Edited by: Sirin A Adham, Sultan Qaboos University, Oman
Reviewed by: William Harless, ENCYT Technologies, Canada; Lubna Chaudhary, Medical College of Wisconsin, United States
*Correspondence: Xuedong Yin,
This article was submitted to Women’s Cancer, a section of the journal Frontiers in Oncology
†These authors have contributed equally to this work
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Immune checkpoint inhibitors (ICIs) have shown promising anti-tumor activity in multiple malignances including breast cancer. However, the responses can vary. This meta-analysis was conducted to evaluate the efficacy and safety profile of adding ICIs to neoadjuvant chemotherapy against triple-negative breast cancer (TNBC) and assess correlation of PD-L1 tumor status with responses.
Eligible studies were retrieved from the PubMed, Embase, and Web of Science databases. Randomized controlled trials (RCTs) that investigated ICI-containing
This study included four RCTs containing 1795 patients with early TNBC. Compared with ICI-free neoadjuvant therapy, ICI-containing neoadjuvant therapy significantly increased the pathological complete response (pCR) rates in TNBC (odds ratio [OR] = 2.14, 95% confidence interval [CI]: 1.37–3.35,
ICI-containing neoadjuvant therapy significantly increased the pCR rate in TNBC patients, independently of PD-L1 status. The addition of ICI to neoadjuvant chemotherapy may be considered an option for TNBC patients.
Neoadjuvant treatment is widely used to reduce the size and extent of tumors in high risk early breast cancer (BC). Patients who achieve a pathological complete response (pCR) after neoadjuvant therapy have better survival outcomes than those with residual invasive disease (
Immune-checkpoint therapy targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis is a promising strategy for several malignances (
To provide up to date evidence on this emerging topic, we performed a meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and safety of adding ICIs to neoadjuvant chemotherapy in early TNBC.
Literatures published before October 01, 2020 were retrieved from the PubMed, Embase, and Web of Science databases with the use of the following keywords: immune checkpoint inhibitors, nivolumab, pembrolizumab, ipilimumab, avelumab, tremelimumab, atezolizumab, durvalumab, and TNBC without further restrictions. The citation lists of relevant studies, reviews, and meta-analyses were manually screened for potentially eligible publications. The literature search was independently performed by two of the authors (LYH and XL). Any discrepancy was solved by discussion with a third author (YXD).
The inclusion and exclusion criteria were prespecified. Eligible studies had to satisfy the following criteria: (a) phase II or phase III RCTs; (b) RCTs including early TNBC patients who received ICI-containing neoadjuvant therapy in the experimental arm and ICI-free neoadjuvant therapy in the control arm; and (c) RCTs with available data on pCR rates in the experimental and control arms for the estimation of an odds ratio (OR) and 95% confidence interval (CI). Studies were excluded if they were: (a) non-RCTs conducted to evaluate the role of ICI-containing neoadjuvant therapy in TNBC patients; (b) single-arm studies; (c) studies to determine appropriate dosages; and (d) ongoing trials or abstracts with insufficient results. If multiple publications from the same trial were identified or if there was case overlap between publications, only the latest or most complete publication was included. Two reviewers (LYH and LF) independently evaluated the risk of bias of the eligible studies using the Cochrane Collaboration risk of bias tool (
Data were independently extracted by two of the authors (LYH and XL). The following data obtained from the eligible studies were recorded in accordance with a prespecified protocol: name of the trial, year of publication, study design, number of randomized patients, details of neoadjuvant therapy regimens administered, number of patients achieving pCR, follow-up information, and number of adverse events (AEs). Hazard ratio (HR) and 95% CI of event-free survival (EFS), OS, and distant recurrence-free survival were extracted when available. If not reported, the HRs and associated statistical data were indirectly calculated using the methods reported by Parmar (
The primary objective of this study was to compare the efficacy of ICI-containing neoadjuvant therapy
ORs and 95% CIs were calculated for pCR and AEs. An OR > 1 indicated higher pCR and AEs rates, whereas an OR < 1 indicated lower pCR and AEs rates in the ICI-containing group than in the ICI-free group. The HR with 95% CI was calculated to estimate the impact of ICI-containing neoadjuvant therapy on survival outcomes. A HR > 1 indicated worse survival outcomes, whereas a HR < 1 indicates better survival outcomes in the ICI-containing group compared with the ICI-free group. Heterogeneity was assessed using the Cochran Q and
A systematic search of the literature identified 2156 records. After removing duplicates, the titles and abstracts of the remaining 1410 records were screened, and 1397 non-relevant records were excluded. Thirteen potentially eligible articles were evaluated in greater detail, of which nine did not met the eligibility criteria for this study. Finally, four RCTs [GeparNuevo (
Flow chart of the literature search and study selection.
A total of 1795 patients with TNBC were included in the study, of whom 1066 (59.4%) received ICI-containing and 729 (40.6%) received ICI-free neoadjuvant therapy. The four RCTs were published between 2019 and 2020. All patients were enrolled between 2015 and 2018 from multicenter. There were two phase II studies (GeparNuevo and I-SPY2) and two phase III studies (IMpassion031 and KEYNOTE-522). The GeparNuevo, IMpassion031, and KEYNOTE-522 trials included only TNBC patients, whereas the I-SPY2 trial included both TNBC and hormone receptor-positive/HER2-negative BC patients. Taxane and/or anthracycline plus cyclophosphamide were included in the neoadjuvant regimens in the four RCTs, whereas the agents in the KEYNOTE-522 trial also contained carboplatin. Durvalumab and atezolizumab were added to the neoadjuvant chemotherapy in the GeparNuevo and IMpassion031 trials, respectively. Pembrolizumab was added to the neoadjuvant chemotherapy in the KEYNOTE-522 and I-SPY2 trials. A placebo was given to the control group in the GeparNuevo, IMpassion031, and KEYNOTE-522 trials. The main characteristics of the four RCTs are presented in
Main characteristics of the included randomized controlled trials.
Study | Year | Trial design | Treatment arms | Primary end points | Secondary end points | No. of TNBC patients |
---|---|---|---|---|---|---|
GeparNuevo15 | 2019 | Multicenter, phase II | Durvalumab+ CT |
pCR |
pCRf, g; PD-L1 |
88 |
Placebo+CT |
86 | |||||
I-SPY212 | 2020 | Multicenter, phase II | Pembrolizumab+CT |
pCR |
RCB; EFS; DRFS | 29 |
CT |
85 | |||||
IMpassion03116 | 2020 | Multicenter, phase III | Atezolizumab+CT |
pCR |
EFS; OS PD-L1 |
165 |
Placebo+CT |
168 | |||||
KEYNOTE-52211 | 2020 | Multicenter, phase III | Pembrolizumab+CT |
pCR |
pCR |
784 |
Placebo+CT |
390 |
CT, chemotherapy; pCR, pathologic complete response; EFS, event-free survival; PD-L1, programmed cell death-ligand 1; OS, overall survival; RCB, residual cancer burden; DRFS, distant recurrence-free survival; TNBC, triple-negative breast cancer.
Durvalumab (750mg) or placebo monotherapy 2 weeks before start of chemotherapy followed by durvalumab (1500mg) or placebo once every 4 weeks plus nab-paclitaxel 125 mg/m2 weekly for 12 weeks, followed by durvalumab (1500mg) or placebo once every 4 weeks plus epirubicin/cyclophosphamide once every 2 weeks for 4 cycles.
Pembrolizumab (200 mg) concurrently with paclitaxel in weeks 1, 4, 7, and 10 (4 cycles). Paclitaxel 80 mg/m2 weekly for 12 weeks, followed by doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 once every 2 to 3 weeks for 4 cycles. No placebo was given in the control group.
Atezolizumab (840 mg) or placebo once every 2 weeks combined with nab-paclitaxel 125 mg/m² once per week for 12 weeks, followed by atezolizumab (840 mg) or placebo combined with doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² once every 2 weeks for 4 cycles.
Pembrolizumab (200mg) or placebo once every 3 weeks plus paclitaxel 80 mg/m2 once weekly plus carboplatin area under curve 5 once every 3 weeks or 1.5 once weekly in the first 12 weeks, followed by pembrolizumab (200mg) or placebo once every 3 weeks plus doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 once every 3 weeks in the subsequent 12 weeks.
The pCR was defined as the absence of residual invasive and in situ in breast and regional nodes (ypT0 ypN0).
The pCR was defined as the absence of invasive tumor in breast and regional nodes (ypT0/Tis ypN0).
The pCR including ypT0 ypN0, the absence of invasive tumor in breast (ypT0/Tis), the absence of residual invasive and in situ in breast (ypT0), and the absence of residual invasive and in situ in regional nodes (ypN0).
The defined pCR for patients with PD-L1 status information.
The pCR rates were analyzed for 1223 TNBC patients. Overall, 422 (61.8%) of 683 patients in the ICI-containing group and 228 (42.2%) of 540 patients in the ICI-free group achieved a pCR after neoadjuvant treatment (OR = 2.14, 95% CI: 1.37–3.35,
Forest plots of meta-analyses of pathological complete response (pCR). Immune checkpoint inhibitor (ICI)-containing neoadjuvant therapy compared with ICI-free neoadjuvant therapy for triple-negative breast cancer (TNBC).
Forest plots of subgroup meta-analyses of pCR based on PD-L1 status.
The median follow-up periods were ranged from 15.5 to 42.0 months in the three RCTs (I-SPY, IMpassion031, and KEYNOTE-522) with EFS information. The pooled data showed that ICI-containing neoadjuvant therapy was significantly associated with a better EFS (HR = 0.66, 95% CI: 0.48–0.89,
Forest plots of meta-analyses for event-free survival (EFS).
There were 64 types of all-grade AEs reported by at least two of the four RCTs and were available for meta-analysis. The pooled effects for all-grade AEs showed that ICI-containing neoadjuvant therapy resulted in a higher incidence of increased aspartate aminotransferase (AST), dry skin, hepatitis, hyperthyroidism, hypothyroidism, infusion related reaction, pain, and pyrexia than ICI-free neoadjuvant therapy (
Meta-analysis for all grade and grade ≥3 adverse events.
Adverse events | All grade | Grade > 3 | ||||
---|---|---|---|---|---|---|
No. of studies | OR (95% CI) |
|
No. of studies | OR (95% CI) |
|
|
Abdominal pain | 3 | 1.50 (0.55–4.05) | 0.43 | NA | ||
Adrenal insufficiency | 3 | 6.77 (0.42–108.65) | 0.18 | 3 | 18.02 (2.36–137.48) |
|
ALT increased | 4 | 1.31 (0.89–1.91) | 0.17 | 3 | 1.51 (0.80–2.87) | 0.21 |
Alopecia | 4 | 1.04 (0.85–1.26) | 0.72 | NA | ||
Anaemia | 4 | 1.14 (0.80–1.61) | 0.47 | 3 | 1.25 (0.94–1.68) | 0.13 |
Anorexia | 2 | 1.13 (0.67–1.91) | 0.65 | NA | ||
Arthralgia | 3 | 1.03 (0.58–1.84) | 0.92 | NA | ||
AST increased | 4 | 1.29 (1.01–1.66) |
|
3 | 4.03 (1.40–11.63) |
|
Asthenia | 3 | 1.00 (0.78–1.27) | 0.97 | NA | ||
Back pain | 3 | 0.89 (0.59–1.34) | 0.59 | NA | ||
Bone pain | 2 | 0.84 (0.46–1.56) | 0.59 | NA | ||
Colitis | 3 | 2.01 (0.69–5.81) | 0.20 | 3 | 3.16 (0.72–13.97) | 0.13 |
Constipation | 4 | 1.06 (0.86–1.31) | 0.58 | NA | ||
Cough | 3 | 1.25 (0.62–2.50) | 0.53 | NA | ||
Decreased appetite | 3 | 1.17 (0.82–1.66) | 0.39 | NA | ||
Depression | 2 | 1.37 (0.81–2.32) | 0.24 | NA | ||
Dermatitis | 2 | 1.02 (0.48–2.19) | 0.96 | NA | ||
Diarrhoea | 4 | 0.97 (0.64–1.48) | 0.90 | 3 | 2.20 (0.92–5.28) | 0.08 |
Dry eye | 2 | 1.46 (0.77–2.78) | 0.24 | NA | ||
Dry skin | 3 | 1.59 (1.04–2.43) |
|
NA | ||
Dysgeusia | 3 | 1.14 (0.69–1.88) | 0.60 | NA | ||
Dyspepsia | 2 | 0.90 (0.54–1.51) | 0.69 | NA | ||
Dyspnea | 3 | 1.43 (0.97–2.11) | 0.07 | NA | ||
Epistaxis | 3 | 1.34 (0.92–1.94) | 0.13 | NA | ||
Fatigue | 4 | 1.13 (0.92–1.38) | 0.24 | 4 | 1.66 (0.56–4.96) | 0.36 |
Febrile neutropenia | 4 | 1.16 (0.90–1.50) | 0.26 | 4 | 1.17 (0.88–1.55) | 0.27 |
Headache | 3 | 1.28 (0.92–1.78) | 0.14 | NA | ||
Hepatitis | 4 | 3.20 (1.06–9.68) |
|
4 | 7.37 (1.28–42.27) |
|
Hot flush | 3 | 1.19 (0.81–1.74) | 0.37 | NA | ||
Hyperglycemia | 2 | 0.94 (0.34–2.61) | 0.90 | NA | ||
Hypertension | 2 | 0.60 (0.30–1.22) | 0.16 | NA | ||
Hyperthyroidism | 4 | 6.43 (2.75–15.03) |
|
NA | ||
Hypophysitis | 2 | 7.04 (0.84–58.70) | 0.07 | NA | ||
Hypotension | 2 | 4.36 (0.05–369.20) | 0.52 | NA | ||
Hypothyroidism | 4 | 4.91 (2.94–8.19) |
|
NA | ||
Infection | 2 | 0.73 (0.27–1.99) | 0.54 | NA | ||
Infusion related reaction | 4 | 1.71 (1.26–2.33) |
|
3 | 2.24 (0.82–6.15) | 0.12 |
Insomnia | 2 | 1.36 (0.92–2.01) | 0.13 | NA | ||
Lacrimation increased | 3 | 1.25 (0.70–2.22) | 0.45 | NA | ||
Leucopenia | 3 | 0.91 (0.41–2.00) | 0.81 | NA | ||
Malaise | 2 | 1.45 (0.32–6.44) | 0.63 | NA | ||
Myalgia | 3 | 1.14 (0.66–1.99) | 0.64 | NA | ||
Nail discoloration | 2 | 1.15 (0.56–2.34) | 0.70 | NA | ||
Nail disorder | 2 | 0.79 (0.42–1.51) | 0.48 | NA | ||
Nausea | 4 | 1.00 (0.82–1.22) | 1.00 | 4 | 1.00 (0.13–7.70) | 1.00 |
Neutropenia | 4 | 1.10 (0.73–1.65) | 0.66 | 4 | 1.04 (0.84–1.29) | 0.73 |
Neutrophil count decreased | 3 | 0.89 (0.66–1.21) | 0.46 | NA | ||
Edema | 2 | 1.04 (0.35–3.07) | 0.94 | NA | ||
Edema peripheral | 2 | 1.26 (0.71–2.24) | 0.43 | NA | ||
Oropharyngeal pain | 2 | 1.11 (0.64–1.92) | 0.71 | NA | ||
Pain | 2 | 1.74 (1.03–2.95) |
|
NA | ||
Pain in extremity | 2 | 1.00 (0.60–1.69) | 0.99 | NA | ||
Paresthesia | 2 | 0.56 (0.23–1.35) | 0.19 | NA | ||
Paronychia | 2 | 0.39 (0.17–0.90) | 0.03 | NA | ||
Peripheral Neuropathy | 3 | 1.16 (0.74–1.82) | 0.53 | NA | ||
Peripheral sensory neuropathy | 4 | 1.02 (0.82–1.28) | 0.83 | 4 | 1.05 (0.57–1.93) | 0.87 |
Pneumonitis | 4 | 1.42 (0.63–3.20) | 0.40 | 4 | 1.56 (0.31–7.77) | 0.59 |
Pruritus | 2 | 1.93 (0.65–5.69) | 0.23 | 2 | 0.37 (0.06–2.29) | 0.29 |
Pyrexia | 3 | 1.79 (1.34–2.40) |
|
NA | ||
Rash | 3 | 1.37 (0.95–1.96) | 0.09 | NA | ||
Stomatitis | 4 | 1.23 (0.97–1.56) | 0.09 | 4 | 5.78 (1.01–33.05) |
|
Upper respiratory tract infection | 2 | 1.08 (0.63–1.85) | 0.77 | NA | ||
Vertigo | 2 | 0.90 (0.20–4.14) | 0.90 | NA | ||
Vomiting | 4 | 1.21 (0.77–1.92) | 0.41 | 4 | 1.66 (0.74–3.70) | 0.22 |
ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; OR, odd ratio; CI, confidence interval; NA, data were not available due to limited number of studies or events.
All meta-analyses were conducted by random-effects model Bold values represent statistically significant (p < 0.05).
Several immunotherapeutic agents, including atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab, are currently being investigated for the treatment of early and metastatic BC (
In subgroup analysis, ICI-containing neoadjuvant therapy significantly increased the pCR rate in both PD-L1-positive and -negative subgroups. Inconsistently, the IMpassion130 study reported that atezolizumab showed PFS and OS benefit for patients with advanced TNBC only in the PD-L1-positive cohort (
In regards to survival outcomes, only EFS was reported by three of the four RCTs. The EFS involving disease progression, local or distant recurrence, development of a second primary tumor, or death were better in the ICI-containing group than the ICI-free group among patients with TNBC. In subgroup analysis, we found that the addition of pembrolizumab to neoadjuvant chemotherapy was significantly associated with better EFS than control group. However, in the KEYNOTE-522 trial (
Endocrine dysfunctions, such as adrenal insufficiency, hypothyroidism, hyperthyroidism, hypophysitis, and insulin-deficient diabetes, are the most common immune-related AEs reported in clinical trials involving ICIs (
There were several limitations in this study that should be addressed. First, only four RCTs were included in this meta-analysis and the number of included patients was relatively small. Therefore, future meta-analyses including RCTs with many more participants are warranted to strengthen the results of this study. Second, there were several potential heterogeneities between the four RCTs, including the study design, treatment regimens, and PD-L1 detection methods, and definition of PD-L1 positivity, which may have negatively affected the pooled results. Third, considering the good prognosis of BC (
The addition of ICIs to neoadjuvant chemotherapy significantly increased the pCR rate in TNBC patients, regardless of PD-L1 status. ICI-containing neoadjuvant therapy was significantly associated with better EFS than ICI-free neoadjuvant therapy in TNBC patients. Although ICIs increased the risks of several kinds of AEs, the toxicity effects were manageable. Future phase III RCTs with larger sample sizes and long-term follow-up periods are required to strengthen the present findings.
The original contributions presented in the study are included in the article/
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.
GR, HYL, and XY conceived and designed the study. YL, LX, and DY performed the literature search, data extraction, quality assessment of the included studies. YL, LX, and LX performed the statistical analysis. YL and LX wrote the paper. FL, HL, LG, and MW reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.
This work was supported by the National Natural Science Foundation of China (No. 82103089).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
The Supplementary Material for this article can be found online at:
Risk of bias assessment on the included four RCTs.
Forest plots of subgroup meta-analyses of pCR based on anti-PD-1 and anti-PD-L1 inhibitors.
Forest plots of subgroup meta-analyses for pCR based on treatment.