LETTURA:
IMMUNO ONCOLOGY IN BREAST CANCER:
OPPORTUNITIES AND CHALLENGES
Pierfranco Conte
DiSCOG - 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 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 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 Status Estimated 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 for advanced 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
Endpoint PFS, 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: Adjuvant Stratum B: Post-neoadjuvant
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
stco-primary endpoint)
Randomization 1:1 balanced for adjuvant and post-neoadjuvant patients. Amendment 2, v3.0:
post-neoadjuvant CT for
up to 6 months allowed
prior 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 PATIENTS
Screening (-30 days) X
4 months from randomization X
12 months from randomization X
At progression (if applicable) X
FECAL SAMPLES ALL PATIENTS
Screening (-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 study of 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 may influence immune responses.
F allele: low affinity
V 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 control
Median 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 stainingEvaluable 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
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
