Download Triple-Negative First-Line Study: Neoadjuvant Trial of nab

Triple-Negative First-Line Study: Neoadjuvant Trial of nab-paclitaxel and Atezolizumab, a PD-L1
inhibitor, in patients with Triple Negative Breast Cancer (TNBC)
J. K. Litton1, S Moulder1, T Helgason1, AR CLayborn1, GM Rauch2, M. Gilcrease3, BE Adrada2, L Huo3, KR Hess4, WF Symmans3, A Thompson5, D Tripathy1, EA Mittendorf5
The University of Texas MD Anderson Cancer Center, Department of Breast Medical Oncology 1, Department of Diagnostic Radiology2, Department of Pathology3, Department of Biostatistics4, Department of Breast Surgical Oncology5,
OBJECTIVES
ABSTRACT
BACKGROUND: TNBC has an especially poor prognosis in
patients (pts) whose tumor does not respond to anthracycline and
taxane-based chemotherapy. Approximately 50% will have chemoinsensitive disease (CID) resulting in extensive residual disease at
the time of surgery. 40-80% of these pts will recur < 3 years.
Recently developed molecular profiling techniques to identify TNBC
subsets detect distinct molecular hallmarks. We designed a clinical
trial to identify and characterize CID (ARTEMIS: A Randomized,
TNBC Enrolling trial to confirm Molecular profiling Improves
Survival). Treatment naïve pts with localized TNBC undergo a
pretreatment biopsy followed by anthracycline-based
chemotherapy (AC). During AC the molecular profile is determined;
these results along with the response assessment (clinical
exam/diagnostic imaging) will identify CID and guide the second
phase of neoadjuvant chemotherapy. Tumor-infiltrating
lymphocytes (TIL) have been identified as having prognostic and
predictive significance in TNBC pts leading to higher pCR rates
post NACT. However, the tumor microenvironment also contains
regulatory T cells and myeloid-derived suppressor cells that are
immunosuppressive.
Programmed death ligand 1 (PD-L1) is
BACKGROND
expressed in 20% TNBC. Targeting this may lead to a more
durable response as compared to chemotherapy alone.
PRIMARY OBJECTIVE: Evaluate the rate of pathologic complete
response (pCR)/RCB-0 + residual cancer burden (RCB)-I
responses in TNBC pts, determined to have CID after anthracycline
-based chemotherapy, then treat with atezolizumab + nabpaclitaxel preoperatively.
TRIAL DESIGN AND STATISITCAL METHODS: Pts deemed to
have CID on the ARTEMIS trial can enter this non-randomized
phase II study. Pts without response to their initial chemotherapy
cycles have a low likelihood (5%) of achieving pCR with additional
cycles of chemotherapy. It would be clinically meaningful for pCR
to improve to 20%. Counting pCR (RCB-0) or RCB-I as response
given similar survival outcomes, a two-stage Gehan-type design
will be employed with 14 pts in the first stage. If at least one pt
responds, 23 more will be added. This design has a 49% chance of
terminating after the first stage if the true response rate is 0.05,
23% chance if the true rate is 0.10, 10% if the true rate is 0.15 and
4% if the true rate is 0.20. If accrual continues to the second stage,
the 95% confidence interval for a 0.20 response rate will extend
from 0.10 to 0.35.
.
HYPOTHESES
Among patients with TNBC who were non-responders to initial
anthracycline and cyclophosphamide chemotherapy, the
combination of atezolizumab and nab-paclitaxel administered in
the neoadjuvant setting will increase pCR and RCB-I rates and 3
year Disease-Free-Survival (DFS)
STUDY DESIGN
PARENT STUDY: ARTEMIS
Primary Objective:
To evaluate the rate of pathologic complete response (pCR) +
residual cancer burden (RCB)-I responses in patients with TNBC,
who were non-responders to initial anthracycline and
cyclophosphamide chemotherapy, then treated with atezolizumab
in combination with nab-paclitaxel in the neoadjuvant setting.
Secondary Objectives:
To estimate Disease Free Survival distribution of TNBC patients
who were non-responders to initial anthracycline Table-1.
and
Patient characteristics
cyclophosphamide chemotherapy, treated with atezolizumab in
combination with nab-paclitaxel in the neoadjuvant setting.
To determine the safety of atezolizumab in combination with nabpaclitaxel in the neoadjuvant setting
•
Atezolizumab will be administered at 1200mg IV every 3 weeks (q3w x 4 doses) for 12
weeks in the neoadjuvant setting in combination with nab-paclitaxel (100 mg/m2 IV
weekly for 12 weeks).
•
Within 4 weeks after surgery, patients will start another 4 cycles of atezolizumab
(1200mg IV q3w) in the adjuvant setting to complete a total of 8 cycles of treatment with
atezolizumab.
•
Definitive surgery within 6 weeks of completing nab-paclitaxel and atezolizumab
•
Radiation can occur during the adjuvant atezolizumab therapy
•
Should growth be observed on the breast ultrasound performed per standard of care
after about 6 weeks of study therapy, a biopsy can be performed. If the disease is shown
to have increased immune infiltrate the patient can continue on therapy. Otherwise
patients will transition to physician’s therapeutic intervention of choice
Exploratory Objective
To investigate the association between biomarkers in the
peripheral blood and tumor tissue with efficacy for TNBC patients
treated with atezolizumab in combination with nab-paclitaxel in the
neoadjuvant setting.
STATISTICAL CONSIDERATIONS
INCLUSION AND EXCLUSION
STUDY SCHEMA
Inclusion:
• Participation in the Parent trial (ARTEMIS)
• Tumor 1.5 cm or greater
• ER and PR both <10% by IHC and HER2 non
amplified
• No prior therapy for breast cancer
• ECOG of 0-1
• Adequate organ function as determined by laboratory
values
• Negative pregnancy test
Exclusion:
• Known metastatic disease
• Prior immunotherapy for breast cnacer
• Recent surgery ( >21 days)
• History of MI within 6 months
• History of auto-immune disease
• Prior allogeneic stem cell or solid organ
transplantation
• History of pulmonary fibrosis or pneumonitis
• Active hepatitis or TB
•
Two-stage Gehan-type design with 19 patients in the first stage. If at least 1 patient
achieves an RCB 0 or 1, then additional 18 patients will be added for a total of 37 patients.
•
Estimating that patients with TNBC who do not respond to 4 cycles of AC chemotherapy
have approximately a 5% rate of RCB 0, then improving from 5 to 20% would warrant
further investigation in a larger neoadjuvant trial.
•
38% terminating after the first stage of true response rate is 0.05, 14% if the true rate is
0.10 and 5% if the true rate is 0.15 and 1% if the true rate is 0.20
•
If we continue to the second stage and enroll a total of 37 patients, then the 95%
confidence interval for a 0.15% response rate will extend from 0.05 to 0.31
PLANNED CORRELATIVES
N=37
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Evaluation of PD-L1 expression by IHC on tumor cells and infiltrating immune cells within
the tumor microenvironment pre- and post-treatment
•
Evaluation of intratumoral CD8+ T cells by IHC pre- and post-treatment
•
Characterization of the immune cell infiltrate as well as T cell co-stimulatory and inhibitory
molecules by multiplex immunofluorescence
•
Characterization of the peripheral blood immune response in peripheral blood
mononuclear cells
•
Serum cytokine analysis
ACKNOWLEDGEMENTS
Supported by the M.D. Anderson Moon Shots Program and Genentech