Oral Chemo-Novel Drug Combo Elicits Better Outcomes in Patients With Metastatic Breast Cancer

Treatment with a combination of oral paclitaxel plus encequidar resulted in higher confirmed tumor response rates among patients with metastatic breast cancer compared with paclitaxel delivered intravenously, according to findings from a recently published study.

The data — which were printed in the Journal of Clinical Oncology — also demonstrated that neuropathy, a side effect that is associated with weakness and pain in the hands and feet, was less frequent and severe in patients who received the combination of the oral paclitaxel plus encequidar.

Taxane-based treatment regimens, such as paclitaxel, have been some of the most effective systemic therapies for early- and late-stage breast cancer, according to the study authors.

However, they noted, these treatments must be administered using a tube or needle inserted into a vein (intravenously). The problem with this delivery method, the investigators wrote, is that the risk for developing neuropathy is high.

Neuropathy, the study authors explained, is a major dose-limiting side effect associated with this treatment method and may significantly affect a patient’s quality of life and limit their treatment options.

For these reasons, the study authors aimed to assess the potential effects of treating patients with a chemotherapy-based regimen delivered orally.

“Potential benefits make oral administration of paclitaxel appealing, including home administration, lack of need for (intravenous) access, and … lack of hypersensitivity reactions or need for corticosteroid and antihistamine prophylaxis,” they wrote.

Paclitaxel has poor bioavailability when delivered into a patient’s body orally, meaning that a very small percentage of the initial drug reaches its target. But when oral paclitaxel is combined with encequidar, the drug can be better absorbed by the body — which is why the researchers decided to test this two-drug combination.

The phase 3 study comprised 402 patients who were postmenopausal and at least 18 years old. The participants were randomly assigned to receive either oral paclitaxel plus encequidar or intravenous paclitaxel.

The main goal of the study was to determine confirmed tumor response rate (the percentage of patients whose disease shrinks or disappears after treatment) among each group. The investigators also aimed to assess the duration of response (the time from treatment randomization to disease progression or death in patients whose disease initially responded to treatment) among both treatment groups, as well as overall survival (the time from treatment until death from any cause) and progression-free survival (the time from treatment until disease progression).

The findings showed that there was a significant difference in terms of the confirmed tumor response between the group that received the oral paclitaxel (36%) regimen versus the intravenous paclitaxel (23%).

As of September 2020, seven patients remained on treatment with the combination versus one patient on the single-agent intravenous paclitaxel.

Treatment with the combination was also associated with a better median progression-free survival (8.4 months) than the paclitaxel which was delivered intravenously (7.4 months).

The median overall survival results were 22.7 months in the oral paclitaxel/encequidar group, compared with 16.5 months in the intravenous paclitaxel group. However, the difference here was not statistically significant, meaning that researchers could not be sure if it was the treatment regimen that resulted in the improved overall survival duration.

More patients in the group that received the combination had to discontinue treatment within the first 10 weeks of the start of the trial (26% versus 17%, respectively). The incidence of neuropathy, however, was drastically higher in the group who received paclitaxel intravenously. In fact, moderate or even worse neuropathy occurred in 31% of those who only received the paclitaxel and 8% in those who received the combination.

In 2021, the Food and Drug Administration rejected the approval request for oral paclitaxel plus encequidar citing concern over a potential increased risk for developing neutropenia as a result of the treatment or the disease. Of note, neutropenia occurs when a person has an abnormally low count of white blood cells. When this occurs, patients may be at greater risk for an infection.

The investigators noted that this study was done to support filing registration for agency approval for the combination of oral paclitaxel and encequidar. They cautioned, however, that future studies are to confirm these findings.

“Patients with elevated liver enzymes, serum bilirubin or low serum albumin at study entry were at increased risk of early high-grade neutropenia and infectious complications, which were in some cases fatal,” the wrote. “Careful patient selection, use of growth factors, and dose reductions along with close monitoring of patients at increased risk is warranted. Further studies to optimize dosing in patients with hepatic dysfunction are warranted.”

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