumab / Placebo
Treatment
Nab-Paclitaxel Paclitaxel CbGem or Taxane
PFS ITT / PD-L1+ PFS in PD-L1+ (CPS>1 and >10)/ITT
Primary endpoint PFS PD-L1+ / ITT
OS ITT / PD-L1+ OS in PD-L1+ (CPS>1 and >10)/ITT
PD-L1+ PD-L1+ PD-L1+
ITT ITT ITT
SP142 IC>1% SP142 IC>1% CPS>10 CPS>1
HR 0.80 HR 0.62 HR 0.86 HR 0.82 HR 0.82 HR 0.65 HR 0.74
PFS
7.2 vs 5.5 7.5 vs 5.0 5.7 vs 5.6 6.0 vs 5.7 7.5 vs 5.6 9.7 vs 5.6 7.6 vs 5.6
HR 0.87 HR 0.67 HR 1.11 HR 1.12
OS NR NR NR
21 vs 18.7 25.4 vs 17.9 22.1 vs 28.3 19.2 vs 22.8
Significant | Not significant | Not formally tested
Cortés J et al. Lancet 2020;396(10265):1817-1828 | Schmid P et al. N Engl J Med. 2018 Nov 29;379(22):2108-2121 |
Schmid P et al. Lancet Oncol. 2020 Jan;21(1):44-59 | Miles D. et al. ESMO 2020
Chemotherapy Dual ICI / TME modulators Targeted therapy Intratumoral therapies Adoptive cell therapy

Combination with Antibody-Drug Conjugates (ADCs)

Ladiratuzumab vedotin (LV) + Pembrolizumab

Puzstai L et al. SITC 2020 | Han A et al. Cancer Res 2020;80(4 Suppl):Abstract PD1-06
 Chemotherapy Dual ICI / TME modulators Targeted therapy Intratumoral therapies Adoptive cell therapy

Combination with Antibody-Drug Conjugates (ADCs)

MORPHEUS TNBC SACI-IO TNBC

Atezolizumab + Sacituzumab govitecan Pembrolizumab + Sacituzumab govitecan

Screening Stage 1

1L PD-L1+Cohort N = 15-30 N = 25
Preliminary Phase Expansion Phase

• Metastatic or
inoperable Atezo + Nab-Paclitaxel + Tocilizumab*
locally advanced PD
TNBC
Entry
Biopsy R Atezo + Sacituzumab* Biopsy
• No prior
Treatment Atezo + Nab-Paclitaxel
• PD-L1 positive

NCT03424005 NCT04468061
Chemotherapy Dual ICI / TME modulators Targeted therapy Intratumoral therapies Adoptive cell therapy

Combination of ICI and/or TME Modulators

LAG-3 TIGIT Adenosine / A2aR

NCT03742349 | NCT01968109 | NCT04252768 | NCT03971409 | NCT02794571 | NCT04584112

Andrews L et al. Nat Immunol 2019;20: 1425–1434 | Leone RD et al. Comput Struct Biotechnol J. 2015 Apr 8;13:265-72.
Chemotherapy Dual ICI / TME modulators Targeted therapy Intratumoral therapies Adoptive cell therapy

Bispecific Antibodies

Bintrafusp alpha

Dees S et al. Trends Cancer. 2021 Feb;7(2):162-173 | Lan Y, et al. Sci Transl Med 2018;10(424)
Chemotherapy Dual ICI / TME modulators Targeted therapy Intratumoral therapies Adoptive cell therapy

PARP inhibitors
- ↑ cytosolic DNA → recruitment and activation of STINGs → expression of IFN and other inflammatory cytokines
- ↑ inflammation and infiltration of tumors by immune cells

DORA Trial: Olaparib +/- Durvalumab (NCT03801369)

Vinayak S et al. JAMA Oncol. 2019 Jun 13;5(8):1132-40 | Domchek S et al. Lancet Oncol 2020; 21: 1155–64
Chemotherapy Dual ICI / TME modulators Targeted therapy Intratumoral therapies Adoptive cell therapy

Human Intra-tumoral Immune Therapies (HIT-IT)

HIT-IT
◆ Local immune stimulation
◆ Systemic effect

Types of HIT-IT
◆ Oncolytic viruses
◆ TLR agonists
◆ STING
◆ Oncolytic peptides
◆ mRNA
◆ Cytokines
◆ …

Champiat S et al. Clin Cancer Res 2021;27;665-79 | Marabelle A et al. Clin Cancer Res 2014;20:1747-1756
Chemotherapy Dual ICI / TME modulators Targeted therapy Intratumoral therapies Adoptive cell therapy

PROMETEO Trial
Pre-surgical T-VEC + Atezolizumab in residual disease after standard NACT

PI: Tomás Pascual | Aleix Prat

NCT03802604
Chemotherapy Dual ICI / TME modulators Targeted therapy Intratumoral therapies Adoptive cell therapy

Adoptive cell therapy

Using cells of our immune system to eliminate cancer: TILs, TCRs, CAR-T Cell, Dendric and NK cells

49yo ER+/HER2- PD-L1-neg

TA-specific TILs
IL-2 + Pembrolizumab

Fuentes-Antrás J et al. Front Oncol 2020;10:605633 | Zacharakis N et al. Nat Med 2018;724(24):724–730
Chemotherapy Dual ICI / TME modulators Targeted therapy Intratumoral therapies Adoptive cell therapy

TILS001 trial
Treatment of advanced or mTNBC with adoptive therapy of PD1+ TILs

A Prat | M Juan | P Villagrasa | E Ciruelos | M Santisteban | C Saura

Chemotherapy Dual ICI / TME modulators Targeted therapy Intratumoral therapies Adoptive cell therapy

CAR-T Cells
Challenges in solid tumors
• Antigen private to the tumor
• Tumor heterogeneity
• Immunosuppressive TME
- TAM, CAF, MDSC, Treg
- Adenosine, IDO, TGF
• Expression of immune checkpoint
molecules on T lymphocytes
• Insufficient trafficking and infiltration of
the tumor

Dees S et al. Mol Cancer Ther 2020;19(12):2409-2421

Chemotherapy Dual ICI / TME modulators Targeted therapy Intratumoral therapies Adoptive cell therapy

Ongoing Phase I Trials of CAR-T Cells in TNBC

Dees S et al. Mol Cancer Ther 2020;19(12):2409-2421

Some Challenges and Future Directions

• Immunotherapy in Breast Cancer has promising results, but still a long path ahead
• Identification of “hot” and “cold” tumors → Single agents vs Combinations
• Not all immunotherapy combinations enhance immune activity → need to know how to choose
optimal combination partners
• A myriad of new drugs with novel mechanisms of action is being developed in breast cancer
• Integration of biomarkers of response and resistance to immunotherapy → tumor genomics,
immune profile (multiplex IHC, transcriptional profiling), peripheral blood analysis
European Society for Medical Oncology (ESMO)
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