On January 8, 2024, the latest research findings from Professor Jiang Zefei's team at the Chinese People's Liberation Army General Hospital were published in the top-tier international journal, Nature Medicine (IF=83; Paper Title: "Toripalimab plus nab-paclitaxel in metastatic or recurrent triple-negative breast cancer: a randomized phase 3 trial"). The TORCHLIGHT study, led by Professor Jiang Zefei's team, is a randomized phase 3 trial evaluating the efficacy and safety of combining Toripalimab and nab-paclitaxel in the treatment of metastatic or recurrent triple-negative breast cancer (TNBC). Following the rapid abstract presentation at the 2023 ASCO Annual Meeting's Late-Breaking Abstract (LBA) session, the study has once again received international recognition in the academic community.The TORCHLIGHT study assessed the efficacy and safety of first-line treatment with Toripalimab plus nab-paclitaxel (n=353; experimental group) compared to placebo plus nab-paclitaxel (n=178; control group) in female patients with metastatic or recurrent TNBC. The primary endpoint was progression-free survival (PFS) in both PD-L1 positive and intention-to-treat (ITT) populations. Secondary endpoints included overall survival (OS) and safety.
Pre-specified interim analysis results showed:
Compared to the control group, the combination of Toripalimab and nab-paclitaxel significantly extended PFS in the PD-L1 positive population (median PFS assessed by blinded independent central review [BICR]: 8.4 vs. 5.6 months), reducing the risk of disease progression or death by 35% (HR=0.65, 95% CI: 0.470–0.906; P=0.0102). There was a similar trend of improvement in PFS in the intention-to-treat population.
Significant overall survival benefits were observed in patients treated with Toripalimab plus nab-paclitaxel in both PD-L1 positive and ITT populations. In the PD-L1 positive population, the median OS was 32.8 vs. 19.5 months (HR=0.62, 95% CI: 0.414–0.914; P=0.0148); in the ITT population, the median OS was 33.1 vs. 23.5 months (HR=0.69, 95% CI: 0.513–0.932; P=0.0145).
Safety-wise, the incidence rates of treatment-emergent adverse events (TEAE) (99.2% vs. 98.9%), ≥3 grade TEAE (56.4% vs. 54.3%), and fatal adverse events (0.6% vs. 3.4%) were similar between the two groups. The study results suggest that the combination of Toripalimab plus nab-paclitaxel significantly improves PFS in PD-L1 positive metastatic or recurrent TNBC patients and has an acceptable safety profile.
Triple-negative breast cancer (TNBC) is characterized by the absence of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) on tumor cells. Due to the lack of actionable targets, treatment options for TNBC are limited beyond conventional chemotherapy. Despite accounting for only 15-20% of all breast cancers, TNBC is associated with the poorest prognosis among breast cancer subtypes. Before the advent of immunotherapy, systemic chemotherapy including taxanes, anthracyclines, and/or platinum agents was the mainstay of first-line treatment for TNBC. However, the median overall survival (mOS) for metastatic TNBC is only 9-12 months, with a 5-year survival rate of approximately 12%, highlighting a critical unmet medical need.
The emergence of immune checkpoint PD-1 inhibitors has revolutionized the treatment landscape for various malignancies, including TNBC. Compared to other breast cancer subtypes, TNBC harbors a relatively higher tumor mutational burden (TMB), which is associated with improved response to immunotherapy. Chemotherapy, including platinum agents and taxanes, is known to induce immunogenic cell death and can synergize with checkpoint blockade to enhance immune activation. Several large randomized phase III trials have evaluated the addition of PD-1/PD-L1 inhibitors to chemotherapy for first-line treatment of TNBC, but results have been inconsistent.
In the TORCHLIGHT study, researchers compared the efficacy and safety of toripalimab plus nab-paclitaxel versus placebo plus nab-paclitaxel as first- or second-line treatment for metastatic or recurrent TNBC. In a pre-specified interim analysis of progression-free survival (PFS), toripalimab plus nab-paclitaxel demonstrated statistically and clinically significant improvement in PFS compared to placebo plus nab-paclitaxel in the PD-L1 positive population (JS311 CPS≥1). In this study, there was a 2.8-month improvement in mPFS, with a 35% reduction in the risk of disease progression or death. Descriptive overall survival (OS) analysis showed a trend of improvement in OS for both the PD-L1 positive population and the intention-to-treat (ITT) population. The results of the TORCHLIGHT study further validate the clinical value of adding PD-1 checkpoint blockade therapy to chemotherapy in the treatment of advanced TNBC.
The progression-free survival (PFS) in PD-L1+ TNBC population (Source: Nature Medicine)
The study recruited patients only from China, but it is speculated that the findings can be extrapolated to Western patients as well, given that previous subgroup analyses in studies such as IMpassion130 and KEYNOTE-355 did not show any racial differences in outcomes. Similarly, no such differences have been observed in other multicenter phase III trials of immunotherapy across different indications. In summary, adding toripalimab to nab-paclitaxel significantly improves PFS in patients with metastatic or recurrent TNBC who are PD-L1 positive (CPS≥1), while maintaining an acceptable safety profile. The final analysis of PFS in the ITT population and the final analysis of overall survival (OS) in the PD-L1 positive subgroup and ITT population will be subjected to statistical validation in the future.
