FDA Grants Priority Review to sNDA for Full Approval of Palbociclib in Breast Cancer

Liz Barrett

The FDA has granted a priority review to a supplemental new drug application (sNDA) supporting the conversion of the accelerated approval of palbociclib (Ibrance) to a full approval for use in combination with letrozole as a frontline treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer.

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

Under the priority designation, the FDA will review the sNDA within 6 months from the acceptance of the filing, compared with the standard 10 months. The FDA is scheduled to make its final decision by April 2017.

“Since its introduction in 2015, more than 45,000 patients have been prescribed Ibrance by more than 9000 providers in the United States,” Liz Barrett, global president and general manager, Pfizer Oncology, the manufacturer of palbociclib, said in a statement. “We are pleased that the PALOMA-2 trial has further demonstrated the significant clinical benefit of Ibrance in the first-line setting, providing additional evidence for its continued use as a standard of care medicine.”

The double-blind, placebo-controlled PALOMA-2 trial randomized 666 patients in a 2:1 ratio to palbociclib plus letrozole or letrozole alone. Palbociclib was administered at 125 mg daily for 3 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 February 26, 2016. The median follow-up was 23 months for the palbociclib 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 palbociclib 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 palbociclib and 57% 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 palbociclib combination was 24.8 months versus 14.5 months with letrozole alone (HR, 0.58; 95% CI, 0.46-0.72; P <.000001. The median PFS by blinded independent central review was 30.5 months versus 19.3 months, respectively (HR, 0.65; 95% CI, 0.51-0.84; P = .0005). The objective response rate was 42% with the combination versus 35% in the control group. The PFS benefit with palbociclib was sustained across subgroups.

In the combination arm, the median treatment duration with palbociclib 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% of patients receiving the combination had dose interruptions with palbociclib 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 palbociclib arm experienced a hematologic adverse event (AE) of any grade, including neutropenia (80%), leukopenia (39%), anemia (24%), and thrombocytopenia (16%). The grade 3 rates of these AEs in the palbociclib arm were 56%, 24%, 5%, and 1%, respectively and the grade 4 rates were 10%, 1%, <1%, and <1%, respectively. Overall, 62% and 14% of patients in the palbociclib 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%), leukopenia (2%), anemia (9%), and thrombocytopenia (1%). The grade 3 rates of these AEs in the control arm were 1%, 0, 2%, and 0, respectively, and neutropenia (<1%) was the only event among the four that produced a grade 4 AE. Overall, 22% and 2% of patients in the palbociclib 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%), nausea (35%), arthralgia, (33%) alopecia (33%), diarrhea (26%), cough (25%), back pain (22%), headache (21%), and hot flush (21%). Sixty-two percent of patients in the palbociclib arm had a grade 3 nonhematologic AE, with the most frequent being fatigue (2%) and asthenia (2%). Grade 4 nonhematologic AEs occurred in 14% of patients in the palbociclib arm.

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

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

Treatment-related discontinuations occurred in 9.7% of the palbociclib arm compared with 5.9% of the placebo arm. Deaths related to AEs occurred in 2.3% and 1.8% 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.

The combination of palbociclib and letrozole was initially granted an accelerated approval in February 2015, based on findings from the phase II PALOMA-1 study.

Finn RS, Martin M, Rugo HS, et al. PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2— advanced breast cancer (ABC). J Clin Oncol 34, 2016 (suppl; abstr 507).