The FDA has issued a complete response letter to Athenex, Inc. stating that it will not, at this time, approve the new drug application for oral paclitaxel in combination with encequidar for the treatment of patients with metastatic breast cancer.
The FDA has issued a complete response letter (CRL) to Athenex, Inc. stating that it will not, at this time, approve the new drug application (NDA) for oral paclitaxel in combination with encequidar for the treatment of patients with metastatic breast cancer.1
The regulatory agency stated that although the review cycle for the NDA is complete, the application is not ready for approval in its current form. Specifically, the FDA cited concerns over safety, as an increase in neutropenia-related effects have been reported in those who received oral paclitaxel/encequidar versus those given intravenous (IV) paclitaxel.
Additionally, the agency also cited concerns over the data from the primary end point of objective response rate (ORR) at week 19 per blinded independent central review (BICR) in the single pivotal phase 3 trial. They felt that the BICR reconciliation and reread process could have introduced unmeasured bias and influence on the BICR.
The FDA recommended that the pharmaceutical company launch a “new, adequate, well-conducted” trial in patients with metastatic breast cancer that is representative of the population in the United States. More risk-mitigation strategies to improve safety are needed to support a potential approval of the regimen, according to the agency; these efforts could include dose optimization and/or exclusion of patients who are at increased risk of toxicity.
“Our clinical and regulatory teams are disappointed by the complete response letter,” Rudolf Kwan, MD, chief medical officer of Athenex, stated 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.”
Data from the phase 3 trial, which supported the application, demonstrated that oral paclitaxel plus encequidar significantly improved ORR vs IV paclitaxel in patients with metastatic breast cancer, meeting the primary end point of the trial. The ORR rates in the investigative and control arms were 36% and 24%, respectively (P = .01).2
Notably, the rate of those who responded to treatment and had a duration of response that was 150 days or longer proved to be 2.5 times longer in those who received oral paclitaxel/encequidar vs those given IV paclitaxel.
The randomized, controlled phase 3 trial enrolled 402 participants with metastatic breast cancer. Study participants were randomized in a 2:1 fashion to either oral paclitaxel/encequidar (n = 265) or IV paclitaxel (n = 137). At baseline, patient characteristics were found to be well balanced across the arms. The primary end point of the trial was ORR per RECIST v1.1 criteria at 2 consecutive time points.
At a cutoff date of July 25, 2019, data from the trial indicated a trend toward an improvement in progression-free survival with oral paclitaxel/encequidar vs IV paclitaxel (P = .077). A trend toward an improvement in overall survival with the investigational regimen was also observed (P = .11).
Patients who received encequidar had been shown to have lower rates of neuropathy vs those who were given IV paclitaxel. Specifically, neuropathy rates were 17% vs 57% in the oral paclitaxel/encequidar and IV paclitaxel arms, respectively. Additionally, lower rates of alopecia, arthralgia, and myalgia were reported in those on the investigative arm vs the control arm.
Although rates of neutropenia were comparable between the 2 arms, more patients who received oral paclitaxel/encequidar experienced grade 4 neutropenia and infection. Participants who received the investigative regimen also had a higher rate of gastrointestinal toxicities vs those on the control regimen.
“We remain committed to the breast cancer community and will explore the best path forward to obtain regulatory approval,” Johnson Lau, MD, chief executive officer of Athenex, added in the release. “In the interim, we will identify and undertake the appropriate internal organizational adjustments accordingly.”