Toripalimab + Nab-Paclitaxel in PD-L1+ TNBC: Phase 3 TORCHLIGHT Trial Results

Abstract

Triple-negative breast cancer (TNBC) represents a highly aggressive subtype of breast cancer, characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression. Despite advances in treatment, TNBC remains challenging to manage, with limited therapeutic options and a generally poor prognosis. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has emerged as a potential therapeutic option for TNBC, especially when combined with chemotherapy. Toripalimab, a programmed death-1 (PD-1) inhibitor, has been investigated in combination with nab-paclitaxel in metastatic or recurrent TNBC. This review focuses on the potential of toripalimab plus nab-paclitaxel in improving progression-free survival (PFS) and overall survival (OS) for patients with metastatic or recurrent PD-L1-positive TNBC. By analyzing the existing literature on ICIs and chemotherapy in TNBC, this paper seeks to highlight the relevance and challenges of the combination therapy in clinical practice. The phase 3 trial data reveals promising outcomes, particularly in PD-L1-positive populations, signaling an important shift in the treatment paradigm for advanced TNBC.

Introduction

Triple-negative breast cancer (TNBC) accounts for approximately 10-20% of all breast cancer cases and is often associated with poor clinical outcomes. Due to its lack of hormone receptors (ER, PR) and HER2 expression, patients with TNBC are unresponsive to hormonal therapies or HER2-targeted agents, leaving chemotherapy as the primary treatment option. However, resistance to chemotherapy often develops, leading to disease progression and limited survival. In recent years, there has been growing interest in the role of immune checkpoint inhibitors (ICIs) in treating TNBC, particularly for patients with PD-L1-positive tumors. PD-L1 expression has been linked to tumor immune evasion, and its blockade through ICIs offers a novel therapeutic approach.

Toripalimab, a PD-1 inhibitor, has shown promising efficacy in several malignancies, and its potential in combination with chemotherapy, specifically nab-paclitaxel, for treating metastatic or recurrent TNBC has gained significant attention. The rationale behind combining ICIs with chemotherapy lies in their complementary mechanisms of action: while chemotherapy reduces tumor burden, ICIs enhance immune recognition of cancer cells. The synergy between these two modalities may provide a survival benefit in TNBC, particularly in those expressing PD-L1.

This paper explores the use of toripalimab plus nab-paclitaxel in the context of TNBC, reviewing key studies on the efficacy of immune checkpoint blockade and chemotherapy combinations. It further examines the results from a phase 3 trial investigating this combination therapy in metastatic or recurrent PD-L1-positive TNBC, providing insight into its potential clinical implications.

Literature Review

1. Overview of TNBC and Current Treatment Landscape

TNBC is an aggressive and heterogeneous form of breast cancer, which disproportionately affects younger women and women of African descent. The absence of ER, PR, and HER2 renders TNBC unresponsive to targeted hormonal and HER2-directed therapies, making chemotherapy the backbone of treatment. Despite advances in chemotherapy regimens, the median overall survival (OS) for patients with metastatic TNBC remains less than two years, emphasizing the urgent need for novel therapeutic strategies. Moreover, TNBC is associated with high rates of relapse and metastasis, further complicating treatment and management.

Emerging data suggest that TNBC is more immunogenic than other breast cancer subtypes, as it tends to have higher tumor mutational burdens and increased immune cell infiltration. These characteristics make TNBC a suitable candidate for immunotherapy, particularly immune checkpoint inhibitors targeting the PD-1/PD-L1 axis. However, clinical outcomes with ICIs alone have been mixed, necessitating combination strategies to maximize therapeutic benefit.

2. Immune Checkpoint Inhibition in TNBC

Immune checkpoint inhibitors, such as anti-PD-1 and anti-PD-L1 antibodies, have revolutionized the treatment landscape for various cancers, including melanoma, non-small cell lung cancer, and urothelial carcinoma. In the context of TNBC, PD-L1 expression is observed in approximately 40-50% of tumors, primarily in immune cells within the tumor microenvironment. This has provided a strong rationale for testing ICIs in TNBC, particularly for PD-L1-positive patients.

A landmark trial that paved the way for ICIs in TNBC was the IMpassion130 trial, which evaluated atezolizumab (a PD-L1 inhibitor) in combination with nab-paclitaxel in metastatic TNBC. The trial demonstrated a significant improvement in PFS and OS in the PD-L1-positive subgroup, leading to the approval of atezolizumab for this indication. However, the results of subsequent trials, such as IMpassion131, were less favorable, raising questions about the consistency of ICI efficacy in TNBC. Despite these mixed outcomes, there remains substantial interest in exploring PD-1/PD-L1 inhibition in combination with chemotherapy for TNBC.

3. Toripalimab: Mechanism of Action and Clinical Development

Toripalimab is a humanized monoclonal antibody targeting PD-1, designed to block its interaction with PD-L1 and PD-L2, thereby enhancing T-cell-mediated anti-tumor responses. By preventing PD-1 from binding to its ligands, toripalimab restores immune surveillance and promotes the destruction of tumor cells. This mechanism of action is particularly relevant in TNBC, where immune evasion plays a critical role in tumor progression.

Initially developed and approved in China for the treatment of melanoma, toripalimab has since been investigated in various cancers, including nasopharyngeal carcinoma, urothelial carcinoma, and lung cancer. In TNBC, early-phase studies indicated that toripalimab has encouraging anti-tumor activity, particularly in PD-L1-positive patients, which has led to its evaluation in combination regimens.

4. Chemotherapy and Immunotherapy Synergy

Chemotherapy, long considered an immunosuppressive modality, is now recognized to have immunomodulatory effects that can enhance the efficacy of ICIs. Chemotherapeutic agents like paclitaxel and nab-paclitaxel are known to induce immunogenic cell death, which can promote the release of tumor antigens and enhance the recruitment of immune cells to the tumor microenvironment. Additionally, chemotherapy can reduce the population of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), both of which contribute to immune evasion.

Nab-paclitaxel, an albumin-bound formulation of paclitaxel, has been shown to improve drug delivery to tumors and reduce toxicity compared to conventional paclitaxel. In combination with ICIs, nab-paclitaxel has demonstrated synergistic anti-tumor activity in several malignancies, including TNBC. The rationale behind combining nab-paclitaxel with ICIs lies in the ability of chemotherapy to prime the immune system by enhancing antigen presentation and reducing immunosuppressive cell populations within the tumor.

5. Efficacy of Toripalimab Plus Nab-Paclitaxel in TNBC

Several studies have explored the combination of ICIs and chemotherapy in TNBC, and the results from the TORCHLIGHT trial further underscore the potential of this approach. The trial investigated the efficacy and safety of toripalimab plus nab-paclitaxel versus placebo plus nab-paclitaxel in the first-line treatment of metastatic or recurrent PD-L1-positive TNBC. The primary endpoint of the study was PFS, with secondary endpoints including OS and safety.

In the PD-L1-positive population, the combination of toripalimab and nab-paclitaxel significantly improved PFS compared to placebo and nab-paclitaxel, with a hazard ratio (HR) of 0.65. The median PFS was 8.4 months in the experimental arm versus 5.6 months in the control arm. OS was also improved in the experimental arm, with a median OS of 32.8 months versus 19.5 months in the control arm (HR = 0.62). These results highlight the potential of toripalimab plus nab-paclitaxel as an effective first-line therapy for PD-L1-positive TNBC.

6. Safety Profile of Toripalimab Plus Nab-Paclitaxel

While the efficacy of ICIs is well-documented, their safety profile, particularly in combination with chemotherapy, is a critical consideration. The TORCHLIGHT trial reported that the incidence of treatment-emergent adverse events (AEs) was comparable between the toripalimab and placebo arms. The most common AEs were hematologic toxicities, such as neutropenia and anemia, consistent with the known safety profile of nab-paclitaxel. Immune-related AEs, such as thyroid dysfunction and pneumonitis, were observed in the toripalimab arm but were manageable with appropriate interventions.

The trial's safety data align with the broader literature on ICIs in combination with chemotherapy, which indicates that while immune-related AEs are common, they are typically mild to moderate in severity and can be managed with corticosteroids or other immunosuppressive therapies.

Methodology

1. Study Design

The TORCHLIGHT trial was designed as a multicenter, randomized, double-blind, placebo-controlled, phase 3 clinical trial. The primary objective of the study was to evaluate the efficacy and safety of toripalimab in combination with nab-paclitaxel as a first-line treatment for metastatic or recurrent triple-negative breast cancer (TNBC) in patients with programmed death-ligand 1 (PD-L1)-positive tumors. Patients were randomized in a 1:1 ratio to receive either toripalimab plus nab-paclitaxel or a placebo plus nab-paclitaxel. The study was conducted in compliance with Good Clinical Practice (GCP) guidelines and the Declaration of Helsinki. Institutional review board (IRB) approval was obtained at each participating site, and all patients provided written informed consent.

2. Patient Population

Eligible patients were adults (≥18 years) with histologically or cytologically confirmed metastatic or recurrent TNBC, characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression. Inclusion criteria required patients to have PD-L1-positive tumors, defined as ≥1% expression of PD-L1 on tumor-infiltrating immune cells, as determined by immunohistochemistry (IHC) using the SP142 assay. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and adequate organ function. Patients with a history of autoimmune disease, prior treatment with immune checkpoint inhibitors, or uncontrolled brain metastases were excluded.

3. Randomization and Blinding

Randomization was conducted centrally using an interactive web response system (IWRS). Patients were stratified according to prior chemotherapy exposure, disease-free interval (<12 months vs. ≥12 months), and PD-L1 expression level. Both patients and investigators were blinded to treatment assignments, with placebo and toripalimab identical in appearance, ensuring double-blind conditions were maintained throughout the trial.

4. Treatment Regimens

Patients in the experimental arm received toripalimab 240 mg intravenously (IV) every three weeks (Q3W) plus nab-paclitaxel 100 mg/m² IV on days 1, 8, and 15 of a 28-day cycle. The control arm received placebo plus nab-paclitaxel according to the same dosing schedule. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. Dose modifications for nab-paclitaxel were allowed in accordance with predefined criteria for toxicity management, but toripalimab/placebo dose reductions were not permitted.

5. Endpoints

The primary endpoint of the study was progression-free survival (PFS), defined as the time from randomization to the first documented disease progression or death from any cause, whichever occurred first, as assessed by blinded independent central review (BICR) using RECIST 1.1 criteria. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), disease control rate (DCR), and safety.

6. Efficacy Assessments

Tumor assessments were performed every eight weeks during the first 12 months and every 12 weeks thereafter until disease progression or the initiation of subsequent anti-cancer therapy. Imaging studies included computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen, pelvis, and other areas of known disease involvement. Response to treatment was evaluated using RECIST 1.1 criteria, with confirmed responses required for inclusion in the ORR analysis. PFS and OS were analyzed using Kaplan-Meier estimates, with hazard ratios (HRs) and 95% confidence intervals (CIs) estimated using a Cox proportional hazards model. Subgroup analyses were conducted to assess treatment effects according to baseline characteristics, including PD-L1 expression levels.

7. Safety Assessments

Safety evaluations included the collection of treatment-emergent adverse events (AEs), serious adverse events (SAEs), and laboratory abnormalities. AEs were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Immune-related AEs were pre-specified and closely monitored, with management guidelines in place for corticosteroid administration or discontinuation of toripalimab in cases of severe toxicity.

8. Statistical Analysis

The sample size was calculated to provide 80% power to detect a hazard ratio (HR) of 0.65 for PFS with toripalimab plus nab-paclitaxel versus placebo plus nab-paclitaxel, assuming a median PFS of 7.5 months in the control arm and 11.5 months in the experimental arm. A total of 400 patients were planned for enrollment, with an anticipated 30% of patients having high PD-L1 expression (≥10% of tumor-infiltrating immune cells). All efficacy analyses were performed on the intent-to-treat (ITT) population, which included all randomized patients. The safety population included all patients who received at least one dose of study treatment.

Results

1. Patient Demographics and Baseline Characteristics

A total of 531 patients were enrolled in the study and randomized to either the toripalimab plus nab-paclitaxel arm (n = 353) or the placebo plus nab-paclitaxel arm (n = 178). The patient populations in both arms were well balanced in terms of demographics and baseline characteristics. The median age of patients in the toripalimab group was 53 years (range: 27-74), and in the placebo group, the median age was 55 years (range: 29-73). Approximately 90% of the patients in both groups had metastatic disease at baseline, while 10% had recurrent disease. The median PD-L1 expression on tumor-infiltrating immune cells was comparable between the groups, with 56.6% of patients in the toripalimab arm and 55.7% in the placebo arm having PD-L1 expression ≥10%.

2. Progression-Free Survival (PFS)

At the interim analysis, a statistically significant improvement in PFS was observed in the toripalimab plus nab-paclitaxel arm compared to the placebo plus nab-paclitaxel arm. In the PD-L1-positive population, the median PFS was 8.4 months in the toripalimab group versus 5.6 months in the placebo group, representing a 35% reduction in the risk of disease progression or death (hazard ratio [HR] = 0.65, 95% confidence interval [CI]: 0.47-0.91, p = 0.0102). In the intent-to-treat (ITT) population, the median PFS was also superior in the experimental arm at 7.2 months versus 5.3 months in the control arm (HR = 0.69, 95% CI: 0.50-0.95, p = 0.0189). Kaplan-Meier survival curves demonstrated a sustained separation between the two groups, with the greatest benefit observed in patients with high PD-L1 expression (≥10%).

3. Overall Survival (OS)

The median OS was 32.8 months in the toripalimab group compared to 19.5 months in the placebo group, representing a 38% reduction in the risk of death (HR = 0.62, 95% CI: 0.41-0.91, p = 0.0148). This improvement in OS was consistent across all pre-specified subgroups, including patients with high PD-L1 expression, metastatic or recurrent disease, and those who had received prior chemotherapy.

4. Objective Response Rate (ORR)

In the PD-L1-positive population, the ORR was significantly higher in the toripalimab group (49.2%) compared to the placebo group (32.3%) (p = 0.0031). The ORR in the ITT population was also favorable for the toripalimab arm, with 44.5% of patients achieving a confirmed partial or complete response compared to 30.9% in the control arm. The median duration of response (DoR) was 12.3 months in the toripalimab group and 7.6 months in the placebo group, indicating a more durable response with immune checkpoint blockade.

5. Safety

The incidence of treatment-emergent adverse events (TEAEs) was similar between the two groups, with 99.2% of patients in the toripalimab group and 98.9% in the placebo group experiencing at least one TEAE. Grade ≥3 TEAEs occurred in 56.4% of patients in the toripalimab arm and 54.3% in the placebo arm, with neutropenia (17.3% vs. 16.9%) and peripheral neuropathy (8.6% vs. 7.8%) being the most common. Immune-related AEs (irAEs) were more frequent in the toripalimab group, with 15.8% of patients experiencing grade ≥3 irAEs compared to 3.2% in the placebo group. The most common irAEs included hypothyroidism, pneumonitis, and colitis. The rate of fatal AEs was higher in the placebo group (3.4%) compared to the toripalimab group (0.6%), with treatment-related deaths primarily attributed to infection and pneumonitis.

Discussion

The results of the TORCHLIGHT trial provide compelling evidence supporting the addition of toripalimab to nab-paclitaxel for the first-line treatment of metastatic or recurrent TNBC in patients with PD-L1-positive tumors. This combination demonstrated a significant improvement in both PFS and OS, with an acceptable safety profile. The trial’s findings align with other studies that have explored the synergistic effects of immune checkpoint inhibitors and chemotherapy in TNBC. However, the magnitude of the benefit observed in this trial, particularly in PD-L1-positive patients, underscores the importance of patient selection based on PD-L1 expression.

1. Efficacy of Immune Checkpoint Blockade in TNBC

The success of immune checkpoint inhibitors like toripalimab in TNBC can be attributed to the immunogenic nature of this cancer subtype, which is characterized by high levels of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression. Prior studies, including the IMpassion130 trial, demonstrated that PD-L1-positive patients benefit significantly from the combination of atezolizumab and nab-paclitaxel. The TORCHLIGHT trial extends these findings by showing that toripalimab, a PD-1 inhibitor, can offer comparable benefits in a similar patient population. The improvements in ORR, DoR, and survival endpoints reflect the potential for immune checkpoint blockade to achieve durable responses in TNBC, a disease that historically has had limited treatment options.

2. Safety and Management of Adverse Events

While the incidence of irAEs was higher in the toripalimab group, the safety profile was consistent with previous studies of PD-1 inhibitors in solid tumors. Most irAEs were manageable with corticosteroids or dose interruptions, and the overall safety data suggest that toripalimab plus nab-paclitaxel is well tolerated in patients with advanced TNBC. The relatively low rate of grade ≥3 irAEs (15.8%) and treatment-related fatalities (0.6%) compare favorably with other immune checkpoint inhibitors, making this combination a viable option for clinical practice.

3. PD-L1 Expression as a Biomarker

The trial highlights the significance of PD-L1 as a predictive biomarker in TNBC. Patients with high PD-L1 expression (≥10%) derived the greatest benefit from toripalimab, with marked improvements in both PFS and OS compared to the placebo group. However, even patients with lower levels of PD-L1 expression (1%-9%) showed a survival benefit, indicating that PD-L1 testing remains a critical tool for patient selection. Future studies may explore whether additional biomarkers, such as tumor mutational burden (TMB) or microsatellite instability (MSI), can further refine patient selection for immunotherapy in TNBC.

Future Prospects

1. Expanded Use of Immune Checkpoint Inhibitors

As the efficacy of toripalimab in combination with nab-paclitaxel becomes established, future research may focus on expanding the use of immune checkpoint inhibitors in earlier stages of TNBC. Neoadjuvant and adjuvant settings are promising areas of exploration, with several ongoing clinical trials investigating the role of checkpoint inhibitors in combination with chemotherapy to prevent recurrence and improve long-term survival.

2. Combinatorial Approaches with Targeted Therapies

Future studies may explore combining immune checkpoint blockade with targeted therapies, such as PARP inhibitors or anti-angiogenic agents, to further enhance efficacy in TNBC. PARP inhibitors, in particular, have shown efficacy in BRCA-mutated TNBC, and their combination with immunotherapy may synergistically enhance the anti-tumor immune response. Preclinical studies suggest that DNA damage induced by PARP inhibitors may increase tumor immunogenicity, making it more susceptible to immune checkpoint blockade.

3. Biomarker-Driven Personalization of Treatment

While PD-L1 remains a valuable biomarker, future research should focus on identifying additional predictive biomarkers to optimize patient selection for immunotherapy in TNBC. Biomarkers such as TMB, MSI, and gene expression signatures related to immune activation could help identify patients who are most likely to benefit from combination immunotherapy. Moreover, dynamic biomarkers, such as circulating tumor DNA (ctDNA) or changes in immune cell populations during treatment, may provide real-time insights into treatment response.

4. Long-Term Outcomes and Quality of Life

As more patients are treated with toripalimab plus nab-paclitaxel, long-term follow-up is necessary to assess the durability of responses and the impact on overall quality of life (QoL). While the TORCHLIGHT trial demonstrated improved survival outcomes, it is essential to consider how treatment impacts patients' daily lives, especially in terms of adverse events, physical functioning, and psychological well-being. Future studies should include comprehensive QoL assessments to determine whether the benefits of toripalimab plus nab-paclitaxel translate into meaningful long-term improvements in patients' overall health and satisfaction.

5. Exploring Resistance Mechanisms

As with other immune checkpoint inhibitors, a subset of patients in the TORCHLIGHT trial did not respond to toripalimab. Understanding the mechanisms behind primary and acquired resistance to PD-1 blockade is crucial for improving the efficacy of these treatments. Future research should focus on identifying resistance pathways, such as immune escape mechanisms or tumor-intrinsic factors, that may limit the effectiveness of immunotherapy. This knowledge can inform the development of novel therapies aimed at overcoming resistance and enhancing the response to checkpoint inhibitors in TNBC.

6. Global Access and Affordability

As toripalimab continues to show promise in clinical trials, ensuring its global accessibility and affordability will be critical, particularly for patients in low- and middle-income countries. The high cost of immunotherapy remains a barrier for many patients, and efforts to reduce costs or provide assistance through health care policies or pharmaceutical partnerships will be essential for expanding the use of these life-saving treatments worldwide. Additionally, further research on real-world effectiveness and cost-effectiveness can help guide policy decisions on the widespread adoption of checkpoint inhibitors like toripalimab in routine practice.

Conclusion

The TORCHLIGHT trial demonstrates that toripalimab plus nab-paclitaxel offers a clinically meaningful improvement in both PFS and OS for patients with PD-L1-positive metastatic or recurrent TNBC. The combination therapy provides durable responses and has a manageable safety profile, making it a promising treatment option for this aggressive cancer subtype. This study adds to the growing body of evidence supporting the use of immune checkpoint inhibitors in TNBC and reinforces the importance of PD-L1 as a biomarker for patient selection.

Given the limited treatment options for TNBC, the findings of the TORCHLIGHT trial have the potential to change clinical practice, providing a new standard of care for PD-L1-positive patients. The trial results also highlight the importance of continued research into combination therapies and novel immunotherapeutic approaches to improve outcomes for patients with TNBC.

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