Professor Wang Ying: Count the progress of TNBC 2022 treatment, see where the future development direction is?

As a hot spot in TNBC research, immunotherapies such as pembrolizumab and atezolizumab have made some progress
.
KEYNOTE-522 STUDY⁶^,⁷ is a study of pembrolizumab neoadjuvant-adjuvant therapy for early TNBC, and pembrolizumab is approved domestically for patients with early-risk TNBC due to its positive outcome of achieving a pathologic complete response (pCR) and event-free survival (EFS) dual endpoint
.
The results of the KEYNOTE-522 exploratory analysis⁸ presented at this year's ASCO Annual Meeting showed that increased residual tumor burden (RCB) scores were associated with worsening of EFS, and that the percentage of patients per RCB category in the pembrolizumab group was lower than in the placebo group in patients with residual disease at the time of surgery, indicating that the addition of pembrolizumab not only increased the pCR (RCB-0) rate, but also reduced the RCB category across the residual disease range to lower levels
。 The analysis suggests that even in non-pCR populations, the addition of immunotherapy can bring significant benefits to patients, reduce the risk of relapse, and prolong survival
.

Figure 1 EFS analysis results for different RCB categories

This year's SABCS Annual Meeting also reported a real-world study of adverse effects as standard therapy for patients with early-stage TNBC according to the KEYNOTE-522 protocol⁹, which found a higher incidence of ≥grade 3 adverse events (AEs) and lower pCR rates than in the KEYNOTE-522 trial
.
This may be due to the smaller sample size and greater heterogeneity of patients in the treatment group, and data from this study need to be validated through long-term follow-up and multicenter validation
.

In addition, several studies evaluating the efficacy of atezolizumab in early TNBC are also being conducted
.
The IMpassion031 study¹⁰ has demonstrated that atezolizul in combination with neoadjuvant therapy can increase the pCR rate of patients with early-stage TNBC by 16.
5%, regardless of PD-L1 status, and can benefit from neoadjuvant immunotherapy combined with chemotherapy
.
In addition, IMpassion030-assisted research is
ongoing.
This year's SABCS Annual Meeting released the interim results of the Phase II randomized multicenter NeoMono study¹¹
.
The study planned to enroll up to 458 patients with primary TNBC and was designed to compare the efficacy
of atezolizumab monotherapy prior to neoadjuvant atezolizumab plus chemotherapy (group A) versus atezolizumab alone plus chemotherapy (group B).
At the time of the interim analysis, 436 patients had been enrolled, and the intention-to-treat (ITT) population consisted of 105 patients, of whom 101 were (50 in group A; Group B 51 patients) could assess pCR, and 4 patients withdrew from the analysis
due to missing pCR data.
Balance of baseline characteristics between the two treatment groups
.

Figure 2 NeoMono study design

The results showed that in the ITT analysis, the pCR rates of group A and group B were 63.
5% (95% CI: 50.
5%-76.
3%) and 71.
7% (95% CI: 59.
6%-83.
4%)
, respectively.
Since the results of ITT analysis did not meet expectations (group A pCR rate was low), post-hoc sensitivity analysis
was performed in people who fit into the protocol set (PP).
In the PP analysis, the pCR rates were higher in both group A and group B, 73.
7% (95% CI: 59.
7%-86.
9%) and 74.
4% (95% CI: 61.
5%-86.
7%)
, respectively.
In group A, the pCR rates based on PD-L1 immune cell (IC) status stratification were 100% (n=12) in the PD-L1 IC-positive group versus 52.
6% (n=20)
in the PD-L1 IC-negative group.
The pCR rates of PD-L1 IC positive and negative groups in group B were 78.
6% (n=11) and 70.
3% (n=26),
respectively.

Figure 3 ITT analysis and PP analysis results

Fig.
4 Proportion of pCR patients in different treatment groups and PD-L1 status subgroups

Based on the results of the first interim analysis, the statistical probability of neoMono reaching the primary study endpoint after full study recruitment was less than 2.
5%.

Therefore, trial recruitment
was terminated as required by the protocol.
Despite the limited study size, the results of the interim analysis of the neoMono trial reported the highest rate of pCR in the
ll/lll phase trial of immune checkpoint inhibitors for TNBC.
The study also found that atezolizumab monotherapy had a very significant benefit in PD-L1-positive TNBC patients, with pCR rates as high as 100%
in PD-L1-positive patients in group A.
Therefore, as the benefit-risk assessment remains positive, patients who have already been recruited will continue to receive neoadjuvant therapy
according to the protocol.
In the future, translational analysis of baseline/longitudinal tissue/liquid biopsy samples will be performed to screen out patients
who can precisely benefit.

In recent years, the development of ADC drugs is also in full swing, and many advances
have been made in TNBC patients.
NeoSTAR is the first ADC to be studied as a neoadjuvant therapy for TNBC, and the results presented at this year's ASCO Annual Meeting¹² confirm that the new ADC drug gorsatuzumab (SG) targeting Trop-2 has good clinical activity for TNBC neoadjuvant therapy (pCR rate of 30%, imaging response rate of 42%), and will continue to explore the combination target and ideal drug cycle of gosartuzumab for neoadjuvant therapy in the future
。

With the in-depth study of new targets and the active exploration of combination drugs, advanced TNBC has accumulated more research data, and has brought more thinking and choices
to the clinic.
What are the domestic and foreign research results in the treatment of advanced TNBC that impressed you? What are your thoughts on the different combination treatment options?