Nab-Paclitaxel/Carboplatin Doublet Superior in Phase II tnAcity Trial

Denise Yardley, MD

The combination of nab-paclitaxel (Abraxane) and carboplatin reduced the risk of progression or death by 40% compared with 2 other chemotherapy doublets as a frontline therapy for patients with metastatic triple-negative breast cancer (TNBC), according to findings from the phase II tnAcity study presented at the 2016 San Antonio Breast Cancer Symposium.¹

The median progression-free survival (PFS) was 7.4 months with nab-paclitaxel plus carboplatin compared with 5.4 months for nab-paclitaxel plus gemcitabine (HR, 0.60; 95% CI, 0.39-0.93; P = .02) and 6.0 months for gemcitabine plus carboplatin (HR, 0.61; 95% CI, 0.39-0.94; P = .03). The 12-month PFS rate was 27% with nab-paclitaxel/carboplatin compared with 13% and 11% for nab-paclitaxel/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, MD, senior investigator at the Sarah Cannon Research Institute. "The Abraxane/carboplatin arm in this phase II study came out demonstrating the ideal efficacy pattern for the triple-negative population."

The phase II study randomized 191 untreated patients with metastatic TNBC to receive the combination of carboplatin and gemcitabine (n = 66) or nab-paclitaxel with carboplatin (n = 64) or gemcitabine (n = 61). Nab-paclitaxel 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 1 and 8 every 3 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 (~48%) and Western Europe (38% to 46%). A quarter of patients had a disease-free interval ≤1 year. The most common site of metastases were the lymph nodes (62% to 78%). Two-thirds of patients had received prior neoadjuvant/adjuvant chemotherapy.

The objective response rate (ORR) with nab-paclitaxel/carboplatin was 72%, which consisted of 7 complete responses (CR; 11%) and 39 partial responses (PR; 61%). The ORR was 39% with nab-paclitaxel/gemcitabine and 44% with gemcitabine/carboplatin. The CR rate in each of these arms was 8%. Twenty-two percent of patients had stable disease for ≥16 weeks in the nab-paclitaxel/carboplatin arm compared with 44% and 32% in the nab-paclitaxel/gemcitabine and gemcitabine/carboplatin arms, respectively.

Median overall survival (OS) was 16.4 months with nab-paclitaxel/carboplatin compared with 12.1 months with nab-paclitaxel/gemcitabine (HR, 0.66; 0.42-1.04; P = .07) and 12.6 months for gemcitabine/carboplatin (HR, 0.74; 0.48-1.16; P = .18). These findings were not statistically significant.

At the time of the analysis, almost all patients had discontinued treatment due primarily to progressive disease (55%) or adverse events (AEs; 18%). 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 treatment-emergent AEs observed in the nab-paclitaxel/carboplatin, nab-paclitaxel/gemcitabine, and carboplatin/gemcitabine arms, respectively, were neutropenia (42%, 27%, 52%), anemia (13%, 12%, 27%), thrombocytopenia (9%, 7%, 28%), leukopenia (6%, 3%, 11%), febrile neutropenia (5%, 2%, 0%), fatigue (3%, 15%, 3%), and peripheral neuropathy (5%, 7%, 2%). Growth factors were needed for 45%, 26%, and 47% of patients in each arm, respectively.

The tnAcity study, which was initiated in 2013, was originally designed to advance the superior of the two nab-paclitaxel doublets into a 550-patient phase III 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 atezolizumab (Tecentriq) plus nab-paclitaxel showed a confirmed objective response rate (ORR) of 46% in patients with metastatic TNBC (n = 13; 95% CI, 19-75).² The complete response in the frontline setting was 8%. 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 III IMpassion130 trial is ongoing for patients with previously untreated metastatic TNBC. This trial is randomizing patients to nab-paclitaxel plus placebo or atezolizumab. 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 III NeoTRIPaPDL1 study is looking at the combination of nab-paclitaxel and carboplatin with or without atezolizumab for patients with locally advanced TNBC. Event-free survival will be the primary endpoint of this neoadjuvant trial (NCT02620280). Additionally, a phase II 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."

References

1. Yardley D, Coleman R, Conte P, et al. nab-paclitaxel + carboplatin or gemcitabine vs gemcitabine/carboplatin as first-line treatment for patients with triple-negative metastatic breast cancer: Results from the randomized phase 2 portion of the tnAcity trial. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract P5-15-03.
2. Adams S, Diamond JR, Hamilton EP, et al. Phase Ib trial of atezolizumab in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2016;34 (suppl; abstr 1009).

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"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."