In this study, we conducted a real-world study in TNBC patients treated with neoadjuvant chemotherapy to compare pCR rates relative to sTIL level across different neoadjuvant chemotherapy regimens: i) non-carboplatin-chemotherapy, ii) carboplatin- chemotherapy, and iii) pembrolizumab- chemotherapy.
While our real-world data represent the early experiences following the introduction of pembrolizumab, we observed a numerical increase in pCR rates across different regimens, consistent with the results of the KeyNote-522 study: non-carboplatin-chemotherapy, 32.4%; carboplatin- chemotherapy, 57.5%; pembrolizumab- chemotherapy, 67.8%. Furthermore, in TNBC cases with high sTILs, referred as to LPBC, the addition of pembrolizumab to chemotherapy resulted in a pCR rate exceeding 80%, whereas the incorporation of carboplatin into AC/T chemotherapy did not enhance the response. Conversely, in non-LPBC, the inclusion of carboplatin in AC/T significantly enhanced the pCR rate. However, the introduction of pembrolizumab did not demonstrate additional efficacy in this subgroup.
When the patients were classified into three groups by sTIL level (Figure 3), the pembrolizumab-chemotherapy group correlated with increased pCR rates in higher TILs subgroups, whereas carboplatin-chemotherapy group did not show this positive trend. In addition, the non-carboplatin-chemotherapy group exhibited a trend of rising pCR rates corresponding to increasing TILs; however, these rates remained noticeably lower than those observed in the pembrolizumab-chemotherapy group. The analysis demonstrates that pembrolizumab-chemotherapy is particularly effective, and its efficacy appears to be related to sTIL levels, suggesting a potential immunological synergy.
When the patients were classified into three groups based on sTILs, the pembrolizumab-chemotherapy group showed elevated pCR rates correlated with the sTIL groups, whereas the carboplatin-chemotherapy group did not exhibit this phenomenon (Figure 3). Additionally, the non-carboplatin-chemotherapy group tended to have increasing pCR rates in relation to increasing sTILs; however, the absolute pCR rate was just above 50% even in the high TIL group. These findings suggest that only pembrolizumab-chemotherapy may enhance responses relative to sTILs.
It is well established that TNBC tumors exhibit a tumor microenvironment (TME) enriched with immune cells, characterized by high levels of sTILs, PD-L1-positivity and up-regulated immune gene signatures [13, 14, 19, 20]. These immune biomarkers exhibit correlations [13, 20]. Presently, in advanced TNBC, pembrolizumab is exclusively indicated for patients with high PD-L1 expression, as identified by the 22C3 pharmDx assay with a cutoff of a combined positive score (CPS) of 10 [21, 22]. However, in early TNBC, pembrolizumab is administered to all patients regardless of PD-L1 status [1, 2]. Nevertheless, pembrolizumab-based immunochemotherapy achieved a pCR rate of 68.9% in the PD-L1-positive group compared to 45.3% in the PD-L1-negative group [1]. Considering positive correlation between PD-L1 status and TILs level [20, 23], these findings suggest that pembrolizumab-based immunochemotherapy may enhance response in TNBC with a more immunogenic TME.
Additionally, in the Neo-PACT trial, which evaluated pembrolizumab-containing immunochemotherapy without anthracyclines in early TNBC, high sTIL as biomarkers for the degree of immune enrichment was predictive of pCR [13]. These findings suggest that the efficacy of pembrolizumab in TNBC is positively correlated with sTIL levels and may reach its maximum in cases classified as LPBC [17, 18, 24], as observed in our study. Currently, ongoing trials are exploring immunochemotherapy with de-escalation of backbone chemotherapy, such as anthracyclines-free regimen or 4 cycles taxane-platinum [25, 26], based on sTIL levels.
Intriguingly, we noted that carboplatin increased pCR rate in non-LPBC (sTIL<50%). While high sTIL levels were associated with pCR in neoadjuvant chemotherapy trials with carboplatin in TNBC, it remains unknown whether carboplatin addition can elevate pCR in non-LPBC.
Among previous trials, the GeparSixto study demonstrated a pCR rate of 74% with carboplatin compared to 43% without carboplatin in LPBC (sTIL ≥60%), while in non-LPBC cases, the rates were 46% with carboplatin and 34% without carboplatin, respectively [4]. In contrast, the study by Dieci MV et al. showed that carboplatin significantly increased the pCR rate in non-LPBC (sTIL < 60%) [27]. The discrepancy between the two studies may be partly explained by differences in backbone chemotherapy regimens; the GeparSixto study utilized weekly paclitaxel and liposomal doxorubicin for 18 weeks, whereas the study by Dieci MV et al. employed AC followed by weekly paclitaxel for 24 weeks. Further investigations are necessary to fully understand the distinct response patterns to incorporation of carboplatin based on TIL levels in TNBC. Additionally, ongoing trials could assess the potential of novel agents, such as TROP2-targeting antibody-drug conjugates, to enhance response rates in non-LPBC cases [28].
Our study has several limitations. Firstly, our study represents early-phase real-world outcomes following the implementation of pembrolizumab-based immunochemotherapy for early-stage TNBC, which has led to a relatively small cohort in the pembrolizumab group, with an even smaller subset of high TILs cases. Additionally, important immune biomarkers, such as PD-L1 CPS score, were not fully evaluated in relation to TILs. Despite these limitations, our study leveraged sTILs and addressed differential responses across three different regimens: carboplatin-based and non-carboplatin-based, as well as pembrolizumab immunochemotherapy. Our findings may provide a foundation for tailoring immunochemotherapy based on stromal TILs in TNBC.