FDA Issues CRL for Oral Paclitaxel and Encequidar for Metastatic Breast Cancer

The FDA has issued a complete response letter (CRL) to Athenex, Inc, regarding the New Drug Application (NDA) for oral paclitaxel in combination with encequidar for the treatment of metastatic breast cancer. The FDA stated that the application review process has been completed, but the NDA is not ready for approval due to safety and efficacy concerns, Athenex, Inc., announced in a press release.¹

“Our clinical and regulatory teams are disappointed by the complete response letter,” said Rudolf Kwan, MD, chief medical officer, Athenex, in a statement. “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.”

In the CRL, the FDA listed the issue of febrile neutropenia in the safety data and the primary end point of objective response rate at 19 weeks per blinded independent central review (BICR). The FDA noted that the re-read of data may have brought on unmeasured bias and influence on the BICR. The agency suggests that the company conduct a new clinical trial that is acceptable. The FDA suggests that the new trial includes risk mitigation strategies that will improve the toxicity profile of the combination.

Findings from the pivotal phase 3 KX-ORAX-001 clinical trial (NCT02594371) supported the NDA; the open-label, randomized, multicenter study explored the use of oral paclitaxel with encequidar in comparison with intravenous (IV) paclitaxel (Taxol) in women with metastatic breast cancer. 

Updated results from the study were recently presented at the 2020 San Antonio Breast Cancer Symposium showing improvement in overall survival for the oral regimen over the IV formulation.² 

The study enrolled 402 women with metastatic breast cancer who were randomized 2:1 to receive either oral paclitaxel at 205 mg/m2 plus 15 mg of encequidar 3 times per week in 3-week cycles or IV paclitaxel at 175 mg/m2 every 3 weeks until disease progression or unacceptable toxicity. A total of 399 patients were treated, but 360 patients were included in the modified intention-to-treat (mITT) population; these patients had measurable disease by RECIST criteria and had received at least 7 days of treatment with the investigational regimen or 1 dose of the IV agent.

The primary end point of the study was tumor response by blinded independent central review on 2 consecutive evaluations, and key secondary end points for efficacy included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). 

Baseline characteristics were similar between the 2 study arms. Patients in the IV arm had a median age of 56 years versus 60 years in the oral arm. Patients were mostly Hispanic/Latino (90% in IV arm vs 89% in oral arm); had an ECOG performance status of 0 (58% vs 60%, respectively); had visceral metastases (77% vs 77%); and HER2-negative, hormone receptor–positive disease (53% vs 59%). In terms of prior treatment, 58% in each arm had received prior anthracyclines, 31% in the IV arm and 29% in the oral arm had received prior taxane therapy, and 68% of the patients who received the IV treatment and 70% who received the oral regimen had not received any chemotherapy in the metastatic setting. 

The median PFS in the mITT analysis was 8.4 months with oral paclitaxel and encequidar versus 7.4 months with IV paclitaxel (HR, 0.739; 95% CI, 0.561-0.974; P = .023) and the median OS was 23.3 months versus 16.3 months with the oral regimen and the IV formulation, respectively (HR, 0.735; 95% CI, 0.556-0.972; P = .026).

According to prior results of the trial, the confirmed response rate in the mITT group was 40.4% in the oral paclitaxel and encequidar arm compared with 25.6% in the IV paclitaxel arm (P = .005).3 Complete responses were observed in 1.3% of those who received the oral regimen and in 0.8% of those who received IV paclitaxel. Stable disease was reached for 23.8% of patients in the oral paclitaxel and encequidar arm and 39.2% of the IV paclitaxel arm. 

In terms of safety, treatment-emergent adverse events (TEAEs) of any grade that were higher with the oral regimen included neutropenia (38.3% vs 33.3% with IV paclitaxel), diarrhea (24.2% vs 8.1%, respectively), nausea (23.1% vs 5.2%), anemia (19.7% vs 10.4%), urinary tract infection (18.9% vs 11.9%), vomiting (17.0% vs 4.4%), abdominal pain (13.6% vs 4.4%), and asthenia (10.6% vs 7.4%). On the other hand, TEAEs that were higher with IV paclitaxel included neuropathy (7.6% with oral paclitaxel and encequidar vs 31.1% with IV paclitaxel), alopecia (28.8% vs 48.1%, respectively), and pain (14.8% vs 33.3%). 

The probability of an adverse event increased over time in the IV arm, unlike in the oral treatment arm.

“We remain committed to the breast cancer community and will explore the best path forward to obtain regulatory approval. In the interim, we will identify and undertake the appropriate internal organizational adjustments accordingly, said Johnson Lau, MD, chief executive officer, Athenex, Inc, in a statement.

_References

_{1. Athenex receives FDA complete response letter for oral paclitaxel plus encequidar for the treatment of metastatic breast cancer. News release. Athenex, Inc. March 1, 2021. Accessed March 1, 2021. https://bit.ly/3dWmH5Z} 

_{2. 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: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PD1-08.}

_{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 III clinical study in metastatic breast cancer. Presented at: 2019 San Antonia Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. Abstract GS6-01.}