Combination Reduces Risk of Death in Triple-Negative Breast Cancer

The combination of Abraxane (nab-paclitaxel) and carboplatin reduced the risk of progression or death by 40 percent compared with two other chemotherapy combinations as a frontline therapy for patients with metastatic triple-negative breast cancer (TNBC), according to recent findings from the phase 2 tnAcity study presented at the 2016 San Antonio Breast Cancer Symposium.

The median progression-free survival (PFS) was 7.4 months with Abraxane plus carboplatin compared with 5.4 months for Abraxane plus gemcitabine and six months for gemcitabine plus carboplatin. The 12-month PFS rate was 27 percent with Abraxane/carboplatin compared with 13 percent and 11 percent for Abraxane/gemcitabine and gemcitabine/carboplatin, respectively.

"I think it's an exciting study because there's such a role for doublet therapy, particularly in the triple-negative population. There's a lot of controversy between sequential single-agent or doublet therapy," said lead investigator Denise A. Yardley, M.D., senior investigator at the Sarah Cannon Research Institute. "The Abraxane/carboplatin arm in this phase 2 study came out demonstrating the ideal efficacy pattern for the triple-negative population."

The phase 2 study randomized 191 untreated patients with metastatic TNBC to receive the combination of carboplatin and gemcitabine (66 patients) or Abraxane with carboplatin (64 patients) or gemcitabine (61 patients). Abraxane was administered at 125 mg/m², carboplatin at AUC2, and gemcitabine was given at 1000 mg/m². In each arm, treatment was administered on day one and eight every three weeks.

Patient characteristics were well balanced between the arms. Patients had an ECOG performance status of 0 or 1 and the majority were enrolled in North America (about 48 percent) and Western Europe (38 percent to 46 percent). A quarter of patients had a disease-free interval less than one year. The most common site of metastases were the lymph nodes (62 percent to 78 percent). Two-thirds of patients had received prior neoadjuvant/adjuvant chemotherapy.

The objective response rate (ORR) with Abraxane/carboplatin was 72 percent, which consisted of seven complete responses (CR; 11 percent) and 39 partial responses (PR; 61 percent). The ORR was 39 percent with Abraxane/gemcitabine and 44 percent with gemcitabine/carboplatin. The CR rate in each of these arms was 8 percent. Twenty-two percent of patients had stable disease for at least 16 weeks in the Abraxane/carboplatin arm compared with 44 percent and 32 percent in the Abraxane/gemcitabine and gemcitabine/carboplatin arms, respectively.

Median overall survival (OS) was 16.4 months with Abraxane/carboplatin compared with 12.1 months with Abraxane/gemcitabine and 12.6 months for gemcitabine/carboplatin. These findings were not statistically significant.

At the time of the analysis, almost all patients had discontinued treatment due primarily to progressive disease (55 percent) or adverse events (AEs; 18 percent). The most common AEs leading to discontinuation were thrombocytopenia, anemia, neutropenia and drug hypersensitivity. Neutropenia was the most common cause of dose reductions.

The most common grade 3 or higher treatment-emergent AEs observed in the /carboplatin, Abraxane /gemcitabine, and carboplatin/gemcitabine arms, respectively, were neutropenia (42 percent, 27 percent, 52 percent), anemia (13 percent, 12 percent, 27 percent), thrombocytopenia (9 percent, 7 percent, 28 percent), leukopenia (6 percent, 3 percent, 11 percent), febrile neutropenia (5 percent, 2 percent, 0 percent), fatigue (3 percent, 15 percent, 3 percent) and peripheral neuropathy (5 percent, 7 percent, 2 percent). Growth factors were needed for 45 percent, 26 percent and 47 percent of patients in each arm, respectively.

"Abraxane has been a very welcomed drug from a toxicity profile," said Yardley. "In the metastatic setting, where patients are going to get multiple lines of therapy, looking at the toxicity profile that Abraxane offers has been quite welcomed, it improves neuropathy issues and myelosuppression, leaving itself very open to be partnered with other agents."

The tnAcity study, which was initiated in 2013, was originally designed to advance the superior of the two Abraxane doublets into a 550-patient phase 3 study comparing the doublet with gemcitabine/carboplatin. However, the introduction of effective immunotherapies since the study was designed caused the investigators to reconsider a chemotherapeutic approach in favor of combination strategies with PD-1/PD-L1 inhibitors.

Upfront treatment with the PD-L1 inhibitor Tecentriq (atezolizumab) plus Abraxane showed a confirmed objective response rate (ORR) of 46 percent in patients with metastatic TNBC (13 patients). The complete response in the frontline setting was 8 percent. The PFS, overall survival, and duration of response data were not yet mature.

"Abraxane is very attractive in the triple-negative population because it partners very well with immunotherapy," said Yardley. "Because it does not require steroid premed, which may mitigate some of the benefits of immune therapy, it is really going in that direction, too."

The phase 3 IMpassion130 trial is ongoing for patients with previously untreated metastatic TNBC. This trial is randomizing patients to Abraxane plus placebo or Tecentriq. The primary endpoint of the study is PFS in the full population and in a PD-L1-positive group. Secondary endpoints include OS, ORR and duration of response. The target enrollment goal for the trial is 350 patients (NCT02425891).

The phase 3 NeoTRIPaPDL1 study is looking at the combination of Abraxane and carboplatin with or without Tecentriq for patients with locally advanced TNBC. Event-free survival will be the primary endpoint of this neoadjuvant trial (NCT02620280). Additionally, a phase 2 study is also assessing the agent with the PD-L1 inhibitor durvalumab in the GeparNuevo study for TNBC (NCT02685059).

"If a patient is not going on a clinical trial, a doublet chemotherapy with an Abraxane backbone seems to be a very reasonable option for patients," said Yardley. "Chemotherapy is here to stay, it still has a role in the triple-negative population."