The phase III PALOMA-2 trial has shown a significant improvement in progression-free survival (PFS) for the frontline combination of palbociclib (Ibrance) and letrozole compared letrozole alone for patients with ER-positive, HER2-negative advanced or metastatic breast cancer.
The combination of palbociclib and letrozole was granted an accelerated approval in February 2015, based on the phase II PALOMA-1 study. Data from the phase III study provide confirmation of the combination's benefits in the frontline setting. Pfizer plans to submit the data to the FDA and other global regulatory agencies for a full approval.
“These results provide confirmatory evidence for PALOMA-1, and will be used to support regulatory submissions around the world, including a request for conversion of Ibrance from accelerated to full approval in the United States,” Mace Rothenberg, MD, chief medical officer, Pfizer Oncology & senior vice president, Global Product Development, Oncology, said in a statement. “We look forward to sharing the detailed results of PALOMA-2 with the oncology community and advancing our discussions with regulatory authorities.”
The 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. Findings from the phase III study will be submitted for presentation at the 2016 ASCO Annual Meeting, according to Pfizer.
In the prior phase II PALOMA-1 study,1165 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.2
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.
The overall response rate was 24.6% for the palbociclib arm compared with 10.9% for the placebo plus fulvestrant arm. The duration of response was 9.3 months versus 7.6 months, respectively.
In the second-line setting with fulvestrant, neutropenia (66%) and leukopenia (31%) were the most common grade 3/4 AEs. The most frequently reported serious AEs in the palbociclib arm were infections, pyrexia, neutropenia, and pulmonary embolism. Dose reductions related to AEs occurred in 36% of patients, and 6% of patients discontinued treatment due to AEs.
In the frontline setting in combination with letrozole, the rate of grade 3/4 neutropenia was also significantly higher in the palbociclib arm compared with letrozole alone (54% vs 1%). Additionally, the rate of grade 3/4 leucopenia (19% vs 0%) and fatigue (4% vs 1%) were higher with palbociclib. No cases of febrile neutropenia or neutropenia-related infections were reported in the study.
“PALOMA-2 represents the third randomized study to demonstrate the benefit of Ibrance when added to hormonal therapy in the management of women with ER-positive, HER2-negative advanced breast cancer," said Rothenberg. "Ibrance remains the only CDK 4/6 inhibitor with phase III data in this disease.”
The open-label phase III PEARL is currently exploring exemestane plus palbociclib versus capecitabine for patients with HR-positive metastatic breast cancer who are resistant to treatment with non-steroidal aromatase inhibitors (NCT02028507). The phase III PENELOPE-B trial will examine post-neoadjuvant treatment with palbociclib plus endocrine therapy in HR-positive patients with residual disease following chemotherapy and surgery (NCT01864746).