SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.
Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers.
Previously published studies have shown that presence of tumor-infiltrating lymphocytes was associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC. Toripalimab, a checkpoint inhibitor, is a humanized IgG4K monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response, and unleashes the tumor-specific effector T cells. Toripalimab provided significant clinical activity with a favorable safety profile in several solid tumors.
The purpose of this study is to compare the efficacy and safety of Toripalimab versus placebo, in combination with nab-Paclitaxel for metastatic or recurrent TNBC. The rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as Toripalimab when given along with chemotherapy can enhance endogenous anticancer immunity.
TORCHLIGHT is a randomized, double-blind, placebo-controlled, multi-center, Phase III trial, in which the safety and efficacy of Toripalimab plus nab-Paclitaxel was compared with placebo plus nab-Paclitaxel in patients with Stage IV or recurrent/metastatic TNBC. In this study, 531 (N=531) eligible patients were randomly assigned 2:1 to receive Toripalimab 240mg IV on Day 1 every 3 weeks (N=353) or placebo (N=178), along with nab-Paclitaxel given at 125 mg/m2 on days 1 and 8 of each cycle. Treatment was continued until disease progression or intolerable toxicity. Patients could not have received more than one line of chemotherapy in the metastatic setting and had to be eligible for taxane monotherapy. Baseline characteristics were well balanced between the treatment groups and patients were stratified based on PD-L1 expression, Paclitaxel therapy history and line of prior therapy at enrollment. In the Toripalimab group, 200 patients had PD-L1 positive disease, whereas 100 patients in the placebo group had PD-L1-positive disease. The Primary endpoint was Progression Free Survival (PFS) assessed by a Blinded Independent Central Review (BICR), first in the PD-L1-positive population and then in the Intent-To-Treat (ITT) population. Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), Duration of Response (DoR), Disease Control Rate and Safety.
At interim analysis, with the median follow up of 14 months, a statistically significant improvement in PFS was demonstrated with Toripalimab in the PD-L1 positive subgroup. The median PFS was 8.4 months versus 5.6 months respectively (HR=0.65; P=0.01). The PFS in the overall population showed a similar trend and was 8.4 months in the Toripalimab group and 6.9 months in the placebo group (HR=0.77; P=0.04). A descriptive Overall Survival analysis showed a trend towards improved OS with Toripalimab in the PD-L1 positive group (median OS 32.8 versus 19.5 months; HR=0.61; P=0.01). In the overall population, the median OS was 33.1 versus 23.5 months (HR=0.69, P=0.01). No new safety signals were identified.
The authors concluded that, for PD-L1 positive metastatic or recurrent Triple Negative Breast Cancer patients receiving first-line treatment, the addition of Toripalimab to nab-Paclitaxel resulted in a significant improvement in Progression Free Survival with an acceptable safety profile. Patients are being followed for the final PFS and OS analysis.
TORCHLIGHT: A randomized, double-blind, phase III trial of toripalimab versus placebo, in combination with nab-paclitaxel(nab-P) for patients with metastatic or recurrent triple-negative breast cancer (TNBC). Jiang Z, Ouyang Q, Sun T, et al. J Clin Oncol 41, 2023 (suppl 17; abstr LBA1013)
