Palbociclib (Ibrance), when added to letrozole, increased the median progression-free survival (PFS) rate in patients with ER-positive, HER2-negative advanced or metastatic breast cancer by >10 months, according to results from the phase III PALOMA-2 trial presented at the 2016 ASCO Annual Meeting.
Dennis J. Slamon, MD
Palbociclib (Ibrance), when added to letrozole, increased the median progression-free survival (PFS) rate in patients with ER-positive, HER2-negative advanced or metastatic breast cancer by >10 months, according to results from the phase III PALOMA-2 trial presented at the 2016 ASCO Annual Meeting.1
The risk of disease progressed was reduced by 42 with the addition of palbociclib, a CDK4/6 inhibitor, when compared with letrozole alone. The combination of palbociclib and letrozole was granted an accelerated approval in February 2015, based on the phase II PALOMA-1 study. These results from PALOMA-2 provide confirmation of the combination's benefits in the frontline setting.
“These data represent the longest frontline improvement in median PFS seen to date in women with advanced ER+ breast cancer,” senior study author Dennis J. Slamon, MD, PhD, chief of the Division of Hematology/Oncology in the UCLA Department of Medicine, said when presenting the findings at ASCO.
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. “All subgroups benefited, regardless of age, ethnicity, site of disease, prior hormonal therapy, disease-free interval, performance status, visceral metastases status, prior chemotherapy, or prior hormonal therapy,” said Slamon.
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.
In the prior phase II PALOMA-1 study,2165 postmenopausal patients with ER-positive, HER2-negative advanced breast cancer were randomized in a 1:1 ratio in two parts: Part 1 contained 66 patients and Part 2 had 99 patients. Continuous daily letrozole was administered at 2.5 mg with or without palbociclib at 125 mg daily for 3 weeks followed by 1 week of rest until progression.
The median PFS with palbociclib was 20.2 versus 10.2 months for letrozole alone (HR, 0.488;P= .0004). The combination resulted in a response rate of 55.4% compared with 39.4% for the monotherapy.
In Part 1 of the study, the median PFS was 26.1 months with palbociclib versus 5.7 months for letrozole alone (HR, 0.299; 95% CI, 0.156-0.572;P= .0001). In the larger Part 2, the median PFS was 18.1 versus 11.1 months, for palbociclib combination and letrozole, respectively (HR, 0.508; 95% CI, 0.303-0.853; P= .0046).
In addition to the accelerated frontline approval, palbociclib is also indicated for use in combination with fulvestrant for pretreated patients with HR-positive, HER2-negative metastatic breast cancer. This approval was based on phase III findings from the phase III PALOMA-3 study, which showed a doubling in PFS with the combination versus fulvestrant alone.3
The double-blind PALOMA-3 study randomized 521 patients with metastatic breast cancer whose disease progressed on or following endocrine treatment in a 2:1 ratio to fulvestrant plus either palbociclib (n = 347) or placebo (n = 174).
Fulvestrant was administered at 500 mg on days 1 and 15 of cycle 1, and then on day 1 of each cycle thereafter, and patients received oral palbociclib at 125 mg/day continuously for the first 3 weeks of each cycle, followed by 1 week off. Treatment cycles were 28 days for both arms. Goserelin was also administered to pre- and perimenopausal patients.
Median PFS was 9.5 months with the palbociclib combination versus 4.6 months in the placebo arm (HR, 0.461; 95% CI 0.360-0.591;P<.0001). The PFS benefit was observed regardless of menopause status and remained consistent across all prespecified patient subgroups. OS were not yet mature at the time of the analysis.
Slamon said it has been “gratifying” to find that the PALOMA-2 data have now upheld a consistent clinical benefit with palbociclib across all 3 of the PALOMA studies.
1. 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 Oncol34, 2016 (suppl; abstr 507).
2. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study.Lancet Oncol.2015;16(1):2535.
3. Turner NC, Ro J, André F, Loi S, et al. Palbociclib in hormone-receptor-positive advanced breast cancer.N Engl J Med.2015;373(3):209-219.