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Wong et al. Cancer Drug Resist 2023;6:768-87 https://dx.doi.org/10.20517/cdr.2023.58 Page 772

Pembrolizumab or its placebo was continued post-operatively for up to 9 cycles. Both primary endpoints of
the trial were met; there was a significant improvement in pCR of 64.8% vs. 51.2%; P = 0.00055, although
[40]
this had reduced by the third interim analysis to 63.0% vs. 55.6%. There was also an improvement in
[41]
3-year event-free survival (EFS) 84.5% vs. 76.8%; P < 0.001 . Interestingly, contrary to data in the metastatic
setting, PD-L1 expression was not predictive of benefit , and consequently the FDA approval in the
[11]
neoadjuvant setting was granted irrespective of PD-L1 expression.

The benefit of ICIs in combination with chemotherapy in the neoadjuvant setting was also echoed in the
IMpassion 031 study evaluating atezolizumab. In IMpassion 031, atezolizumab was evaluated in the
neoadjuvant setting in patients with stage II-III TNBC treated for curative intent. This was a double-blind
phase III randomised trial where patients received either atezolizumab or its placebo, in combination with
nab-paclitaxel, followed by doxorubicin and cyclophosphamide. The investigators found an increase in pCR
rates from 58% vs. 41% in the all-comers population; P = 0.0044, (significance boundary 0.0184), and 69% vs.
49% in PD-L1 positive patients; P = 0.021, (significance boundary 0.0184). As it did not hit the prespecified
boundary of significance for its second co-primary endpoint, the study is not formally powered for further
survival analyses .
[42]

However, not all trials evaluating the addition of ICIs in combination with chemotherapy in the
neoadjuvant setting for TNBC have yielded similar results. Both the NeoTRIP and GeparNeuvo evaluating
atezolizumab and durvalumab, respectively, in the neoadjuvant setting were negative for pCR benefit.
Patients in the NeoTRIP study were randomised to receive neoadjuvant carboplatin and nab-paclitaxel with
or without 8 cycles of atezolizumab. Anthracyclines were given in the adjuvant setting after definitive
surgery. The addition of atezolizumab resulted in numerically higher but nonsignificant pCR rates: 48.6% vs.
44.4%; P = 0.48 . Similarly, the GeparNuevo trial studied the addition of durvalumab to neoadjuvant
[43]
chemotherapy with paclitaxel followed by epirubicin and cyclophosphamide, which found a nonsignificant
but numerically superior pCR rates of 53.4% vs. 44.2%; P = 0.224 . Interestingly, a survival benefit with the
[44]
addition of durvalumab compared to placebo was observed; 3-year invasive disease-free survival (iDFS) was
[45]
84.9% vs. 76.9% (HR 0.54; P = 0.0559) and 3-year OS 95.1% vs. 83.1% (HR 0.26; P = 0.0076) .
While there is general consensus for the use of ICIs in combination with chemotherapy in the neoadjuvant
setting for TNBC, its optimal duration is currently still widely discussed. In both KEYNOTE-522 and
IMpassion 031, the ICI was continued post-operatively for a total of 1 year, while NeoTRIP and
GeparNuevo only administered ICI in the neoadjuvant setting. GeparNuevo is the only study that has
shown survival benefits with the use of ICI despite being administered only in the neoadjuvant context
without continuation in the adjuvant setting, leading to questions of whether there is a need for continual
ICI in the adjuvant setting. Additionally, the pCR benefit that was observed in the durvalumab group in
GeparNuevo was exclusively seen in the cohort of patients who received a 2-week lead-in of durvalumab
prior to chemotherapy, although the reason for this observation is currently unclear. We have summarised
the trials evaluating the use of ICI both as monotherapy and in combination with chemotherapy in Table 1.

In the adjuvant setting, there are ongoing trials such as the A-BRAVE trial investigating the use of
[46]
[47]
avelumab in the treatment of high-risk TNBC, as well as the ALEXANDRA/IMpassion030 trial evaluating
standard chemotherapy with or without atezolizumab in patients with early-stage TNBC. Additionally, the
use of ICIs in early relapsing TNBC is also being investigated in the IMpassion 132 trial, a phase III
randomised trial evaluating the role of combining atezolizumab with chemotherapy in patients with locally
[48]
recurrent inoperable or metastatic TNBC within 12 months from receiving curative-intent treatment .