Danny Pham

Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus
placebo and chemotherapy in patients with early-stage triple-negative breast cancer

Introduction:
Triple-negative breast cancer (TNBC) is associated with having the worst prognosis among the subtypes of breast
cancer.
Early-stage TNBC accounts for 10-20% of new diagnoses of early breast cancer and neoadjuvant and adjuvant
chemotherapy regimens have been shown to improve outcomes in these patients.
In patients with residual disease at surgery, 5-year metastasis-free survival is only approximately 70% even with
adjuvant capecitabine, so improvements in treatment is needed.
In the NCCN guidelines, recommended options for TNBC include dose-dense AC followed by paclitaxel every 2
weeks, dose-dense AC followed by weekly paclitaxel, or docetaxel and cyclophosphamide
Backgroun Immunotherapy is a big focus in oncology and there are benefits of immunotherapy in patients with breast cancer.
d Specifically, the use of atezolizumab with albumin-bound paclitaxel has a category 1 recommendation per NCCN in
patients with TNBC metastatic/recurrent disease who were PD-L1 positive.
Atezolizumab or Tecentriq is a monoclonal antibody that selectively binds to PD-L1 and works to modulate the
body’s immune system and response to the tumor cells.
Early-phase trials of immune checkpoint blockade monotherapy in early TNBC showed promising results,
warranting further research on combination with chemotherapy.
Among chemotherapy options to combine with atezolizumab, nab-paclitaxel is an option because it can avoid the
immunosuppressive effects from concurrent steroid use and paclitaxel has shown to have benefit with doxorubicin
and cyclophosphamide for early-stage TNBC.
To evaluate and compare the efficacy and safety of atezolizumab versus placebo combined with nab-paclitaxel
Objective
followed by doxorubicin plus cyclophosphamide as neoadjuvant treatment for early-stage TNBC

Methods:
Study: double-blind, randomized, phase 3 study with a two-stage adaptive enrichment design
Location: 75 academic centers and community oncology practices in 13 countries (USA, UK, Germany, Japan etc.)

Treatment arms:
Treatment group:
 Atezolizumab 840 mg IV q2 weeks combined with nab-paclitaxel at 125 mg/m2 once per week for 12
weeks, followed by IV atezolizumab 840 mg q2weeks combined with doxorubicin at 60 mg/m2 and
cyclophosphamide at 600 mg/m2 q2 weeks, with filgrastim or pregfilgrastim support for 8 weeks, and breast
Study surgery. After surgery, patients were unmasked to treatment assignment and continued to receive IV
Methods atezolizumab at 1200 mg q3weeks for 11 cycles for approximately 12 months.
 Placebo group: Same treatment except instead of atezolizumab, placebo was given. After surgery, no
treatment was given.
 Additionally, management of patients for whom a pathological complete response was not found followed
standard of care guidelines.
Funding: F Hoffmann-La Roche/Genentech

Randomization and masking:

Patients were randomly assigned 1:1 and stratified based on staging and tumor PD-L1 expression.
Patient
Populatio ≥18 years of age
n Clinical stage T2-T4 and No-N3 histologically documented TNBC
Inclusion
No previous systemic therapy for breast cancer
Criteria:
No previous systemic therapy with anthracyclines or taxanes for any malignancy
ECOG score of 0 or 1
Previous treatment with an anti-CTLA-4, anti-PD-1, or anti-PD-L1 agent
History of ductal or pleomorphic lobular carcinoma in situ unless more than 5 years before the
Exclusion
current diagnosis and treated only surgically
Criteria:
Bilateral breast cancer

Baseline 455 patients were recruited and assessed between 7/7/17 and 9/24/19. 33 patients were
Characteristics randomly assigned to the treatment group (n=165) or control group (n=168)
Well-balanced between the two groups, although a slight imbalance in clinical nodal
involvement (more patients in the treatment group had N0 or compared to control group 66%
vs 57%)

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Danny Pham
Median age was 51 years, 100% were female, 63% white. 77% had stage 2 at diagnosis, 38%
had baseline lymph node involvement.

Primary  Co-primary endpoints were pathological complete response (eradication of invasive

Endpoints tumor for both breast and lymph nodes) in both the intention-to-treat and the PD-L1-
positive populations
Endpoints
 Event-free survival in both populations
 Disease-free survival in both populations
Secondary
 Overall survival in both populations
Endpoints
 Patient reported outcomes
 Safety and tolerability

The overall one-sided type 1 error for testing the co-primary endpoint of pathological complete response was a of
0.025 which meant approximately 324 patients were planned to be enrolled in the study.
Statistical Pathological complete response rates were calculated by study stage and overall for study groups in both the all-
Analysis randomized and PD-L1-positive populations. Kaplan-Meier analysis was applied to estimate median duration of
event-free survival, disease-free survival and overall survival.
Safety was assessed for all patients who received any dose of study medication.

Results:
All randomized population
 Pathological complete response was 58% vs 41% (rate difference 17% 95% CI 6-27 p=0.0044)
which crossed the significance boundary of p<0.0184
Primary PD-L1 positive population
Outcomes  Pathological complete response was observed in 69% vs 49% (rate difference 20% 95% CI 4-35
p=0.021 which did not cross the significance boundary of p<0.0184).
PD-L1 negative population
 Pathological complete response was 48% vs 34% (rate difference 13%, 95% CI -1-28)
Not formally powered for event-free survival, disease-free survival, or overall survival
 Event-free survival: HR 0.76 95% CI 0.40-1.44
 Disease-free survival HR 0.74 95% CI 0.32-1.70
Secondar  Overall survival HR 0.69 95% CI 0.25-1.87
y Adverse events: 63% had grade 3-4 adverse events in treatment group vs 60%
Outcomes Serious adverse events occurred in 30% in the treatment group vs 18% in the control group.
Incidence of serious adverse events including febrile neutropenia, PNA, and pyrexia occurred in more patients
in the treatment group.
More hypothyroidism, hepatic laboratory abnormalities and infusion-related reactions in the treatment group.

Critique:
Not that many patients discontinued from study (6.7% vs 8.9%)
Safety was assessed
Percentage of patients with pathological complete response in the placebo was consistent with those reported in
Strengths other studies of neoadjuvant regimens containing taxanes plus anthracycline and cyclophosphamide.
Inclusion of node-positive patients
Standard of care was implemented after surgery
The addition of atezolizumab did not compromise the ability to receive chemotherapy
Compared to not standard of care
Inclusion of non-PD-L1 patient population
Small population size
Not adequately powered for secondary outcomes
Not sure about powered for PD-L1 positive population
Limitations
Difference in baseline characteristics
Use of pathological complete response
Short follow-up duration
Unmasking after phase 1 of the study

Conclusions:

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Danny Pham
In patients with early-stage TNBC, neoadjuvant treatment with atezolizumab in
Author’s combination with nab-paclitaxel and anthracycline-based chemotherapy significantly
Conclusion improved pathological complete response rates with an acceptable safety profile.

My
Conclusions

Mittendorf EA, Zhang H, Barrios CH, et al. Neoadjuvant atezolizumab in combination with sequential nab-
paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage
triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet.
2020;396(10257):1090-1100.
Reference
s
National Comprehensive Cancer Network. Breast Cancer (Version
1.2021). https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf