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Page 771 Wong et al. Cancer Drug Resist 2023;6:768-87 https://dx.doi.org/10.20517/cdr.2023.58

[34]
PFS . This led to Genentech voluntarily withdrawing the previously granted accelerated FDA approval for
atezolizumab on 27 August 2021. Eventually, when the final OS was read out for the IMpassion 130 trial, the
[35]
addition of atezolizumab to nab-paclitaxel failed to meet statistical significance, precluding further testing .

Pembrolizumab
Pembrolizumab is currently FDA-approved for use in TNBC in the first-line metastatic and neoadjuvant
settings, both in combination with chemotherapy. It first received FDA approval on 13 November 2020 as
combination therapy with chemotherapy for patients with unresectable locally-advanced or metastatic
[10]
TNBC whose tumours have a PD-L1 CPS ≥ 10 based on the Dako 22C3 assay . This was based on
KEYNOTE-355, a phase III randomised placebo-controlled study evaluating the role of pembrolizumab in
combination with chemotherapy in patients in the above-mentioned setting. It reported a median OS
(mOS) benefit of about 7 months in patients whose tumours expressed PD-L1 CPS ≥ 10 (mOS 23.0 vs. 16.1
months; HR 0.73, P = 0.0185). In patients whose tumours expressed PD-L1 CPS ≥ 1 or in the intention-to-
treat population, there was no survival benefit shown.

In addition, pembrolizumab also has tumour-agnostic FDA approval for advanced unresectable or
[12]
metastatic solid tumours that are dMMR or MSI-H . This was based on the combined results of 5 single-
arm trials where a total of 149 patients with dMMR/MSH-H solid tumours achieved an ORR of 39.6%, with
78% of patients having responses lasting 6 months or more. It should be noted, however, that only 2 out of
the 149 patients had breast cancer. They both achieved partial responses, with duration of response (DoR)
[36]
of 7.6 and 15.9 months .

Dostarlimab
Most recently, on 17 August 2021, dostarlimab also received accelerated FDA approval for recurrent or
[13]
advanced solid tumours that are dMMR based on the GARNET trial . This was an open-label, non-
randomised, multicohort phase I trial evaluating dostarlimab as monotherapy in the above-mentioned
clinical setting. In these patients, there was an ORR of 41.6%, with 9.1% complete responses and 32.5%
partial responses. The median DoR was 34.7 months, with 95.4% of patients still showing continued
response at 6 months. In cohort F, which enrolled 106 non-endometrial solid tumours, 1 patient had
dMMR breast cancer and reported a complete response .
[37]

With the promising results of a combination of ICI therapy and chemotherapy in the metastatic setting,
efforts were then shifted to study it in the earlier curative stages of breast cancer. One of these trials is the
phase II I-SPY 2 trial, which adopted an adaptive trial design to evaluate various novel therapeutics in
combination with chemotherapy, comparing that to standard treatment as in the neoadjuvant setting for
early-stage breast cancer . Pembrolizumab was included in one of the study arms, where patients were
[38]
randomised to receive 4 cycles of pembrolizumab given in combination with weekly paclitaxel vs. weekly
paclitaxel alone, followed by doxorubicin/cyclophosphamide and then definitive surgery. Compared to
standard chemotherapy alone, the addition of pembrolizumab improved pathologic complete response
(pCR) rates in all breast cancer subtypes: 44% vs. 17% in HER2-negative breast cancers, 30% vs. 13% in HR-
positive/HER2-negative breast cancers, and 60% vs. 22% in TNBC .
[39]

Focusing on the TNBC subtype, the role of pembrolizumab in the neoadjuvant setting was proven in the
confirmatory phase III KEYNOTE-522 trial, which subsequently led to pembrolizumab receiving its second
breast cancer-specific FDA approval on 26 July 2021 . In this phase III randomised controlled study, 1,174
[11]
patients with previously untreated stage II or III TNBC were randomised in a 2:1 ratio to receive
pembrolizumab or a placebo, respectively, in combination with chemotherapy , before undergoing surgery.