FDA Issues Response Letter for Oral Paclitaxel and Encequidar in Metastatic Breast Cancer


The developers of an oral formulation of paclitaxel will have to revisit efficacy and safety data in order to provide sufficient evidence for FDA approval.

A complete response letter (CRL) was issued by the FDA to Athenex, Inc. for the company’s new drug application (NDA) for a novel formulation of paclitaxel that allows for oral administration in the treatment of metastatic breast cancer.1

The Prescription Drug User Fee Act (PDUFA) target action date for this application was originally set for February 28, 2021.

The agency indicated that there are concerns regarding safety of the drug due to high rates of neutropenia-related sequalae with the oral formulation versus its intravenous counterpart. Issuance of a CLR is indicative of the end of the application’s review cycle as the FDA does not believe it can be approved in its present form.

“Our clinical and regulatory teams are disappointed by the complete response letter,” Rudolf Kwan, MBBS, chief medical officer of Athenex, said in a press release. “We plan to work with the agency to resolve the issues raised in the CRL and to obtain approval for oral paclitaxel plus encequidar in metastatic breast cancer.”

According to the FDA, there were also concerns about the results of the primary end point of objective response rate (ORR) at 19 weeks by blinded independent central review (BICR) in the supporting clinical trial. BICR reconciliation and re-read process may have allowed for unmeasured bias to influence these results.

To compensate for the current weaknesses in the application, the FDA recommended that Athenex conduct a new clinical trial in patients with metastatic breast cancer, adding that risk-mitigation strategies–such as dose optimization or exclusion of patients considered to be at high risk of toxicities–be implemented to improve the safety profile.

The NDA was initially supported by data from the randomized, multinational phase 3 KX-ORAX-001study (NCT02594371), which evaluated oral paclitaxel plus encequidar versus intravenous (IV) paclitaxel in women with metastatic breast cancer.2 Results from this study were presented in December 2019 at the San Antonio Breast Cancer Symposium (SABCS). Updated progression-free survival (PFS) and overall survival (OS) analyses comprising an additional 14 additional months of follow-up data were presented in December 2020 at SABCS.3,4

In the study, participants were randomized 2:1 to receive either oral paclitaxel at a dose of 205 mg/m2 and encequidar at a dose of 15 mg for 3 consecutive days per week for 3 weeks or IV paclitaxel at a dose of 175 mg/m2 over 3-hour infusion periods every 3 weeks. Treatment continued until disease progression or toxicity.

A total of 402 patients were enrolled in the intent-to-treat (ITT) population, including 265 in the combination arm and 137 in the IV paclitaxel arm, of whom 399 received treatment. Investigators also evaluated a modified ITT patient population (mITT; N = 360), in which participants received at least 7 days of oral paclitaxel plus encequidar (n = 235) or 1 dose of IV paclitaxel (n = 125).

The dual primary end points of the study were confirmed tumor response per blinded independent central review (BICR) among the mITT population on 2 consecutive evaluations as well as safety and tolerability. Key secondary end points included duration of response, PFS, and OS.

In the mITT population, the combination of oral paclitaxel and encequidar met the study’s primary end point of a superior radiologic response rate at the dose and schedule approved for patients with metastatic breast cancer. The centrally confirmed overall response rate increased from 25.6% with IV paclitaxel to 40.4% with oral paclitaxel and encequidar (P = .005).

Among those treated with oral paclitaxel and encequidar in the ITT population at the updated analysis, the median PFS was 8.4 months compared with 7.4 months for those treated with IV paclitaxel (HR, 0.768; 95% CI, 0.584-1.010; P = .046). Moreover, patients in the oral paclitaxel and encequidar arm had a median OS of 22.7 months versus 16.5 months in the IV paclitaxel arm (HR, 0.794; 95% CI, 0.607-1.037; P = .082). Survival results were similar in the mITT population.

Regarding safety, combination treatment with oral paclitaxel and encequidar was found to be associated with a lower incidence of neuropathy and alopecia, but a higher incidence of low-grade gastrointestinal adverse events compared with IV paclitaxel.

Ultimately, the investigators indicated the study findings suggest oral paclitaxel plus encequidar provides an important oral therapeutic option for patients with metastatic breast cancer.

“We remain committed to the breast cancer community and will explore the best path forward to obtain regulatory approval,” Johnson Lau, MD, MBBS, Chief Executive Officer of Athenex, said in a press release. “In the interim, we will identify and undertake the appropriate internal organizational adjustments accordingly.”


1. Athenex receives FDA complete response letter for oral paclitaxel plus encequidar for the treatment of metastatic breast cancer. News release. Athenex. Published March 1, 2021. Accessed March 1, 2021. https://ir.athenex.com/news-releases/news-release-details/athenex-receives-fda-complete-response-letter-oral-paclitaxel

2. Athenex Announces FDA Acceptance for Filing of U.S. NDA for Oral Paclitaxel and Encequidar in Metastatic Breast Cancer with Priority Review. News release. Athenex. Published September 1, 2020. Accessed March 1, 2021. https://www.globenewswire.com/news-release/2020/09/01/2086762/0/en/Athenex-Announces-FDA-Acceptance-for-Filing-of-U-S-NDA-for-Oral-Paclitaxel-and-Encequidar-in-Metastatic-Breast-Cancer-with-Priority-Review.html

3. Umanzor G, Rugo HS, Barrios FJ, et al. Oral paclitaxel with encequidar (OPE): The first orally administered paclitaxel shown to be superior to IV paclitaxel on confirmed response and survival with less neuropathy: a phase 3 clinical study in metastatic breast cancer. Presented at the San Antonio Breast Cancer Symposium, held December 10-14, 2019. Abstract GS6-01.

4. Umanzor G, Rugo HS, Barrios FJ, et al. Oral Paclitaxel and Encequidar (oPac+E) versus IV paclitaxel (IVPac) in the treatment of metastatic breast cancer (mBC) patients (Study KX-ORAX-001): progression-free survival (PFS) and overall survival (OS) updates. Presented at the San Antonio Breast Cancer Symposium, held December 8-11, 2020. Abstract PD1-08.

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