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Wong et al. Cancer Drug Resist 2023;6:768-87 https://dx.doi.org/10.20517/cdr.2023.58 Page 770

there was a suggestion of improved ORR in less heavily pre-treated patients (ORR 21.4% vs. 5.3%) in Cohort
B vs. all-comers in Cohort A. This was consistent with other similar phase 1 trials evaluating avelumab
[17]
[18]
(JAVELIN study) and atezolizumab (PCD4989g trial) as monotherapy in metastatic TNBC, suggesting
clinical benefit when used in earlier lines of treatment and PD-L1 expressing tumours.

A subsequent KEYNOTE-119 randomised phase III trial compared pembrolizumab monotherapy vs. single
agent physicians’ choice chemotherapy in patients who progressed on 1 or 2 prior lines of treatment for
metastatic TNBC . While the trial was negative for its primary endpoint of OS in all subgroups, there was a
[19]
positive trend to survival benefit in patients with PD-L1 CPS ≥ 10 (12.7 vs. 11.6 months, HR 0.78; P = 0.057).

The limited efficacy of single-agent immunotherapy observed in breast cancer might be due to intrinsic
tumour resistance due to its complex and enigmatic relationship with the immune system. Breast cancer
was traditionally thought to be poorly immunogenic, also known as a “cold tumour”. Immunogenicity, or
the ability to elicit an antitumoural response by the body’s immune system, is dependent upon the
formation of neo-antigens that are derived from gene mutations, viral oncogenes alternative splicing, or
gene rearrangement [20-22] . It is assessed by the antigenicity of a cancer, which in turn is evaluated by its
[23]
mutagenicity . One measure of the antigenicity of cancer is its mutational load or tumour mutational
burden (TMB), which refers to the average number of somatic mutations per (Mb) [23,24] . Cancers like
melanoma and lung cancer are known to be “hot tumours”, as observed in a study by Chalmers et al. who
[25]
reported their median TMB levels to be 13.5 mut/Mb and 7.2 mut/Mb, respectively . In contrast, the TMB
[26]
in breast cancer is generally much lower. In a study by Barroso-Sousa et al. of 3,969 patients with breast
cancer, the median TMB reported was 2.63 mut/Mb, while another Chinese study of 196 breast cancer
patients demonstrated a higher median TMB of 4.03 mut/Mb . Due to the poor efficacy observed with the
[27]
use of single-agent immunotherapy treatment, further efforts were directed at exploring combination
treatment.

Combining ICIs with chemotherapy in TNBC
The rationale for combination treatment with chemotherapy was that chemotherapeutic agents had been
shown to have synergistic effects with ICIs by inducing immunogenic cell death, causing the release of
tumour-associated neoantigens as well as its ability to stimulate immune surveillance [28,29] . Indeed, this has
proven to be an effective strategy in several subgroups of TNBC.

The initial results of several phase I studies evaluating this combination in the setting of metastatic TNBC
were promising, reporting response rates ranging between 23.4%-39% [30,31] . Several phase III trials confirmed
these positive preliminary findings, leading to the first FDA-approved indication for an ICI for use in breast
cancer treatment.

Atezolizumab
The first FDA accelerated approval of an ICI for breast cancer was with the anti-PD-L1 inhibitor
[32]
atezolizumab, which was granted on 8 March 2019 based on the IMpassion 130 trial . This phase III
[33]
placebo-controlled randomised trial evaluated 902 patients with treatment naïve, unresectable locally
advanced or metastatic TNBC. Patients were randomised to receive either atezolizumab or its placebo, in
combination with albumin-bound paclitaxel (nab-paclitaxel). In patients whose tumours expressed PD-L1
based on the VENTANA PD-L1 SP142 assay, there was a significant median PFS benefit: 7.5 months in
patients receiving atezolizumab vs. 5.0 months with placebo (HR 0.62, P < 0.001). The final approval of this
combination was contingent upon the results of the IMpassion 131 trial evaluating atezolizumab with
paclitaxel in TNBC in the same setting, which unfortunately failed to meet its primary endpoint of superior