DetermaIO™ Test for Immunotherapy Response in Triple-Negative Breast Cancer
KOL Call hosted by Oncocyte09/28/2021
Forward Looking Statement
Any statements that are not historical fact (including, but not limited to statements that contain words such as “will,” “believes,”“plans,” “anticipates,” “expects,” “estimates,” “may,” and similar expressions) are forward-looking statements. These statementsinclude those pertaining to the commercial launch of DetermaRx, development and clinical use of DetermaIO and planned newdiagnostic tests, clinical trials and studies, commercialization plans, future financial and/or operating results, and futureopportunities for Oncocyte, along with other statements about the future expectations, beliefs, goals, plans, or prospectsexpressed by management. Forward-looking statements involve risks and uncertainties, including, without limitation, the potentialimpact of COVID-19 on our financial and operational results, risks inherent in the development and/or commercialization ofdiagnostic tests or products, uncertainty in the results of clinical trials or regulatory approvals, potential interruptions to our supplychain, the need and ability to obtain future capital, maintenance of intellectual property rights, and the need to obtain third partyreimbursement for patients’ use of any diagnostic tests we commercialize, and risks inherent in acquisitions such as failure torealize anticipated benefits, unexpected expenditures or assumed liabilities, unanticipated difficulties in conforming businesspractices including accounting policies, procedures and internal controls, greater than estimated allocations of resources todevelop and commercialize technologies, or failure to maintain any laboratory accreditation or certification. Actual results maydiffer materially from the results anticipated in these forward-looking statements and accordingly such statements should beevaluated together with the many uncertainties that affect the business of Oncocyte, particularly those mentioned in the “RiskFactors” and other cautionary statements found in Oncocyte’s Securities and Exchange Commission filings, which are availablefrom the SEC’s website. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of thedate on which they were made. Oncocyte undertakes no obligation to update such statements to reflect events that occur orcircumstances that exist after the date on which they were made, except as required by law.
2
Mission Statement
3
Oncocyte is a molecular diagnostics company whose mission is to provide actionable answers at critical decision
points across the cancer care continuum, with the goal of improving patient
outcomes by accelerating and optimizing diagnosis and treatment.
4
Oncocyte’s Determa Platform StrategyDelivers Critical Information Throughout the Patient Journey Improving Outcomes and Reducing Costs
Treatment Stratification
Treatment Selection
Therapy Monitoring
Diagnosis of Cancer
Should I give adjuvant chemo?
Should I give immunotherapy?
Is the therapy working?
Treatment Decision
Is the cancercoming back?
Targeted Therapy Selection
Should I give targeted therapy?
Screening
Does patient have cancer?
Patient Monitoring
Available for Research Use Only Clinical Launch 2H21Tx
Tx
TxMRDFor Research Use Only in 2H21 In DevelopmentClinical Launch 2H21Available for Clinical Use
Recurrence Detection
Differentiated Tests To Address Unmet Needs Across All Stages Of Cancer.
Intro to DetermaIO
Clinical validation data presented in multiple tumor types to date
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Data Summary Recap
REFERENCES1. Nielsen et al. Heliyon2. Ranganath et al. SITC 2019 Poster3. Bianchini et al. ESMO 2021 Podium Presentation4. Seitz et al. AACR 2021 Podium Presentation5. Seitz et al. ASCO 2021 Poster
Non small cell lung cancer (NSCLC)Multiple cohorts (100+ patients) showing improved response rates to ICI among DetermaIO+ patients and better predictive ability than PD-L1 and TMB 1,2
Triple Negative Breast Cancer (TNBC)Randomized clinical trial (241 patients) treated with standard chemo +/-atezolizumab in neoadjuvant setting. Study showed DetermaIO was predictive of response to ICI in Atezo arm only.3
Metastatic Urothelial CancerAnalysis of IMvigor210 study (348 patients) showed that IO+ patients had significantly better median OS, 2-yr OS, and ORR than IO-. DetermaIO was independent of all other biomarkers studied (incl. PD-L1 and TMB) 4
Renal Cell CarcinomaInitial data in 43 patients showed that IO+ patients had significantly better 1yr PFS and extended median PFS as compared to IO- 5
Validated in:900+ Patients
Across 4Tumor Types
Against all 4Approved Immune
Checkpoint Inhibitors
Shown to be predictive of ICI response, not
chemotherapy response
Determine Sensitivity to IO Therapies
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Test Results Stratification
RNA Expression via qPCR
Proprietary Algorithm
Patients likely to respond to current Immune Checkpoint Inhibitor therapies
Patients unlikely to respond to ICIs and should be considered for other treatment opportunities
IO+IO-• Real-time PCR test on FFPE
biopsy or resection specimen• Measures 27 genes• Pan-cancer application
Shown to be a successful predictor of response in all indications tested to date
Based on an algorithm and threshold that have been
locked down & unchanged among all studies performed
Measures both tumor gene expression and the immunemicroenvironment (TIME)
DetermaIO has its origins in a refined molecular classification of
Triple Negative Breast Cancer (TNBC)
8
Basal-Like 1
Basal-Like 2
Mesenchymal
Luminal AR
Immunomodulatory
MesenchymalStem-Like
BL1
BL2
M
MSL
LAR
IM
-Lehmann BD Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011-Ring BZ Generation of an algorithm based on minimal gene sets to clinically subtype triple negative breast cancer patients. BMC Cancer. 2016-Lehmann BD Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PLoS One. 2016
2188Genes
Tumor-ImmuneMicro-Environment Signatures
TNBC Tumor Subtypes
BL1 BL2 LAR
M
MSLIM
2011: Lehmann TNBC Classification SystemSix Subtypes of TNBC tumors;1800+ Literature References to date
2016: Lehmann & Ring RefinementsDistinction between native TNBCtumor subtypes and TME components
2018: Stand-alone IO TME SignatureMeasures components of tumor and immune micro-environment to determine sensitivity to IO therapies
101Genes
27Genes
NON-CONFIDENTIAL
Physiology of a tumor in an immune environment
9
Tumor-Immune
homeostasis
Immune Attack
PD-L1 Expression
15-40%
Anti-PD-(L)/PD1 Immunotherapy
60-85%
Tumor selection / Secondary Escape
Immune system keeps tumorsin check
Cancer breaks through immune surveillance
Immune Surveillancere-established
Oncogene mutation and
neoantigen generation
CheckpointTx resistant
Immune Resistant
CheckpointTx sensitiveHOT
Cancer breaks throughImmune surveillance
Immune Fortification
CAF - COLD
Immune Desert
EMT - COLD
Immune Suppressionand Tumor Growth
Primary Response
Immune Attack
Immune Cloaked
Targetable by 2nd Generation Agents
(e.g. Immune stimulants, IL-12, VEGF, TGF-β)
+/- Checkpoint Inhibitors
Advanced NSCLC Clinical Cohort
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• DetermaIO+ patients were significantly associated with improved PFS
• DetermaIO outperformed PD-L1 and TMB (and was significantly independent of either test)
• Also independent of pembrolizumab vs nivolumab (~1:1), adenocarcinoma vs squamous cell, primary site biopsy vs metastatic Presented at SITC 2019
Submitted for Peer-Reviewed Publication
n = 59 p = 0.60
n = 36 p = 0.50
n = 67 p < 0.001
In Collaboration with the West Cancer Center
Metastatic Urothelial Carcinoma
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• DetermaIO+ was significantly associated with response to Atezo in Pt progression arm
• DetermaIO was significant in multivariate analysis with PD-L1 and TMB
• DetermaIO was independent of all other biomarkers and molecular signatures in the study
Podium Presentation at AACR 2021Preparing manuscript for submission
IMvigor210 Clinical Trial
N = 348, HR = 0.61295%CI (0.466, 0.803) p<0.001
Applying DetermaIO to Triple Negative Breast CancerMD Anderson / Yale Collaboration
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Study Design (Phase I/II trial - NCT02489448):
• 55 patients with stage I-III primary TNBC pCR: n=25 (45%); No pCR: n=30 (55%)
• Treated with neoadjuvant immunotherapy + chemotherapy (durvalumab with weekly paclitaxel followed by dose-dense anthracycline/cyclophosphamide)
Results:
• DetermaIO-positive patients are 4x more likely to respond than DetermaIO-negative patients
• DetermaIO has 23.3% better predictive value than PD-L1
Odds Ratio 95% CI p-Value
4.125 1.36 – 13.47 < 0.015
PD-L1 Expression 2.63 0.82 – 9.21 0.11
Patients who had a lack of complete response had an average
DetermaIO score of -0.18
Patients who had a complete response had an average DetermaIO score of 0.24
Presented at ASCO 2020Currently in Press
TNBC
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Today’s KOL Speakers
Priyanka Sharma, MDProfessor of Medicine
University of Kansas Medical Center
Giampaolo Bianchini, MDHead, Breast Cancer Group
San Raffaele Hospital, Milano, Italy
Unmet need for predicting immunotherapy response in
early stage TNBCPriyanka Sharma, MD
Professor of Medicine University of Kansas Medical Center
Immune Checkpoint Inhibitor (ICI) Therapy
James Allison, PhD Tasuku Honjo, MD, PhD
Nobel Prize in Physiology or Medicine, 2018
Immunotherapy in TNBC
Rationale for immunotherapy in TNBC
Early stage TNBCCurrent chemotherapy landscapeEmerging role of immune check point inhibitors
Future directionsSelection criterion BiomarkersPersonalized de-escalation and escalation
Rationale for Immunotherapy in TNBC• High TILs in TNBC: evidence of anti-tumor immune
response. • TIL-enrichment associated with better outcomes/pCR
Cold Hot
ER+ HER-2+ TNBCHigh TILsCD8+T cells/mRNAImmune signature
Luen et al, Breast 2016, Stanton et al, Jama Onc 2016, Nanda et al, JCO 2016, Adams et al Ann Oncol 2019, Emens et al, JAMA Onc 2019, Gatti-Mays et al, Nature Breast Cancer 2019, Loi et al, JCO 2019, Adams et al, JAMA Onc 2019, Denkert et al, Lancet Oncol 2018, Page et al, Nature Breast Cancer 2019, Galluzzi et al, Nat Rev Clin Oncol 2020, Chen Immunity 2013
Rationale for Immunotherapy in TNBC• High TILs in TNBC: evidence of anti-tumor immune
response. • TIL-enrichment associated with better outcomes/pCR
• PD-L1 expressed mainly in infiltrating immune cells in BC; blocking PD-1/PD-L1 can augment T-cell response
Cold Hot
ER+ HER-2+ TNBCHigh TILsCD8+T cells/mRNAImmune signature
Luen et al, Breast 2016, Stanton et al, Jama Onc 2016, Nanda et al, JCO 2016, Adams et al Ann Oncol 2019, Emens et al, JAMA Onc 2019, Gatti-Mays et al, Nature Breast Cancer 2019, Loi et al, JCO 2019, Adams et al, JAMA Onc 2019, Denkert et al, Lancet Oncol 2018, Page et al, Nature Breast Cancer 2019, Galluzzi et al, Nat Rev Clin Oncol 2020, Chen Immunity 2013
Rationale for Immunotherapy in TNBC• High TILs in TNBC: evidence of anti-tumor immune
response. • TIL-enrichment associated with better outcomes/pCR
• PD-L1 expressed mainly in infiltrating immune cells in BC; blocking PD-1/PD-L1 can augment T-cell response
• Chemotherapy SOC in TNBC and can have several immunogenic effects
Cold Hot
ER+ HER-2+ TNBCHigh TILsCD8+T cells/mRNAImmune signature
Luen et al, Breast 2016, Stanton et al, Jama Onc 2016, Nanda et al, JCO 2016, Adams et al Ann Oncol 2019, Emens et al, JAMA Onc 2019, Gatti-Mays et al, Nature Breast Cancer 2019, Loi et al, JCO 2019, Adams et al, JAMA Onc 2019, Denkert et al, Lancet Oncol 2018, Page et al, Nature Breast Cancer 2019, Galluzzi et al, Nat Rev Clin Oncol 2020, Chen Immunity 2013
Rationale for Immunotherapy in TNBC• High TILs in TNBC: evidence of anti-tumor immune
response. • TIL-enrichment associated with better outcomes/pCR
• PD-L1 expressed mainly in infiltrating immune cells in BC; blocking PD-1/PD-L1 can augment T-cell response
• Chemotherapy SOC in TNBC and can have several immunogenic effects
• Combination with chemotherapy synergistic by targeting different steps in the cancer immunity cycle
Cold Hot
ER+ HER-2+ TNBCHigh TILsCD8+T cells/mRNAImmune signature
Luen et al, Breast 2016, Stanton et al, Jama Onc 2016, Nanda et al, JCO 2016, Adams et al Ann Oncol 2019, Emens et al, JAMA Onc 2019, Gatti-Mays et al, Nature Breast Cancer 2019, Loi et al, JCO 2019, Adams et al, JAMA Onc 2019, Denkert et al, Lancet Oncol 2018, Page et al, Nature Breast Cancer 2019, Galluzzi et al, Nat Rev Clin Oncol 2020, Chen Immunity 2013
Neoadjuvant chemotherapy landscape for TNBC
EBCTCG meta-analysis: aggregate benefit for anthracycline and taxane-based regimens over CMF-based regimens
EBCTCG Lancet Oncology 2012
Addition of Taxane to Anthracycline 16% reduction in risk of recurrence
(absolute gain 4.6%) 14% reduction in risk of breast
cancer mortality (absolute gain 2.8%)
Anthracycline regimens compared to no chemotherapy 27% reduction in risk of recurrence
(absolute gain 9%) 21% reduction in risk of breast
cancer mortality (absolute gain 6.5%)
10-year risk of death from breast cancer can be reduced by about a third. Benefit independent of age, grade, ER status and stage
Priyanka Sharma, MD
Platinum agents
Neoadjuvant trials incorporating Platinum in TNBC
Study Design Chemotherapy Regimen N
pCR (%)
Control Platinum
pCR
deltaAnthracycline containing regimens
GeparSixto Randomized Phase IIWeekly Paclitaxel 80 mg/m2 + NPLD 20 mg/m2 weekly + bev 15 mg/kg q 3 wks ± carboplatin AUC 1.5-2 weekly x 18 wks
315 37% 53% 16%
Alliance/CALGB 40603
Randomized Phase II (2x2 factorial design)
Weekly paclitaxel 80 mg/m2 x 12 ± carboplatin AUC 6 q 3 wks x 4 → AC q 2 weeks x 4 ± bev 10 mg/kg q 2 wks x 9 cycles
433 41% 54% 13%
BrighTNessRandomized Phase III (3-arm)
Weekly paclitaxel ± carboplatin AUC 6 ± veliparib 50 mg x 12 wks, followed by AC q 2-3 wks x 4 cycles
634 31% 57% (carbo)
53% (carbo + vel)26%
ISPY-2 Randomized Phase IIWeekly paclitaxel 80 mg/m2 x 12 ± carboplatin AUC 6 q 3 wks x 4 and veliparib 50 mg BID PO → AC q 2 wks x 4 cycles
6026% (est)
51% (est) -
NeoSTOP Randomized phase II Weekly paclitaxel 80 mg/m2 x 12 + carboplatin AUC 6 q 3 wks x 4 → AC q 2 weeks x 4 (ARM A) vs Carboplatin AUC 6 + docetaxel 75 mg/m2 q 3 wks x 6 cycles (ARM B)
100 —54% (Arm A)
52% (Arm B)-
Anthracycline-sparing regimens
WSG-ADAPT Randomized Phase IIWeekly nab-paclitaxel 125mg/m2 + carboplatin AUC 2 or gemcitabine 1000 mg/m2 days 1 and 8 q 3 weeks x 4 cycles
336 29% 45%
Sharma et al Single ArmCarboplatin AUC 6 + docetaxel 75 mg/m2 q 3 wks x 6 cycles
190 — 55%
TBCRC 030 R d i d h II Paclitaxel 80 mg/m2 x 12 weeks or
140 12% 15%
Priyanka Sharma, MD
Neoadjuvant trials incorporating Platinum in TNBC
Study Design Chemotherapy Regimen N
pCR (%)
Control Platinum
pCR
deltaAnthracycline containing regimens
GeparSixto Randomized Phase IIWeekly Paclitaxel 80 mg/m2 + NPLD 20 mg/m2 weekly + bev 15 mg/kg q 3 wks ± carboplatin AUC 1.5-2 weekly x 18 wks
315 37% 53% 16%
Alliance/CALGB 40603
Randomized Phase II (2x2 factorial design)
Weekly paclitaxel 80 mg/m2 x 12 ± carboplatin AUC 6 q 3 wks x 4 → AC q 2 weeks x 4 ± bev 10 mg/kg q 2 wks x 9 cycles
433 41% 54% 13%
BrighTNessRandomized Phase III (3-arm)
Weekly paclitaxel ± carboplatin AUC 6 ± veliparib 50 mg x 12 wks, followed by AC q 2-3 wks x 4 cycles
634 31% 57% (carbo)
53% (carbo + vel)26%
ISPY-2 Randomized Phase IIWeekly paclitaxel 80 mg/m2 x 12 ± carboplatin AUC 6 q 3 wks x 4 and veliparib 50 mg BID PO → AC q 2 wks x 4 cycles
6026% (est)
51% (est) -
NeoSTOP Randomized phase II Weekly paclitaxel 80 mg/m2 x 12 + carboplatin AUC 6 q 3 wks x 4 → AC q 2 weeks x 4 (ARM A) vs Carboplatin AUC 6 + docetaxel 75 mg/m2 q 3 wks x 6 cycles (ARM B)
100 —54% (Arm A)
52% (Arm B)-
Anthracycline-sparing regimens
WSG-ADAPT Randomized Phase IIWeekly nab-paclitaxel 125mg/m2 + carboplatin AUC 2 or gemcitabine 1000 mg/m2 days 1 and 8 q 3 weeks x 4 cycles
336 29% 45%
Sharma et al Single ArmCarboplatin AUC 6 + docetaxel 75 mg/m2 q 3 wks x 6 cycles
190 — 55%
TBCRC 030 R d i d h II Paclitaxel 80 mg/m2 x 12 weeks or
140 12% 15%
Priyanka Sharma, MD
Increase in pCR but also increase in toxicities
Neoadjuvant trials incorporating Platinum in TNBC
Study Design Chemotherapy Regimen N
pCR (%)
Control Platinum
pCR
deltaAnthracycline containing regimens
GeparSixto Randomized Phase IIWeekly Paclitaxel 80 mg/m2 + NPLD 20 mg/m2 weekly + bev 15 mg/kg q 3 wks ± carboplatin AUC 1.5-2 weekly x 18 wks
315 37% 53% 16%
Alliance/CALGB 40603
Randomized Phase II (2x2 factorial design)
Weekly paclitaxel 80 mg/m2 x 12 ± carboplatin AUC 6 q 3 wks x 4 → AC q 2 weeks x 4 ± bev 10 mg/kg q 2 wks x 9 cycles
433 41% 54% 13%
BrighTNessRandomized Phase III (3-arm)
Weekly paclitaxel ± carboplatin AUC 6 ± veliparib 50 mg x 12 wks, followed by AC q 2-3 wks x 4 cycles
634 31% 57% (carbo)
53% (carbo + vel)26%
ISPY-2 Randomized Phase IIWeekly paclitaxel 80 mg/m2 x 12 ± carboplatin AUC 6 q 3 wks x 4 and veliparib 50 mg BID PO → AC q 2 wks x 4 cycles
6026% (est)
51% (est) -
NeoSTOP Randomized phase II Weekly paclitaxel 80 mg/m2 x 12 + carboplatin AUC 6 q 3 wks x 4 → AC q 2 weeks x 4 (ARM A) vs Carboplatin AUC 6 + docetaxel 75 mg/m2 q 3 wks x 6 cycles (ARM B)
100 —54% (Arm A)
52% (Arm B)-
Anthracycline-sparing regimens
WSG-ADAPT Randomized Phase IIWeekly nab-paclitaxel 125mg/m2 + carboplatin AUC 2 or gemcitabine 1000 mg/m2 days 1 and 8 q 3 weeks x 4 cycles
336 29% 45%
Sharma et al Single ArmCarboplatin AUC 6 + docetaxel 75 mg/m2 q 3 wks x 6 cycles
190 — 55%
TBCRC 030 R d i d h II Paclitaxel 80 mg/m2 x 12 weeks or
140 12% 15%Priyanka Sharma, MD
STUDY DESIGN
aEfficacy was assessed in all randomized patients and safety in all patients who received ≥1 doseAUC, area under the curve; BID, twice a day; ECOG PS, Eastern Cooperative Oncology Group performance status; EFS, event-free survival; OS, overall
survival; pCR, pathological complete response; Q2W, every 2 weeks; Q3W, every 3 weeks; R, randomization; TNBC, triple negative breast cancer.
Postsurgery assessment was performed every 3 months until 1 year after surgery, then every 6 months until 2 years after surgery, then yearly until 4 years after surgery, or until an EFS event
2–8 weeks afterthe last dose of chemotherapy
Doxorubicin, 60 mg/m2
Cyclophosphamide, 600 mg/m2, Q2W or
Q3W (4 cycles)
Paclitaxel, 80 mg/m2, weekly (12 doses in up to 16 weeks)
Paclitaxel + carboplatin placebo + veliparib placebo (N = 158)Carboplatin placebo, Veliparib placebo
Paclitaxel + carboplatin + veliparib (N = 316)Carboplatin, AUC 6 mg/mL/min, Q3W (4 cycles)
Veliparib, 50 mg, orally BID
Key inclusion criteria• Women aged ≥18 years• Histologically or cytologically confirmed invasive stage II/III TNBC• ECOG PS 0–1• Candidates for potentially curative surgery with documented gBRCA status
Segment 1 Segment 2 Surgery
Paclitaxel + carboplatin + veliparib placebo (N = 160)Carboplatin, AUC 6 mg/mL/min, Q3W (4 cycles)
Veliparib placebo
Randomization was stratified according to gBRCA status, nodal stage, and planned schedule of doxorubicin and cyclophosphamide administration
Endpointsa
Primary endpoint• pCRSecondary endpoints• EFS• OS• SafetyEFS according to pCR was also examined in a post hoc analysisRates of second primary malignancies were assessed per Standardized Medical Dictionary for Regulatory Activities (MedDRA) version 21.1
Key exclusion criteria• Previous anticancer treatment• Previous or concurrent cancer• On ovarian hormonal replacement therapy
Randomized patientsN = 634
R2:1:1
Loibl et al ESMO 2021
BrighTNess: EFS RESULTS
aStratified by BRCA status, lymph node status, and planned doxorubicin/cyclophosphamide dose intensity.C, carboplatin; CI, confidence interval; EFS, event-free survival; HR, hazard ratio; P, paclitaxel; V, veliparib.
censored
Prob
abilit
y of E
FS
Months since randomization
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.0
0.1
0 3 6 9 15 18 21 24 27 30 33 6012 4236 39 45 725448 51 57 63 66 69
No of patients at riskP + C + V
P + CP
316160158
311157147
301154147
290151142
273143132
266134125
257129120
248121115
241118112
228112102
21311095
0
1
283148139
281312
1999787
1889174
133 0
235115107
22211198
102
1305541
20610291
1959480
957
Paclitaxel + carboplatin + veliparib
Paclitaxel + carboplatin Paclitaxel
Events n/N 65/316 30/160 47/158
Hazard ratio (95% CI)a
Paclitaxel + carboplatin + veliparib vs paclitaxelPaclitaxel + carboplatin + veliparib vs paclitaxel + carboplatinPaclitaxel + carboplatin vs paclitaxel (post hoc analysis)
0.63 (0.43–0.92), P=0.021.12 (0.72–1.72), P=0.620.57 (0.36–0.91), P=0.02
4-year EFS, % (95% CI) 78.2 (73.5–83.2) 79.3 (72.9–86.2) 68.5 (61.3–76.6)
Loibl et al ESMO 2021
MEDIAN FOLLOW-UP OF 4.5 YEARS
BrighTNess: EFS RESULTS
aStratified by BRCA status, lymph node status, and planned doxorubicin/cyclophosphamide dose intensity.C, carboplatin; CI, confidence interval; EFS, event-free survival; HR, hazard ratio; P, paclitaxel; V, veliparib.
censored
Prob
abilit
y of E
FS
Months since randomization
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.0
0.1
0 3 6 9 15 18 21 24 27 30 33 6012 4236 39 45 725448 51 57 63 66 69
No of patients at riskP + C + V
P + CP
316160158
311157147
301154147
290151142
273143132
266134125
257129120
248121115
241118112
228112102
21311095
0
1
283148139
281312
1999787
1889174
133 0
235115107
22211198
102
1305541
20610291
1959480
957
Paclitaxel + carboplatin + veliparib
Paclitaxel + carboplatin Paclitaxel
Events n/N 65/316 30/160 47/158
Hazard ratio (95% CI)a
Paclitaxel + carboplatin + veliparib vs paclitaxelPaclitaxel + carboplatin + veliparib vs paclitaxel + carboplatinPaclitaxel + carboplatin vs paclitaxel (post hoc analysis)
0.63 (0.43–0.92), P=0.021.12 (0.72–1.72), P=0.620.57 (0.36–0.91), P=0.02
4-year EFS, % (95% CI) 78.2 (73.5–83.2) 79.3 (72.9–86.2) 68.5 (61.3–76.6)
Loibl et al ESMO 2021
MEDIAN FOLLOW-UP OF 4.5 YEARS
Carboplatin EFS 11%
BrighTNess: EFS RESULTS
aStratified by BRCA status, lymph node status, and planned doxorubicin/cyclophosphamide dose intensity.C, carboplatin; CI, confidence interval; EFS, event-free survival; HR, hazard ratio; P, paclitaxel; V, veliparib.
censored
Prob
abilit
y of E
FS
Months since randomization
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.0
0.1
0 3 6 9 15 18 21 24 27 30 33 6012 4236 39 45 725448 51 57 63 66 69
No of patients at riskP + C + V
P + CP
316160158
311157147
301154147
290151142
273143132
266134125
257129120
248121115
241118112
228112102
21311095
0
1
283148139
281312
1999787
1889174
133 0
235115107
22211198
102
1305541
20610291
1959480
957
Paclitaxel + carboplatin + veliparib
Paclitaxel + carboplatin Paclitaxel
Events n/N 65/316 30/160 47/158
Hazard ratio (95% CI)a
Paclitaxel + carboplatin + veliparib vs paclitaxelPaclitaxel + carboplatin + veliparib vs paclitaxel + carboplatinPaclitaxel + carboplatin vs paclitaxel (post hoc analysis)
0.63 (0.43–0.92), P=0.021.12 (0.72–1.72), P=0.620.57 (0.36–0.91), P=0.02
4-year EFS, % (95% CI) 78.2 (73.5–83.2) 79.3 (72.9–86.2) 68.5 (61.3–76.6)
Loibl et al ESMO 2021
MEDIAN FOLLOW-UP OF 4.5 YEARS
Carboplatin EFS 11%
No EFS benefit for addition of veliparib
BrighTNess: EFS RESULTS
aStratified by BRCA status, lymph node status, and planned doxorubicin/cyclophosphamide dose intensity.C, carboplatin; CI, confidence interval; EFS, event-free survival; HR, hazard ratio; P, paclitaxel; V, veliparib.
censored
Prob
abilit
y of E
FS
Months since randomization
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.0
0.1
0 3 6 9 15 18 21 24 27 30 33 6012 4236 39 45 725448 51 57 63 66 69
No of patients at riskP + C + V
P + CP
316160158
311157147
301154147
290151142
273143132
266134125
257129120
248121115
241118112
228112102
21311095
0
1
283148139
281312
1999787
1889174
133 0
235115107
22211198
102
1305541
20610291
1959480
957
Paclitaxel + carboplatin + veliparib
Paclitaxel + carboplatin Paclitaxel
Events n/N 65/316 30/160 47/158
Hazard ratio (95% CI)a
Paclitaxel + carboplatin + veliparib vs paclitaxelPaclitaxel + carboplatin + veliparib vs paclitaxel + carboplatinPaclitaxel + carboplatin vs paclitaxel (post hoc analysis)
0.63 (0.43–0.92), P=0.021.12 (0.72–1.72), P=0.620.57 (0.36–0.91), P=0.02
4-year EFS, % (95% CI) 78.2 (73.5–83.2) 79.3 (72.9–86.2) 68.5 (61.3–76.6)
Loibl et al ESMO 2021
MEDIAN FOLLOW-UP OF 4.5 YEARS
Carboplatin EFS 11%
? HRD/immune status on carboplatin EFS benefit
No EFS benefit for addition of veliparib
Immune Checkpoint Inhibition
Priyanka Sharma, MD
GeparNuevo: Addition of Durvalumab to a taxane-anthracycline containing chemotherapy in TNBC
Loibl Annals of Oncology 2019
N=88 N=86
pCR
Priyanka Sharma, MD
No adjuvnat ICB
GeparNuevo: Addition of Durvalumab to a taxane-anthracycline containing chemotherapy in TNBC
Loibl Annals of Oncology 2019
53.… 44…
0%20%40%60%80% P=0.28
N=88 N=86
pCR
Priyanka Sharma, MD
No adjuvnat ICB
PRESENTED BY: SIBYLLE LOIBL, MD PRESENTED AT:#ASCO21 │ Content of this presentation is property of the author, licensed by ASCO. Permission required for reuse
GeparNuevo: iDFS
3yr 77.2%
3yr 85.6%
Stratified HR* Durvalumab to Placebo = 0.48 (95%CI 0.24, 0.97), p=0.0398
Time (months)
Inva
sive
Dis
ease
-Fre
e Su
rviv
al R
ate
(%)
Patients at risk:* Stratified by sTILs
Median follow-up 43.7 (range 4.9-56.1) months
PRESENTED BY: SIBYLLE LOIBL, MD PRESENTED AT:#ASCO21 │ Content of this presentation is property of the author, licensed by ASCO. Permission required for reuse
Time (months)
Ove
rall
Surv
ival
Rat
e (%
)
3yr 83.5%
3yr 95.2%
Stratified HR* Durvalumab to Placebo = 0.24 (95%CI 0.08, 0.72), p=0.0108
GeparNuevo: DDFS and OSDDFS
Patients at risk:
OS
Time (months)
Dis
tant
Dis
ease
-Fre
e Su
rviv
al R
ate
(%)
Stratified HR* Durvalumab to Placebo = 0.31 (95%CI 0.13, 0.74), p=0.0078
Patients at risk:
3yr 78.4%
3yr 91.7%
* Stratified by sTILs
PRESENTED BY: SIBYLLE LOIBL, MD PRESENTED AT:#ASCO21 │ Content of this presentation is property of the author, licensed by ASCO. Permission required for reuse
iDFS in Subgroups (univariate Cox regression model)Subgroup Hazard RatioN p-Value Test for
(95% CI)patients Interaction
Overall 0.48 (0.24, 0.97)174 .0398
sTILs 0.705low (0-10%) .423 (.156, 1.15)66 0.090intermediate/high (11-100%) .553 (.205, 1.50)108 0.244
Window Arm 0.891w indow .524 (.220, 1.25)117 0.145no w indow .465 (.140, 1.55)57 0.211
Breast Cancer Stage 0.940Stage 0 or I .553 (.092, 3.31)61 0.517Stage IIA and higher .519 (.241, 1.12)113 0.093
Age 0.552<40 .344 (.089, 1.33)47 0.122>=40 .573 (.251, 1.31)127 0.187
PD-L1 0.463negative .795 (.133, 4.76)20 0.801positive .436 (.188, 1.01)138 0.053
pCR (ypT0 ypN0) 0.222no .674 (.295, 1.54)88 0.350yes .220 (.046, 1.06)85 0.059
10.1 0.2 0.5 2.0 3.0
Longer iDFS with Durvalumab Longer iDFS with Placebo
HR
*
* Stratified by sTILs
aMust consist of at least 2 separate tumor cores from the primary tumor. bCarboplatin dose was AUC 5 Q3W or AUC 1.5 Q1W.cPaclitaxel dose was 80 mg/m2 Q1W.
dDoxorubicin dose was 60 mg/m2 Q3W.eEpirubicin dose was 90 mg/m2 Q3W.fCyclophosphamide dose was 600 mg/m2 Q3W.
KEYNOTE-522 Study Design (NCT03036488)
Stratification Factors:• Nodal status (+ vs -)• Tumor size (T1/T2 vs T3/T4)• Carboplatin schedule (Q1W vs Q3W)
Key Eligibility Criteria• Age ≥18 years• Newly diagnosed TNBC of
either T1c N1-2 or T2-4 N0-2• ECOG PS 0-1• Tissue sample for PD-L1
assessmenta
Neoadjuvant Treatment 1(cycles 1-4; 12 weeks)
Neoadjuvant Treatment 2 (cycles 5-8; 12 weeks)
Adjuvant Treatment(cycles 1-9; 27 weeks)
Carboplatinb + Paclitaxelc
Doxod/Epirubicine+ Cyclophosphamidef
Pembrolizumab 200 mg Q3W
Pembrolizumab 200 mg Q3W
Placebo
Placebo
R 2:1
Neoadjuvant Phase Adjuvant Phase
Carboplatinb + Paclitaxelc
Doxod/Epirubicine + Cyclophosphamidef
SURGERY
Primary endpoints: pCR (ypT0/Tis ypN0) by local review, EFS by local review Secondary endpoints: pCR (ypT0 ypN0 and ypT0/Tis), OS, EFS, AE Exploratory endpoints: RCB, pCR by subgroups, EFS by pCR
KEYNOTE-522: Pathological complete response (IA1, N=602)
Schmidt et al NEJM 2020
KEYNOTE-522: EFS, IA4
EFS by pCREFS in subgroups
IMpassion031: Addition of Atezolizumab to Neoadjuvant Chemotherapy in Stage II-III TNBC
Harbeck. ESMO 2020. Abstr LBA11, Mittendorf et al Lancet 2020
pCR in ITT Population
Harbeck. ESMO 2020. Abstr LBA11, Mittendorf et al Lancet 2020
pCR (95% CI), ypT0/is ypN0
57.6%
41.1
95/165 69/168
Δ 16.5%
Atezo + CT0
20
40
60
80
100
pCR,
% (9
5% C
I)
Pbo + CT
P = .0044
n/N =
pCR by PD-L1 StatusPD-L1 Positive
68.8%
49.3%
53/77 37/75
Δ 19.5%
Atezo + CT0
20
40
60
80
100
pCR,
% (9
5% C
I)
Pbo + CT
n/N =
PD-L1 Negative
47.7%
34.4%
42/88 32/93
Δ 13.3%
Atezo + CT0
20
40
60
80
100
pCR,
% (9
5% C
I)
Pbo + CT
n/N =
IMpassion031: Pathologic Complete Response
P = .021a
asignificance boundary 0·0184
*HER-2 negative, ER and PgRnegativeearly high-risk (T1cN1; T2N1; T3N0) or locally advanced unilateralbreast cancer
Neoadjuvant Therapy in TRIPle Negative Breast Cancer With antiPDL1 (NeoTRIPaPDL1)
*Estrogen receptor, progesterone receptor, HER2 and PD-L1 were centrally assessed before randomization
FOLLOWUP
Carboplatin AUC 2 + nab-paclitaxel 125mg/m2weekly for 2 wks every 3for 8 cycles
Carboplatin AUC 2 + nab-paclitaxel 125mg/m2weekly for 2 wks every 3for 8 cycles+ Atezolizumab day 1 every 3 wks for 8 cycles
R
AC/EC/FECfor 4 cycles
AC/EC/FECfor 4 cycles
S
S
Gianni et al SABCS 2019
*HER-2 negative, ER and PgRnegativeearly high-risk (T1cN1; T2N1; T3N0) or locally advanced unilateralbreast cancer
Neoadjuvant Therapy in TRIPle Negative Breast Cancer With antiPDL1 (NeoTRIPaPDL1)
*Estrogen receptor, progesterone receptor, HER2 and PD-L1 were centrally assessed before randomization
FOLLOWUP
Carboplatin AUC 2 + nab-paclitaxel 125mg/m2weekly for 2 wks every 3for 8 cycles
Carboplatin AUC 2 + nab-paclitaxel 125mg/m2weekly for 2 wks every 3for 8 cycles+ Atezolizumab day 1 every 3 wks for 8 cycles
R
AC/EC/FECfor 4 cycles
AC/EC/FECfor 4 cycles
S
S
Gianni et al SABCS 2019
Primary end point: EFSSecondary end point: pCR
*HER-2 negative, ER and PgRnegativeearly high-risk (T1cN1; T2N1; T3N0) or locally advanced unilateralbreast cancer
Neoadjuvant Therapy in TRIPle Negative Breast Cancer With antiPDL1 (NeoTRIPaPDL1)
*Estrogen receptor, progesterone receptor, HER2 and PD-L1 were centrally assessed before randomization
FOLLOWUP
Carboplatin AUC 2 + nab-paclitaxel 125mg/m2weekly for 2 wks every 3for 8 cycles
Carboplatin AUC 2 + nab-paclitaxel 125mg/m2weekly for 2 wks every 3for 8 cycles+ Atezolizumab day 1 every 3 wks for 8 cycles
R
AC/EC/FECfor 4 cycles
AC/EC/FECfor 4 cycles
S
S
N=28087% Node positive45% T3-T456% PD-L1 positive
Gianni et al SABCS 2019
Primary end point: EFSSecondary end point: pCR
NeoTRIPaPDL1: pCR
Bianchini et al ESMO 2020
NeoTRIPaPDL1: pCR
Bianchini et al ESMO 2020
NeoTRIPaPDL1: pCR
Bianchini et al ESMO 2020
pCR and PD-L1 IC groups
Neoadjuvant chemo + ICI trials KEYNOTE-522 (NCT03036488)
GeparNeuvo IMpassion031(NCT03197935)
NeoTRIPaPDL1 (NCT02620280)
N=1174 N=174 N=333 N=280
End points Co-Primary: pCR and EFS Primary: pCRSecondary: iDFS, DDFS, OS
Primary: pCRSecondary: EFS
Primary: EFSSecondary: pCR
LN+ 51% 33%, stage I: 36% 36% 87%
Regimen Paclitaxel/carbo AC/EC + pembrolizumab/placebo CbP-AC
nab-paclitaxel EC +Durvalumab/placebonP-EC
nab-paclitaxel EC + durvalumab/placebo. nP-AC
Wkly carbo/nab-paclitaxel+Atezolizumab/Placebo X 8 cycles CbP
Adj treatment Pembro/placebo X 27 wks No ICI Atezo/placebo X 22 wks EC/AC/FEC
ICI Type Anti-PD-1 Anti PD-L1 Anti-PD-L1 Anti-PD-L1
Treatment duration
24 weeks 20 weeks 20 weeks 24 weeks
PD-L1+ 83% (CPS>1) 87%(SP263 antibody) 46% (IC >1%) 56% (IC>1%)PCR ITT: 65 vs 51% (63 vs 55.6%)
PD-L1+: 70 vs 55%PD-L1-ve: 45 vs 30%
53 vs 44%n.s ITT: 58 vs 41%PD-L1+: 69 vs 49%n.s
PD-L1-ve: 47 vs 34%
ITT: 52 vs 47%n.s.
PD-L1+: 56 vs 44%PD-L1-ve: 35 vs 41%
EFS/DFS/OS 3-year EFS 84.5% vs 76.8% HR=0.63, p=0.00033-year OS: 89.6% vs 86.9% HR=0.72, p=0.032n.s
3-year iDFS: 85.6% vs 77.2% HR=0.48, p=0.03983-year OS: 95% vs 83%HR=0.24, p=0.018
Pending Pending
Schmid et al, NEJM 2020, Mittendorf et al, Lancet 2020, Gianni et al SABCS 2019, Bianchini et al ESMO 2020, Schmidt et al ESMO virtual session, Loibl et al ASCO 2021
Safety of Immune check point inhibitors in metastatic TNBC
D’Abreo and Adams. Nat Rev Clin Oncol 2019, Brahmer et al, J Clin Oncol 2018
irAE incidence in eTNBC
• Any grade: 40-44%
• Grade 3-5: 14-15%
• Early recognition and prompt management
• Management guidelines ASCO/NCCN
KEYNOTE-522 : iAE
Most frequent iAEs: Infusion reactions (18%), hypothyroidism (15%), severe skin reactions (5.8%), Hyperthyroidism (5.2%), adrenal insufficiency (2.6%), pneumonitis (2,2%), thyroiditis (2%), Hypophysitis (1.9%)
IMpassion031: AEs of special interest in neoadjuvant phase
Neo/adjuvant IC inhibitors in TNBC
Neo/adjuvant IC inhibitors in TNBC Addition of ICI improves pCR and EFS/iDFSNeo (plus adjuvant) Pembrolizumab + chemotherapy FDA approved
Neo/adjuvant IC inhibitors in TNBC Addition of ICI improves pCR and EFS/iDFSNeo (plus adjuvant) Pembrolizumab + chemotherapy FDA approved
Improvement in outcomes but overtreatment of many 54-55% pCR with chemotherapy alone
4-year EFS 79% with CbT-AC (BrighTNess)iAEs in early vs. metastatic setting: Long term toxicity ? Cost
Neo/adjuvant IC inhibitors in TNBC Addition of ICI improves pCR and EFS/iDFSNeo (plus adjuvant) Pembrolizumab + chemotherapy FDA approved
Improvement in outcomes but overtreatment of many 54-55% pCR with chemotherapy alone
4-year EFS 79% with CbT-AC (BrighTNess)iAEs in early vs. metastatic setting: Long term toxicity ? Cost
Role of chemo backboneAthra+Platinum, Anthra, Platinum+taxane
Neo/adjuvant IC inhibitors in TNBC Addition of ICI improves pCR and EFS/iDFSNeo (plus adjuvant) Pembrolizumab + chemotherapy FDA approved
Improvement in outcomes but overtreatment of many 54-55% pCR with chemotherapy alone
4-year EFS 79% with CbT-AC (BrighTNess)iAEs in early vs. metastatic setting: Long term toxicity ? Cost
Role of chemo backboneAthra+Platinum, Anthra, Platinum+taxane
Future research Role of adjuvant ICI: after pCR? For RD after neoadjuvant ICI?Upfront vs guided by pathological response: S1418 de-escalating chemo back-bone: ISPY2, NeoPACTBiomarkers: PD-L1 not the best predictor of response in early stage TNBC
THANK YOU
Predictive value of gene-expression profiles (GEPs) and their dynamics during therapy in the NeoTRIPaPDL1 trial
Giampaolo Bianchini, Matteo Dugo, Chiun-Sheng Huang, Daniel Egle, Begoña Bermejo, Claudio Zamagni, Robert S Seitz, Tyler J Nielsen, Marc Thill, Antonio Anton, Stefania Russo, Eva Maria Ciruelos, Brock L Schweitzer, Balazs Gyorffy, Richard Greil, Vladimir Semiglazov, Pinuccia Valagussa, Giuseppe Viale, Maurizio Callari, Luca Gianni
Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
NeoTRIP trial: timing of successful RNA-sequencing (in PPP)
Giampaolo Bianchini ([email protected])
TN high-risk (T1cN1; T2N1; T3N0) or locally advanced Su
rger
y
R
Carboplatin (AUC2) + nab-paclitaxel (125 mg/m2) weekly for 2 wks every 3; 8 cy; Atezolizumab (1200 mg) day 1 every 3 wks for 8 cycles(§) Results in the Per-Protocol-Population (Bianchini G ESMO 2020 LBA13)
Carboplatin + nab-paclitaxel + Atezolizumab
Carboplatin+nab-paclitaxel
Gianni L SABCS 2019 (Abstract G3-02)PPP: Per-protocol-population (patients evaluable for pCR)
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NeoTRIP trial: timing of successful RNA-sequencing (in PPP)
Giampaolo Bianchini ([email protected])
TN high-risk (T1cN1; T2N1; T3N0) or locally advanced Su
rger
y
RCarboplatin + nab-paclitaxel + Atezolizumab
Carboplatin+nab-paclitaxel
Baseline(Pre-treatment)
Timing of tumor sample collection
Rate of successful RNA-seq 93.8 %
Gianni L SABCS 2019 (Abstract G3-02); Bianchini G ESMO 2020 (LBA13) PPP: Per-protocol-population (patients evaluable for pCR)
Rate oftissue collection 100 %
(242/258)
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Methods and Aim (I)
Giampaolo Bianchini ([email protected])
In this post-hoc study, we evaluated on pre-treatment samples the association with pCR of- IO score1 (research-based version of DetermaIOTM) which has been associated with immune checkpoint
inhibitor benefit independently of PD-L1 or TMB in NSCLC2 and metastatic urothelial cancer (IMvigor210)3, and also with pCR in TNBC treated with neoadjuvant durvalumab and chemotherapy (NCT02489448)4 (pre-specified analysis)
- TNBCtypes by 101-gene score algorithm (BL1, BL2, LAR, M and MSL)5(exploratory analysis)
1 Nielsen TJ Heliyon 2021; 2 Ranganath H SITC 2019; 3 Seitz RS AACR 2021; 4 Iwase T ASCO 2020; 5 Ring BZ BMC Cancer 2016
Chemotherapy +/- Atezolizumab
SurgeryPre-treatmentpCR
RDBaseline biopsy
IO scoreTNBCtypes
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Methods and Aim (II)
Giampaolo Bianchini ([email protected])
Analysis flow1) RNA-sequencing has been generated in OncoCyte’s lab (blinded to clinical outcome information)2) RNA-seq QC performed in my lab3) IO score (binary and continuous) and TNBC types generated in OncoCyte’s lab (blinded to clinical outcome
information)4) Results provided to my lab5) Association of IO score and TNBC types with PD-L1, sTILs and pCR (breast and nodes) according to a pre-
specified SOP- IO score binary (primary analysis)- IO score continuous and TNBC types (secondary exploratory analysis)
1 Nielsen TJ Heliyon 2021; 2 Ranganath H SITC 2019; 3 Seitz RS AACR 2021; 4 Iwase T ASCO 2020; 5 Ring BZ BMC Cancer 2016
IO score balanced among arms
IO score is associated with PD-L1 and sTILs
CT/Atezo OR 3.64 (1.68-7.90) p=0.001
Binary IO score (pos vs neg, primary analysis)
Test of interaction p=0.029(adjusted for PD-L1 ad sTILs)
CT OR 1.31 (0.64-2.67) p=0.46
Logistic regression analysis
IO score (continuous score, exploratory analysis)
CT/Atezo OR 3.65 (1.45-9.24) p=0.006CT OR 1.56 (0.69-3.54) p=0.283
Wilcoxon test
Logistic regression analysis
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How does IO score compare with immune signatures?
Giampaolo Bianchini ([email protected])
We also explored the association with pCR of 151 selected tumor intrinsic and extrinsic gene-signatures (HALLMARK1, Consensus clusters2, Nanostring3, and few selected from literature4,5,6,7,8) evaluated on pre-treatment samples. None of the immune-related signatures (over 60) outperformed IO score.
Pre-treatmentBaseline biopsy
151 tumor intrinsic and extrinsic gene-signatures
1 Liberzon A Cell Syst 2015; 2 Jimenez-Sanchez A Cancer Res 2019; 3 https://www.nanostring.com/; 4 Callari M CCR 2016; 5 Bianchini G Ann Oncol 2015; 6 Bianchini G Breast Cancer Res 2013; 7 Masiero M Cancer Cell 2013; 8 Mak MP CCR 2016
Only two immune related-signatures were associated with pCR in atezolizumab arm (with a p value between 0.01 and 0.05)
TNBC types balanced among arms
TNBC types association with PD-L1 and sTILs
• The LAR subtype had the lowest pCR rate (CT/A 22.2%, CT 18.8%), whereas BL1 had the highest [CT/A 70.3%, CT 54.3%) (p=0.001)
• All tests of interaction not significant
TNBC types association with pCR
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Conclusions (I)
• IO score, but not TNBCtype, is predictive of atezolizumab benefit over CT alone (significant test of interaction after adjustment for PD-L1 and sTILs)
Giampaolo Bianchini ([email protected])
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Acknowledgments
Giampaolo Bianchini ([email protected])
Patients, their families and all the investigators
HSRMatteo DugoBarbara GalbardiMarco Barreca
Fondazione MichelangeloMaurizio CallariGiuseppe VialePinuccia ValagussaLuca Gianni
Other collaboratorsH Raza AliBalazs Gyorffy Lucia Del MastroCatherine KellyMarco ColleoniGabriella Mariani
OncoCyteRobert S SeitzTyler J NielsenBrock L SchweitzerDouglas T Ross
@BianchiniGP @mauricallari @FondazioneBona1
Q&A Discussion