Ibrance Gets Full FDA Approval for Breast Cancer

Ibrance (palbociclib) was granted full FDA approval for use in combination with letrozole (Femara) in the frontline setting of patients with postmenopausal women who have ER-positive, HER2-negative metastatic breast cancer.

The approval of the CDK 4/6 inhibitor is based on the phase 3 PALOMA-2 trial, in which adding Ibrance to letrozole reduced the risk of disease progression by 42 percent compared with letrozole alone. The median progression-free survival (PFS) was improved by more than 10 months with the addition of Ibrance.

The combination of Ibrance and letrozole was initially granted an accelerated approval in February 2015, based on findings from the phase 2 PALOMA-1 study. The FDA has now also expanded the indication of Ibrance to include use in combination with other aromatase inhibitors in this setting.

“In the two years since its initial approval, Ibrance has been prescribed to more than 50,000 patients by more than 9,800 physicians in the United States,” Liz Barrett, global president and general manager, Pfizer Oncology, the manufacturer of Ibrance, said in a statement. “This important update to the Ibrance label underscores the strength of the data we continue to generate for Ibrance. We are proud of the impact this innovative medicine continues to have on patients’ lives.”

The double-blind, placebo-controlled PALOMA-2 trial randomized 666 patients in a 2-1 ratio to Ibrance plus letrozole or letrozole alone. Ibrance was administered at 125 mg daily for three weeks in a 28-day cycle. Continuous letrozole was administered at 2.5 mg.

Patients were enrolled between February 2013 and July 2014 in 186 locations across 17 countries. The data cutoff was Feb. 26, 2016. The median follow-up was 23 months for the Ibrance combination arm and 22.3 months for the letrozole alone group.

Patient characteristics were well balanced between the study arms. The majority of patients were white, had an ECOG performance status of 0 or 1, and were less than 65 years old. The median patient age in the Ibrance and control arms was 62 and 61 years, respectively. About half of the patients in each arm had visceral metastases. Fifty-six percent of patients receiving Ibrance and 57 percent of patients in the letrozole-alone group had prior neoadjuvant and/or adjuvant hormonal therapy.

The primary endpoint for the trial was investigator-assessed PFS, with secondary outcome measures including response, overall survival, safety, biomarkers, and patient-reported outcomes.

The investigator-assessed median PFS with the Ibrance combination was 24.8 months versus 14.5 months with letrozole alone. The median PFS by blinded independent central review was 30.5 months versus 19.3 months, respectively. The objective response rate was 42 percent with the combination versus 35 percent in the control group. The PFS benefit with Ibrance was sustained across subgroups.

In the combination arm, the median treatment duration with Ibrance and letrozole was 19.9 and 20.3 months, respectively. In the control arm, the median duration of therapy with letrozole was 13.8 months. Seventy percent and 53 percent of patients receiving the combination had dose interruptions with Ibrance and letrozole, respectively. Forty-five percent of patients in the control arm had a dose interruption of letrozole.

Ninety-nine percent of patients in the Ibrance arm experienced a hematologic adverse event (AE) of any grade, including neutropenia (80 percent), leukopenia (39 percent), anemia (24 percent) and thrombocytopenia (16 percent). The grade 3 rates of these AEs in the Ibrance arm were 56 percent, 24 percent, 5 percent and 1 percent, respectively and the grade 4 rates were 10 percent, 1 percent, less than 1 percent, and less than 1 percent, respectively. Overall, 62 percent and 14 percent of patients in the Ibrance arm experienced a grade 3 and grade 4 hematologic AE, respectively.

Ninety-five percent of patients in the letrozole-alone arm experienced a hematologic AE of any grade, including neutropenia (6 percent), leukopenia (2 percent), anemia (9 percent) and thrombocytopenia (1 percent). The grade 3 rates of these AEs in the control arm were 1 percent, 0, 2 percent and 0, respectively, and neutropenia (less than 1 percent) was the only event among the four that produced a grade 4 AE. Overall, 22 percent and 2 percent of patients in the Ibrance arm experienced a grade 3 and grade 4 hematologic AE, respectively.

In the combination arm, the most common nonhematologic all-grade AEs included fatigue (37 percent), nausea (35 percent), arthralgia, (33 percent) alopecia (33 percent), diarrhea (26 percent), cough (25 percent), back pain (22 percent), headache (21 percent) and hot flush (21 percent). Sixty-two percent of patients in the Ibrance arm had a grade 3 nonhematologic AE, with the most frequent being fatigue (2 percent) and asthenia (2 percent). Grade 4 nonhematologic AEs occurred in 14 percent of patients in the Ibrance arm.

Among patients receiving letrozole alone, the most common nonhematologic all-grade AEs were arthralgia (34 percent), hot flush (31 percent), fatigue (28 percent), nausea (28 percent), headache (26 percent) and back pain (22 percent). Twenty-two percent of patients in the control arm had a grade 3 nonhematologic AE, with the most common being nausea (2 percent) and headache (2 percent). Grade 4 nonhematologic AEs occurred in 2 percent of the letrozole-alone arm.

Serious AEs occurred in 19.6 percent of the Ibrance arm compared with 12.6 percent of the control arm. The most common serious AEs with the Ibrance combination versus letrozole alone were neutropenia (1.6 percent vs 0) and pulmonary embolism (0.9 percent vs 1.4 percent).

Treatment-related discontinuations occurred in 9.7 percent of the Ibrance arm compared with 5.9 percent of the placebo arm. Deaths related to AEs occurred in 2.3 percent and 1.8 percent of the two arms, respectively. In the control arm, there was one on-study death due to pulmonary embolism/respiratory failure that the investigator considered treatment-related.