FDA Approves TECENTRIQ® and ABRAXANE® Combination for Advanced Triple Negative Breast Cancer

SUMMARY: The FDA on March 8, 2019 granted accelerated approval to TECENTRIQ® (Atezolizumab) in combination with ABRAXANE® (Paclitaxel protein-bound) for adult patients with unresectable locally advanced or metastatic Triple Negative Breast Cancer (TNBC) whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering 1% or more of the tumor area), as determined by an FDA-approved test. The FDA also approved the VENTANA PD-L1 (SP142) Assay as a companion diagnostic device for selecting TNBC patients for TECENTRIQ®. 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. Approximately 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease.

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. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Nonetheless, patients with TNBC often receive chemotherapy in the neoadjuvant, adjuvant or metastatic settings and approximately 30-40% of patients achieve a pathological Complete Response (pCR) in the neoadjuvant setting. Those who do not achieve a pathological Complete Response tend to have a poor prognosis. It therefore appears that there are subsets of patients with TNBC who may be inherently insensitive to cytotoxic chemotherapy. Three treatment approaches appear to be promising and they include immune therapies, PARP inhibition and inhibition of PI3K pathway. Previously published studies have shown that tumor-infiltrating lymphocytes were 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.

TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors, and thus enabling the activation of T cells. Single-agent TECENTRIQ® is presently approved for the treatment of metastatic Urothelial carcinoma and Non Small Cell Lung Cancer (NSCLC). TECENTRIQ® has also been shown to have clinical activity with acceptable safety profile in patients with other solid tumors including Triple Negative Breast Cancer. The premise for combining chemotherapy with immune checkpoint inhibitors is that chemotherapy may enhance release of tumor antigens and antitumor responses to immune checkpoint inhibition. Taxanes in particular may additionally activate toll-like receptor activity and promote dendritic-cell activity. ABRAXANE® (Nanoparticle Albumin-Bound – nab Paclitaxel) was selected as a chemotherapy partner in the present study because at the time that this trial was designed, the glucocorticoid premedication that is required with solvent-based Paclitaxel (TAXOL®), had been hypothesized to affect immunotherapy activity.

IMpassion130 is an international, randomized, double-blind, placebo-controlled phase III trial in which first-line treatment with TECENTRIQ® plus ABRAXANE®, was compared with placebo plus ABRAXANE®, in patients with locally advanced or metastatic Triple Negative Breast Cancer. Patients with untreated metastatic Triple Negative Breast Cancer (N=902) were randomly assigned in a 1:1 ratio and received TECENTRIQ® 840 mg IV or placebo on days 1 and 15 and ABRAXANE® 100 mg/m2 IV on days 1, 8, and 15 of every 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. Stratification factors included presence or absence of liver metastases, use or non-use of neoadjuvant or adjuvant taxane treatment, and PD-L1 expression on tumor-infiltrating immune cells as a percentage of tumor area (less than 1% was considered PD-L1 negative versus1% or more considered PD-L1 positive) according to ImmunoHistochemical testing (IHC). Both treatment groups were well balanced. Approximately 40% of the patients were PD-L1 positive. The two Primary end points were Progression Free Survival (PFS) and Overall Survival (OS).

At a median follow up of 12.9 months, the median PFS in the intent-to-treat population was 7.2 months with TECENTRIQ® plus ABRAXANE®, as compared with 5.5 months with placebo plus ABRAXANE® (HR=0.80; P=0.002). This suggested a 20% improvement in PFS with the TECENTRIQ® combination. At the time of the first interim analysis, the median overall survival was 21.3 months in the TECENTRIQ® plus ABRAXANE® group and 17.6 months in the placebo plus ABRAXANE® group (HR for death=0.84; P=0.08). The Objective Response Rate (ORR) in the intent-to-treat population was 56% in the TECENTRIQ® and ABRAXANE® group versus 45.9% in the placebo plus ABRAXANE® group.

Among patients with PD-L1–positive tumors, the benefit was even more significant. The addition of TECENTRIQ® improved PFS by 38% (HR=0.62; P<0.001) and similar benefit was noted in the OS, with a median OS of 25 months with the TECENTRIQ® combination and 15.5 months with placebo plus ABRAXANE® (HR=0.62). Grade 3 or 4 adverse events were 48.7% in the TECENTRIQ® and ABRAXANE® and 42.2% in the placebo plus ABRAXANE® group.

It was concluded that TECENTRIQ® plus ABRAXANE® significantly prolonged Progression Free Survival among patients with metastatic Triple Negative Breast Cancer in both the intent-to-treat population and the PD-L1 positive subgroup, and could potentially change how we manage patients with Triple Negative Breast Cancer. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. Schmid P, Adams S, Rugo HS, et al. N Engl J Med 2018; 379:2108-2121