Audience during the San Antonio Breast Cancer Symposium (SABCS) being held at the Henry B. Gonzalez Convention Center in San Antonio, TX. Photo courtesy 2019 © Todd Buchanan.
Audience during the San Antonio Breast Cancer Symposium (SABCS) being held at the Henry B. Gonzalez Convention Center in San Antonio, TX. Photo courtesy 2019 © Todd Buchanan.

Taxanes have been a cornerstone of breast cancer treatment over more than three decades, improving the lives of patients with both early- and late-stage disease. [1]

However, while taxane-based regimens are considered to be among the most effective and commonly used systemic therapies for breast cancer, particularly in the adjuvant setting, clinicians are seeking new therapeutic strategies to optimize treatment outcomes, this includes treatment of patients in a metastatic setting.

The development of resistance to taxane has resulted in the investigation of numerous combination therapies. And while these taxane-containing combination therapies have been recognized to benefits patients in terms of response rates and PFS, guidlines developed by the National Comprehensive Cancer Network (NCCN), point to the lack of Overall Survival (OS) and the potential for increased toxicities.

In an attempt to improve benefits to patients, while, at the same time, reducing some of the noted adverse events, investigators are looking at a new therapeutic strategy.

Results from a Phase III study, funded by Athenex, in which metastatic breast cancer patients received an oral formulation paclitaxel demonstrated that these patients had better response and survival and less neuropathy than patients who received intravenous paclitaxel (Taxol® / Onxal™).[2]

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The data were presented at the San Antonio Breast Cancer Symposium (SABCS), held in San Antonio, Texas, December 10-14, 2019.

Paclitaxel is widely used chemotherapeutic agent used to treat patients with metastatic breast cancer. It is generally administered intravenously because the drug has poor oral bioavailability due to excretion by P-glycoprotein (P-gp) on intestinal cells.

However, in this trial, researchers evaluated an oral formulation of the drug, given in combination with encequidar (Athenex; formerly known as HM30181A), a potent and specific P-glycoprotein pump (P-gp) inhibitor with minimal systemic absorption that allows the oral paclitaxel to be absorbed into the bloodstream.

P-glycoprotein is an active drug transport protein that determine the uptake and efflux of a range of therapeutic agents, affecting their plasma and tissue concentrations and ultimately their final effects.

Gerardo Antonio Umanzor Funez, MD, speaks during the San Antonio Breast Cancer Symposium (SABCS) being held at the Henry B. Gonzalez Convention Center in San Antonio, TX. Photo Courtesy 2019 © Todd Buchanan 2019

A number of anti-cancer agents are substrates P-glycoprotein. As a result, when orally administered, these drugs will be pumped back from inside to outside the cell, thereby limiting the drugs to intravenous administration.

Encequidar, as a selective and potent P-glycoprotein inhibitor, has demonstrated potential to allow oral delivery of these chemotherapy agents.

Oral administration
Based on prior studies, the bioavailability of 205 mg/m2 oral paclitaxel + 15 mg encequidar 3 days per week was predicted to produce similar paclitaxel exposure as 80 mg/m2 IV paclitaxel. [3]

“Oral administration of cancer chemotherapy is very important for [many] cancer patients. [This may especially be the case] in areas where patients have difficulty accessing infusion clinics regularly,” noted Gerardo Antonio Umanzor Funez, MD, medical oncologist with Centro Oncologico Integral, who conducted the study with DEMEDICA of San Pedro Sula, Honduras. Umanzor is also the study’s lead investigator.[2]

Trial design
In this trial, researchers enrolled 402 metastatic breast cancer patients.

The patients were randomly assigned in a 2:1 ratio to receive either 205mg/m² of oral paclitaxel plus encequidar (Pac+E) for three days a week, or 175mg/ m² paclitaxel intravenously (IV Pac) every three weeks.

Study design: This phase III open-label, randomized study included 360 evaluable adult female patients with histologically- or cytologically-confirmed metastatic breast cancer for whom treatment with IV paclitaxel monotherapy has been recommended by their oncologist. OPE (n=240) and IV Paclitaxel (n=120) 80% power, 15% difference in confirmed RR (P=0.045)  The participating patient had measurable metastatic target lesion disease as per RECIST v1.1 criteria. Subjects were randomized in a 2:1 ratio to either Oraxol or IV paclitaxel (as Taxol or generic).

Their tumors were evaluated for response and confirmed at two consecutive evaluations by a blinded, independent radiology company.

Primary endpoint
The primary endpoint was radiologically confirmed tumor response rate at two consecutive timepoints; secondary endpoints were progression free survival (PFS) and overall survival (OS).

One cycle in the treatment schedule: Oral Paclitaxel and Encequidar (OPE) – Encequidar was administered as a 15 mg tablet. Oral paclitaxel was administered with each capsule contains 30 mg solubilized paclitaxel. Treatment was administered as oral paclitaxel (205 mg/m2) and encequidar (15 mg) for 3 consecutive days/week for 3 weeks (1 cycle). The second arm included intravenous Paclitaxel which was administered as 175 mg/m2 over  3-hour infusion every 3 weeks (1 cycle)

Results showed that 35.8% of the Pac+E group had a confirmed tumor response, compared with 23.4% in the IV Pac group.

In evaluating the pre-specified modified intention to treat population, which excludes patients who did not have target tumors that could be evaluated by the central radiologist per RECIST or who did not receive sufficient treatments, the response rate was 40.4% for the Pac+E group and 25.6% for the IV Pac group.

In measuring the durability of response, the researchers found that in 51% of the Pac+E group who had a confirmed response, the response lasted more than 150 days, compared with 38% of the IV Pac group who had a response. Furthermore, a higher percentage of Pac+E patients are continuing to receive treatment.

Ongoing analysis of PFS showed a median of 9.3 months for the Pac+E group, compared with 8.3 months for the IV Pac group. OS was 27.9 months for the Pac+E group, compared with 16.9 months for the IV Pac group.

The researchers said the Pac+E group reported higher rates of neutropenia, infection, and gastrointestinal side effects. They reported lower incidence and severity of neuropathy — 17%, compared with 57% in the IV Pac group. Grade 3 neuropathic symptoms were experienced by 1 percent of the patients in the Pac+E group, versus 8% in the IV Pac group.

The study results demonstrated that oral paclitaxel and encequidar was associated with improved overall survival in the modified intent-to-treat population. Oral paclitaxel and encequidar was also associated with a lower incidence of neuropathy and alopecia but a higher incidence of low-grade gastrointestinal adverse events compared to IV paclitaxel.

New therapeutic option
“This oral form of paclitaxel provides a new therapeutic option for patients, in particular, for those who cannot easily travel,” Umanzor said.

“While blood counts still need to be monitored, oral administration allows patients to remain home during therapy, and avoid spending significant time in the chemotherapy unit,” he added.

“We were pleasantly surprised that responses were durable, conferring an early survival advantage with minimal neuropathy,” he continued.

“Oral paclitaxel and encequidar is the first oral taxane to demonstrate in a Phase III study statistically significant improvement in response rate and median overall survival compared to IV paclitaxel, in the treatment of metastatic breast cancer while associated with a much lower incidence and severity of neuropathy.” Rudolf Kwan, MD, Chief Medical Officer of Athenex, the study’s sponsor.

“We believe these data suggest the potential for oral paclitaxel and encequidar to provide an important advance in the management of patients with metastatic breast cancer,” he concluded.

Next steps
The next step, according to Umanzor, will be testing the tolerability of oral paclitaxel in patients at high risk of developing peripheral neuropathy. He confirmed that the oral formulation may also be studied in other cancers, either as a monotherapy or in combination with other agents.

Umanzor further pointed out that while the study’s primary endpoint of confirmed tumor response was evaluated blindly, the study could not be blinded at the clinical site. This may have created bias in the reporting of adverse events, he explained. Also, the study was statistically powered only for confirmed response rate and not for the secondary endpoints.

Clinical trials
Ph3 Study To Determine Safety,Tolerability&Tumor Response Of Oraxol Compared To Taxol In Metastatic Breast Cancer – NCT02594371
A Study to Determine the Bioequivalence of Oraxol in Cancer Patients Treated With Intravenous Paclitaxel – NCT04035473

[1] Gradishar WJ. Taxanes for the treatment of metastatic breast cancer. Breast Cancer (Auckl). 2012;6:159–171. doi:10.4137/BCBCR.S8205
[2] Umanzor G, Cutler DL, Barrios FJ, Vassallo RH, Chivalan MA, Bejarano SA, Ramirez JR, Fein L, et al. Oral paclitaxel with encequidar: The first orally administered paclitaxel shown to be superior to IV paclitaxel on confirmed response and survival with less neuropathy: A phase III clinical study in metastatic breast cancer – GS6-01. Presentation during the 42nd San Antonio Breast Cancer Symposium (SABCS) held December 10 – 14, 2019 in San Antonio, Texas.[Abstract]
[3] Jackson CGCA, Deva S, Bayston K, McLaren B, Barlow P, Hung NA, Clarke K, Segelov E, Chao T, et al. An international randomized cross-over bio-equivalence study of oral paclitaxel + HM30181A (Oraxol) compared with weekly intravenous (IV) paclitaxel 80mg/m2in advanced solid tumours 477P. Annals of Oncology (2019) 30 (suppl_5): v159-v193. 10.1093/annonc/mdz244 [ESMO 2019][ESMO 2019 Poster 477P]

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